The American Society of Clinical Oncology (ASCO) named “Progress in Treating Rare Cancers” as the Advance of the Year for 2018, citing five major studies as examples of significant breakthroughs.

In an ASCO Special Article published in the Journal of Clinical Oncology, Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif., and colleagues, identified five studies that notably advanced cancer research.

Each study “reflects the impressive gains we have made in understanding these so-called orphan diseases and in tailoring treatments to target their unique characteristics,” wrote ASCO president Monica M. Bertagnolli, MD, in an introduction to the report.

One of the significant advances included use of a new combination of targeted therapies for a rare thyroid cancer that elicited responses in more than two-thirds of patients. A second study showed sorafenib improving progression-free survival for patients with desmoid tumors. In addition, patients with advanced midgut neuroendocrine tumors had a 79% lower risk of disease progression or death when treated with a new therapy of targeted radiation to tumor cells, lutetium-177 (177Lu)–Dotatate, compared with standard therapy; and trastuzumab, a standard treatment for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, expanded its reach and significantly slowed progression of HER2-positive uterine serous carcinoma, the authors wrote. Finally, the “first promising therapy – the colony-stimulating factor-1 (CSF-1) inhibitor pexidartinib – for a rare cancer of the joints known as tenosynovial giant cell tumor, showed an overall response rate of 39.3% in patients taking pexidartinib versus 0% in patients taking a placebo,” they said.

For the first time, the ASCO progress report included a list of priorities to guide future research efforts, stated as follows:

• Identify strategies that better predict response to immunotherapies.
• Better define the patient populations that benefit from postoperative (adjuvant) therapy.
• Translate innovations in cellular therapies to solid tumors.
• Increase precision medicine research and treatment approaches in pediatric cancers.
• Optimize care for older adults with cancer.
• Increase equitable access to cancer clinical trials.
• Reduce the long-term consequences of cancer treatment.
• Reduce obesity and its impact on cancer incidence and outcomes.
• Identify strategies to detect and treat premalignant lesions.

“These priority areas, listed in no particular order, address an unmet need or help fill a knowledge gap in areas critical to improving patient care and outcomes,” the authors wrote.

The report acknowledged the value of federally funded research and the importance of ongoing federal investment in cancer research.

Dr. Pal disclosed relationships with Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, Eisai, and Medivation. Coauthors disclosed relationships with these and other companies.

SOURCE: Pal SK et al. J Clin Oncol. 2019 Jan 31. doi: 10.1200/JCO.18.02037.

The American Society of Clinical Oncology (ASCO) named “Progress in Treating Rare Cancers” as the Advance of the Year for 2018, citing five major studies as examples of significant breakthroughs.

In an ASCO Special Article published in the Journal of Clinical Oncology, Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif., and colleagues, identified five studies that notably advanced cancer research.

Each study “reflects the impressive gains we have made in understanding these so-called orphan diseases and in tailoring treatments to target their unique characteristics,” wrote ASCO president Monica M. Bertagnolli, MD, in an introduction to the report.

One of the significant advances included use of a new combination of targeted therapies for a rare thyroid cancer that elicited responses in more than two-thirds of patients. A second study showed sorafenib improving progression-free survival for patients with desmoid tumors. In addition, patients with advanced midgut neuroendocrine tumors had a 79% lower risk of disease progression or death when treated with a new therapy of targeted radiation to tumor cells, lutetium-177 (177Lu)–Dotatate, compared with standard therapy; and trastuzumab, a standard treatment for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, expanded its reach and significantly slowed progression of HER2-positive uterine serous carcinoma, the authors wrote. Finally, the “first promising therapy – the colony-stimulating factor-1 (CSF-1) inhibitor pexidartinib – for a rare cancer of the joints known as tenosynovial giant cell tumor, showed an overall response rate of 39.3% in patients taking pexidartinib versus 0% in patients taking a placebo,” they said.

For the first time, the ASCO progress report included a list of priorities to guide future research efforts, stated as follows:

• Identify strategies that better predict response to immunotherapies.
• Better define the patient populations that benefit from postoperative (adjuvant) therapy.
• Translate innovations in cellular therapies to solid tumors.
• Increase precision medicine research and treatment approaches in pediatric cancers.
• Optimize care for older adults with cancer.
• Increase equitable access to cancer clinical trials.
• Reduce the long-term consequences of cancer treatment.
• Reduce obesity and its impact on cancer incidence and outcomes.
• Identify strategies to detect and treat premalignant lesions.

“These priority areas, listed in no particular order, address an unmet need or help fill a knowledge gap in areas critical to improving patient care and outcomes,” the authors wrote.

The report acknowledged the value of federally funded research and the importance of ongoing federal investment in cancer research.

Dr. Pal disclosed relationships with Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, Eisai, and Medivation. Coauthors disclosed relationships with these and other companies.

SOURCE: Pal SK et al. J Clin Oncol. 2019 Jan 31. doi: 10.1200/JCO.18.02037.

The American Society of Clinical Oncology (ASCO) named “Progress in Treating Rare Cancers” as the Advance of the Year for 2018, citing five major studies as examples of significant breakthroughs.

In an ASCO Special Article published in the Journal of Clinical Oncology, Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center, Duarte, Calif., and colleagues, identified five studies that notably advanced cancer research.

Each study “reflects the impressive gains we have made in understanding these so-called orphan diseases and in tailoring treatments to target their unique characteristics,” wrote ASCO president Monica M. Bertagnolli, MD, in an introduction to the report.

One of the significant advances included use of a new combination of targeted therapies for a rare thyroid cancer that elicited responses in more than two-thirds of patients. A second study showed sorafenib improving progression-free survival for patients with desmoid tumors. In addition, patients with advanced midgut neuroendocrine tumors had a 79% lower risk of disease progression or death when treated with a new therapy of targeted radiation to tumor cells, lutetium-177 (177Lu)–Dotatate, compared with standard therapy; and trastuzumab, a standard treatment for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, expanded its reach and significantly slowed progression of HER2-positive uterine serous carcinoma, the authors wrote. Finally, the “first promising therapy – the colony-stimulating factor-1 (CSF-1) inhibitor pexidartinib – for a rare cancer of the joints known as tenosynovial giant cell tumor, showed an overall response rate of 39.3% in patients taking pexidartinib versus 0% in patients taking a placebo,” they said.

For the first time, the ASCO progress report included a list of priorities to guide future research efforts, stated as follows:

• Identify strategies that better predict response to immunotherapies.
• Better define the patient populations that benefit from postoperative (adjuvant) therapy.
• Translate innovations in cellular therapies to solid tumors.
• Increase precision medicine research and treatment approaches in pediatric cancers.
• Optimize care for older adults with cancer.
• Increase equitable access to cancer clinical trials.
• Reduce the long-term consequences of cancer treatment.
• Reduce obesity and its impact on cancer incidence and outcomes.
• Identify strategies to detect and treat premalignant lesions.

“These priority areas, listed in no particular order, address an unmet need or help fill a knowledge gap in areas critical to improving patient care and outcomes,” the authors wrote.

The report acknowledged the value of federally funded research and the importance of ongoing federal investment in cancer research.

Dr. Pal disclosed relationships with Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, Eisai, and Medivation. Coauthors disclosed relationships with these and other companies.

SOURCE: Pal SK et al. J Clin Oncol. 2019 Jan 31. doi: 10.1200/JCO.18.02037.

SAN ANTONIO – Researchers at MD Anderson Cancer Center in Houston and the University of New South Wales (UNSW) in Sydney are among teams from around the world working toward human breast cell atlas development using single-cell genomics, and their efforts to date have yielded new understanding of both the normal breast cell ecosystem and the breast cancer tumor microenvironment.

Pradit_Ph/Thinkstock

The work at MD Anderson, for example, has led to the identification of a number of new gene markers and multiple cell states within breast cell types, according to Tapsi Kumar Seth, who reported early findings from an analysis of more than 32,000 cells from normal breast tissue during a presentation at the San Antonio Breast Cancer Symposium.

At the UNSW’s Garvan Institute of Medical Research, Alexander Swarbrick, PhD, and his colleagues are working to better define the tumor microenvironment at the single-cell level. At the symposium, Dr. Swarbrick presented interim findings from cellular analyses in the first 23 breast cancer cases of about 200 that will be studied in the course of the project.

Improved understanding of the cellular landscape of both normal breast tissue and breast cancer tissue should lead to new stromal- and immune-based therapies for the treatment of breast cancer, the investigators said.
 

The normal breast cell ecosystem

The MD Anderson researchers studied 32,148 stromal cells from pathologically normal breast tissues collected from 11 women who underwent mastectomy at the center.

Unbiased expression analysis identified three major cell types, including epithelial cells, fibroblasts, and endothelial cells, as well as several minor cell types such as macrophages, T-cells, apocrine cells, pericytes, and others, said Ms. Seth, a graduate student in the department of genetics at the center and a member of the Navin Laboratory there.

The work is designed to help identify the presence and function of cells and explain how they behave in a normal breast ecosystem, she said.

“We know that a female breast undergoes a lot of changes due to age, pregnancy, or when there is a disease such as cancer, so it’s essential to chart out what a normal cell reference would look like,” she said.

Toward that goal, a protocol was developed to dissociate the tissue samples within 2 hours due to the decline in viability seen in cells and RNA over time. Analysis of the cell states revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types, she said.

A map was created to show gene expression and to identify transcriptomally similar cells.

“We were able to identify most of the major cell types that are present in human breasts,” she said. “What was interesting was that the composition of these cells also varied across women.”

For example, the proportion of fibroblasts was lower in 3 of the 11 patients, and even though the cells were pathologically normal, immune cell populations, including T-cells and macrophages, were also seen.

Adipocytes cannot be evaluated using this technology because they are large and the layer of fat cells must be removed during dissociation to prevent clogging of the machines, she noted, adding that “this is really a limitation of our technology.”

A closer look was taken at each of the major cell types identified.
 

Epithelial cells

Both canonical and new gene markers were used to identify luminal and basal epithelial cells, Ms. Seth noted.

Among the known markers were KRT18 for luminal epithelial cells and KRT5, KRT6B, KRT14, and KRT15 for basal epithelial cells. Among the new markers were SLC39A6, EFHD1 and HES1 for the luminal epithelial cells, and CITED4, CCK28, MMP7, and MDRG2 for the basal epithelial cells.

“We went on and validated these markers on the tissue section using methods like spatial transcriptomics,” she said, explaining that this “really helps capture the RNA expression spatially,” and can resolve the localization of cell types markers in anatomical structures.

For these cells, the expression of the newly identified gene markers was mostly confined to ducts and lobules.

In addition, an analysis of cell states within the luminal epithelial cells showed four different cell states, each of which have “different kinds of genes that they express, and also different pathways that they express, suggesting that these might be transcriptomally different,” Ms. Seth said.

Of note, these cells and cells states are not biased to a specific condition or patient, suggesting that they are coming from all of the patients, she added.

Two of the four cell states – the secretory and hormone responsive states – have previously been reported, but Ms. Seth and her colleagues identified two additional cell states that may have different biological functions and are present in the different anatomical regions of the breast.
 

Fibroblasts

Fibroblasts, the cells of the connective tissue, were the most abundant cell type. Like the epithelial cells, both canonical collagen markers (COL6A3, MMP2, FBN1, FBLN2, FBN, and COL1A1) and newly identified gene markers (TNXB, AEBP1, CFH, CTSK, TPPP3, MEG3, HTRA1, LHFP, and OGN) were used to identify them.

Endothelial cells

Breast tissue is highly vascular, so endothelial cells, which line the walls of veins, arteries, and lymphatic vessels, are plentiful.

“Again, for both these cell types, we identified them using the canonical marker CD31, and we identified some new gene markers,” she said, noting that the new markers include CCL21, CLDN5, MMRN1, LYVE1, and PROX1 for lymphatic endothelial cells, and RNASE1 and IFI27 for vascular endothelial cells.

Two different groups – or states – of vascular endothelial cells were identified, with each expressing “very different genes as well as very different pathways, again suggesting that they might have different biological functions, which we are still investigating,” she said.
 

Additional findings and future directions

In addition to stromal cells, some immune cells were also seen. These included T cells that came mostly from two patients, as well as macrophages and monocytes, which comprised the most abundant immune cell population.

Of note, all of these cells are also found in the tumor microenvironment, but they are in a transformed state. For example cancer-associated fibroblasts, tumor endothelial cells, tumor-associated macrophages, and tumor-associated adipocytes have been seen in that environment, she said.

“So what we are trying to do with this project is ... learn how these cells are, and how these cells behave in the normal ecosystem,” she explained, noting that the hope is to provide a valuable reference for the research community with new insights about how normal cell types are transformed in the tumor microenvironment.

In an effort to overcome the adipocyte-associated limitation of the technology, adipocytes are “now being isolated by single nucleus RNA sequencing.”

“This [sequencing] technology has helped us identify multiple cell states within a cell type; and most of these cell states may have different biological functions, which probably can be investigated by spatial transcriptomic methods,” she said.

Spatial transcriptomics also continue to be used for validation of the new gene markers identified in the course of this research, she noted.
 

The breast tumor microenvironment

At the Garvan Institute, current work is focusing more on defining the landscape of the breast tumor microenvironment at single-cell resolution, according to Dr. Swarbrick, a senior research fellow and head of the Tumour Progression Laboratory there.

vitanovski/Thinkstock.com

“Breast cancers ... are complex cellular ecosystems, and it’s really the sum of the interactions between the cell types that play major roles in determining the etiology of disease and its response to therapy,” he said. “So I think that going forward toward a new age of diagnostics and therapeutics, there’s wonderful potential in capitalizing on the tumor microenvironment for new developments, but this has to be built on a really deep understanding of the tumor microenvironment, and – I might say – a new taxonomy of the breast cellular environment.”

vitanovski/ThinkStock

Fibroblasts

A notable finding of this project was the presence of “not one, but two populations of fibroblasts,” Dr. Swarbrick said, noting that fibroblasts are typically discussed as a single entity.

“This is arguing that there are at least two major types present within the breast, and almost every case has these populations present at roughly equal amounts,” he said.

This is of particular interest, because it has been shown in prior studies that targeting fibroblasts can have therapeutic outcomes.

“So we think this is a very important population within the tumor microenvironment,” he added.

With respect to gene expression features, CAF-1 is dominated by signatures of extracellular matrix deposition and remodeling, which “look like the classic myofibroblasts that we typically think of when we study cancer-associated fibroblasts.”

“In contrast, the CAF-2 population ... have what appears to be quite a predominant secretory function, so we see a lot of cytokines being produced by these cells, but we also see a very high level of expression of a number immune checkpoint ligands,” he said, adding that his team is actively pursuing whether these cells may be undergoing signaling events with infiltrating lymphocytes in the tumor microenvironment.

The signatures for both CAF types are prognostic within large breast cancer data sets, suggesting that they do actually have an important role in disease, he noted.

Markers for these cells include ACTA2, which was previously known to be a marker, and which is almost exclusively restricted to CAF-1, and the cell surface protein CD34 – a progenitor marker in many different cellular systems, “which is actually beautifully expressed on the CAF-2 population” as demonstrated using CITE-seq.

“So we’re now using this as a way to prospectively identify these cells, pull them out of tumors, and conduct biologic assays to learn more about them,” he said.
 

The immune milieu

“We’re in the age of immunotherapy, and this is an area of huge interest, but we have a long way to go in making it as effective as possible for breast cancer patients,” Dr. Swarbrick said. “I believe part of that is through a very deep understanding of the taxonomy.”

RNA data alone are useful but insufficient to fully identify subsets of immune cells due to a “relatively low-resolution ability to resolve T cells.”

“But because we’re now using the panel of 125 antibodies in parallel, we can now start to use protein levels to split up these populations and we can start to now identify, with higher resolution, more unique populations within the environment,” he said, noting that the availability of protein data not only helps identify subtypes, but is also therapeutically important as it allows for certainty regarding whether the protein target of therapeutic antibodies is expressed on the surface of cells.

Ultimately the hope is that this effort to build a multi-omic breast cancer atlas will continue to drive new discoveries in personalized medicine for breast cancer, Dr. Swarbrick concluded, adding that the field is moving fast, and it will be very important for labs like his and the Navin Lab to communicate to avoid needlessly duplicating efforts.

“I think it’s going to be really exciting to start to put some of these [findings] together,” he said.

The MD Anderson project is funded by the Chan Zuckerberg Initiative as part of its work in supporting the Human Cell Atlas project. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.

[email protected]

SOURCE: Seth T et al. SABCS 2018, Abstract GS1-02; Swarbrick A et al. SABCS 2018, Abstract GS1-01

SAN ANTONIO – Researchers at MD Anderson Cancer Center in Houston and the University of New South Wales (UNSW) in Sydney are among teams from around the world working toward human breast cell atlas development using single-cell genomics, and their efforts to date have yielded new understanding of both the normal breast cell ecosystem and the breast cancer tumor microenvironment.

Pradit_Ph/Thinkstock

The work at MD Anderson, for example, has led to the identification of a number of new gene markers and multiple cell states within breast cell types, according to Tapsi Kumar Seth, who reported early findings from an analysis of more than 32,000 cells from normal breast tissue during a presentation at the San Antonio Breast Cancer Symposium.

At the UNSW’s Garvan Institute of Medical Research, Alexander Swarbrick, PhD, and his colleagues are working to better define the tumor microenvironment at the single-cell level. At the symposium, Dr. Swarbrick presented interim findings from cellular analyses in the first 23 breast cancer cases of about 200 that will be studied in the course of the project.

Improved understanding of the cellular landscape of both normal breast tissue and breast cancer tissue should lead to new stromal- and immune-based therapies for the treatment of breast cancer, the investigators said.
 

The normal breast cell ecosystem

The MD Anderson researchers studied 32,148 stromal cells from pathologically normal breast tissues collected from 11 women who underwent mastectomy at the center.

Unbiased expression analysis identified three major cell types, including epithelial cells, fibroblasts, and endothelial cells, as well as several minor cell types such as macrophages, T-cells, apocrine cells, pericytes, and others, said Ms. Seth, a graduate student in the department of genetics at the center and a member of the Navin Laboratory there.

The work is designed to help identify the presence and function of cells and explain how they behave in a normal breast ecosystem, she said.

“We know that a female breast undergoes a lot of changes due to age, pregnancy, or when there is a disease such as cancer, so it’s essential to chart out what a normal cell reference would look like,” she said.

Toward that goal, a protocol was developed to dissociate the tissue samples within 2 hours due to the decline in viability seen in cells and RNA over time. Analysis of the cell states revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types, she said.

A map was created to show gene expression and to identify transcriptomally similar cells.

“We were able to identify most of the major cell types that are present in human breasts,” she said. “What was interesting was that the composition of these cells also varied across women.”

For example, the proportion of fibroblasts was lower in 3 of the 11 patients, and even though the cells were pathologically normal, immune cell populations, including T-cells and macrophages, were also seen.

Adipocytes cannot be evaluated using this technology because they are large and the layer of fat cells must be removed during dissociation to prevent clogging of the machines, she noted, adding that “this is really a limitation of our technology.”

A closer look was taken at each of the major cell types identified.
 

Epithelial cells

Both canonical and new gene markers were used to identify luminal and basal epithelial cells, Ms. Seth noted.

Among the known markers were KRT18 for luminal epithelial cells and KRT5, KRT6B, KRT14, and KRT15 for basal epithelial cells. Among the new markers were SLC39A6, EFHD1 and HES1 for the luminal epithelial cells, and CITED4, CCK28, MMP7, and MDRG2 for the basal epithelial cells.

“We went on and validated these markers on the tissue section using methods like spatial transcriptomics,” she said, explaining that this “really helps capture the RNA expression spatially,” and can resolve the localization of cell types markers in anatomical structures.

For these cells, the expression of the newly identified gene markers was mostly confined to ducts and lobules.

In addition, an analysis of cell states within the luminal epithelial cells showed four different cell states, each of which have “different kinds of genes that they express, and also different pathways that they express, suggesting that these might be transcriptomally different,” Ms. Seth said.

Of note, these cells and cells states are not biased to a specific condition or patient, suggesting that they are coming from all of the patients, she added.

Two of the four cell states – the secretory and hormone responsive states – have previously been reported, but Ms. Seth and her colleagues identified two additional cell states that may have different biological functions and are present in the different anatomical regions of the breast.
 

Fibroblasts

Fibroblasts, the cells of the connective tissue, were the most abundant cell type. Like the epithelial cells, both canonical collagen markers (COL6A3, MMP2, FBN1, FBLN2, FBN, and COL1A1) and newly identified gene markers (TNXB, AEBP1, CFH, CTSK, TPPP3, MEG3, HTRA1, LHFP, and OGN) were used to identify them.

Endothelial cells

Breast tissue is highly vascular, so endothelial cells, which line the walls of veins, arteries, and lymphatic vessels, are plentiful.

“Again, for both these cell types, we identified them using the canonical marker CD31, and we identified some new gene markers,” she said, noting that the new markers include CCL21, CLDN5, MMRN1, LYVE1, and PROX1 for lymphatic endothelial cells, and RNASE1 and IFI27 for vascular endothelial cells.

Two different groups – or states – of vascular endothelial cells were identified, with each expressing “very different genes as well as very different pathways, again suggesting that they might have different biological functions, which we are still investigating,” she said.
 

Additional findings and future directions

In addition to stromal cells, some immune cells were also seen. These included T cells that came mostly from two patients, as well as macrophages and monocytes, which comprised the most abundant immune cell population.

Of note, all of these cells are also found in the tumor microenvironment, but they are in a transformed state. For example cancer-associated fibroblasts, tumor endothelial cells, tumor-associated macrophages, and tumor-associated adipocytes have been seen in that environment, she said.

“So what we are trying to do with this project is ... learn how these cells are, and how these cells behave in the normal ecosystem,” she explained, noting that the hope is to provide a valuable reference for the research community with new insights about how normal cell types are transformed in the tumor microenvironment.

In an effort to overcome the adipocyte-associated limitation of the technology, adipocytes are “now being isolated by single nucleus RNA sequencing.”

“This [sequencing] technology has helped us identify multiple cell states within a cell type; and most of these cell states may have different biological functions, which probably can be investigated by spatial transcriptomic methods,” she said.

Spatial transcriptomics also continue to be used for validation of the new gene markers identified in the course of this research, she noted.
 

The breast tumor microenvironment

At the Garvan Institute, current work is focusing more on defining the landscape of the breast tumor microenvironment at single-cell resolution, according to Dr. Swarbrick, a senior research fellow and head of the Tumour Progression Laboratory there.

vitanovski/Thinkstock.com

“Breast cancers ... are complex cellular ecosystems, and it’s really the sum of the interactions between the cell types that play major roles in determining the etiology of disease and its response to therapy,” he said. “So I think that going forward toward a new age of diagnostics and therapeutics, there’s wonderful potential in capitalizing on the tumor microenvironment for new developments, but this has to be built on a really deep understanding of the tumor microenvironment, and – I might say – a new taxonomy of the breast cellular environment.”

vitanovski/ThinkStock

Fibroblasts

A notable finding of this project was the presence of “not one, but two populations of fibroblasts,” Dr. Swarbrick said, noting that fibroblasts are typically discussed as a single entity.

“This is arguing that there are at least two major types present within the breast, and almost every case has these populations present at roughly equal amounts,” he said.

This is of particular interest, because it has been shown in prior studies that targeting fibroblasts can have therapeutic outcomes.

“So we think this is a very important population within the tumor microenvironment,” he added.

With respect to gene expression features, CAF-1 is dominated by signatures of extracellular matrix deposition and remodeling, which “look like the classic myofibroblasts that we typically think of when we study cancer-associated fibroblasts.”

“In contrast, the CAF-2 population ... have what appears to be quite a predominant secretory function, so we see a lot of cytokines being produced by these cells, but we also see a very high level of expression of a number immune checkpoint ligands,” he said, adding that his team is actively pursuing whether these cells may be undergoing signaling events with infiltrating lymphocytes in the tumor microenvironment.

The signatures for both CAF types are prognostic within large breast cancer data sets, suggesting that they do actually have an important role in disease, he noted.

Markers for these cells include ACTA2, which was previously known to be a marker, and which is almost exclusively restricted to CAF-1, and the cell surface protein CD34 – a progenitor marker in many different cellular systems, “which is actually beautifully expressed on the CAF-2 population” as demonstrated using CITE-seq.

“So we’re now using this as a way to prospectively identify these cells, pull them out of tumors, and conduct biologic assays to learn more about them,” he said.
 

The immune milieu

“We’re in the age of immunotherapy, and this is an area of huge interest, but we have a long way to go in making it as effective as possible for breast cancer patients,” Dr. Swarbrick said. “I believe part of that is through a very deep understanding of the taxonomy.”

RNA data alone are useful but insufficient to fully identify subsets of immune cells due to a “relatively low-resolution ability to resolve T cells.”

“But because we’re now using the panel of 125 antibodies in parallel, we can now start to use protein levels to split up these populations and we can start to now identify, with higher resolution, more unique populations within the environment,” he said, noting that the availability of protein data not only helps identify subtypes, but is also therapeutically important as it allows for certainty regarding whether the protein target of therapeutic antibodies is expressed on the surface of cells.

Ultimately the hope is that this effort to build a multi-omic breast cancer atlas will continue to drive new discoveries in personalized medicine for breast cancer, Dr. Swarbrick concluded, adding that the field is moving fast, and it will be very important for labs like his and the Navin Lab to communicate to avoid needlessly duplicating efforts.

“I think it’s going to be really exciting to start to put some of these [findings] together,” he said.

The MD Anderson project is funded by the Chan Zuckerberg Initiative as part of its work in supporting the Human Cell Atlas project. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.

[email protected]

SOURCE: Seth T et al. SABCS 2018, Abstract GS1-02; Swarbrick A et al. SABCS 2018, Abstract GS1-01

SAN ANTONIO – Researchers at MD Anderson Cancer Center in Houston and the University of New South Wales (UNSW) in Sydney are among teams from around the world working toward human breast cell atlas development using single-cell genomics, and their efforts to date have yielded new understanding of both the normal breast cell ecosystem and the breast cancer tumor microenvironment.

Pradit_Ph/Thinkstock

The work at MD Anderson, for example, has led to the identification of a number of new gene markers and multiple cell states within breast cell types, according to Tapsi Kumar Seth, who reported early findings from an analysis of more than 32,000 cells from normal breast tissue during a presentation at the San Antonio Breast Cancer Symposium.

At the UNSW’s Garvan Institute of Medical Research, Alexander Swarbrick, PhD, and his colleagues are working to better define the tumor microenvironment at the single-cell level. At the symposium, Dr. Swarbrick presented interim findings from cellular analyses in the first 23 breast cancer cases of about 200 that will be studied in the course of the project.

Improved understanding of the cellular landscape of both normal breast tissue and breast cancer tissue should lead to new stromal- and immune-based therapies for the treatment of breast cancer, the investigators said.
 

The normal breast cell ecosystem

The MD Anderson researchers studied 32,148 stromal cells from pathologically normal breast tissues collected from 11 women who underwent mastectomy at the center.

Unbiased expression analysis identified three major cell types, including epithelial cells, fibroblasts, and endothelial cells, as well as several minor cell types such as macrophages, T-cells, apocrine cells, pericytes, and others, said Ms. Seth, a graduate student in the department of genetics at the center and a member of the Navin Laboratory there.

The work is designed to help identify the presence and function of cells and explain how they behave in a normal breast ecosystem, she said.

“We know that a female breast undergoes a lot of changes due to age, pregnancy, or when there is a disease such as cancer, so it’s essential to chart out what a normal cell reference would look like,” she said.

Toward that goal, a protocol was developed to dissociate the tissue samples within 2 hours due to the decline in viability seen in cells and RNA over time. Analysis of the cell states revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types, she said.

A map was created to show gene expression and to identify transcriptomally similar cells.

“We were able to identify most of the major cell types that are present in human breasts,” she said. “What was interesting was that the composition of these cells also varied across women.”

For example, the proportion of fibroblasts was lower in 3 of the 11 patients, and even though the cells were pathologically normal, immune cell populations, including T-cells and macrophages, were also seen.

Adipocytes cannot be evaluated using this technology because they are large and the layer of fat cells must be removed during dissociation to prevent clogging of the machines, she noted, adding that “this is really a limitation of our technology.”

A closer look was taken at each of the major cell types identified.
 

Epithelial cells

Both canonical and new gene markers were used to identify luminal and basal epithelial cells, Ms. Seth noted.

Among the known markers were KRT18 for luminal epithelial cells and KRT5, KRT6B, KRT14, and KRT15 for basal epithelial cells. Among the new markers were SLC39A6, EFHD1 and HES1 for the luminal epithelial cells, and CITED4, CCK28, MMP7, and MDRG2 for the basal epithelial cells.

“We went on and validated these markers on the tissue section using methods like spatial transcriptomics,” she said, explaining that this “really helps capture the RNA expression spatially,” and can resolve the localization of cell types markers in anatomical structures.

For these cells, the expression of the newly identified gene markers was mostly confined to ducts and lobules.

In addition, an analysis of cell states within the luminal epithelial cells showed four different cell states, each of which have “different kinds of genes that they express, and also different pathways that they express, suggesting that these might be transcriptomally different,” Ms. Seth said.

Of note, these cells and cells states are not biased to a specific condition or patient, suggesting that they are coming from all of the patients, she added.

Two of the four cell states – the secretory and hormone responsive states – have previously been reported, but Ms. Seth and her colleagues identified two additional cell states that may have different biological functions and are present in the different anatomical regions of the breast.
 

Fibroblasts

Fibroblasts, the cells of the connective tissue, were the most abundant cell type. Like the epithelial cells, both canonical collagen markers (COL6A3, MMP2, FBN1, FBLN2, FBN, and COL1A1) and newly identified gene markers (TNXB, AEBP1, CFH, CTSK, TPPP3, MEG3, HTRA1, LHFP, and OGN) were used to identify them.

Endothelial cells

Breast tissue is highly vascular, so endothelial cells, which line the walls of veins, arteries, and lymphatic vessels, are plentiful.

“Again, for both these cell types, we identified them using the canonical marker CD31, and we identified some new gene markers,” she said, noting that the new markers include CCL21, CLDN5, MMRN1, LYVE1, and PROX1 for lymphatic endothelial cells, and RNASE1 and IFI27 for vascular endothelial cells.

Two different groups – or states – of vascular endothelial cells were identified, with each expressing “very different genes as well as very different pathways, again suggesting that they might have different biological functions, which we are still investigating,” she said.
 

Additional findings and future directions

In addition to stromal cells, some immune cells were also seen. These included T cells that came mostly from two patients, as well as macrophages and monocytes, which comprised the most abundant immune cell population.

Of note, all of these cells are also found in the tumor microenvironment, but they are in a transformed state. For example cancer-associated fibroblasts, tumor endothelial cells, tumor-associated macrophages, and tumor-associated adipocytes have been seen in that environment, she said.

“So what we are trying to do with this project is ... learn how these cells are, and how these cells behave in the normal ecosystem,” she explained, noting that the hope is to provide a valuable reference for the research community with new insights about how normal cell types are transformed in the tumor microenvironment.

In an effort to overcome the adipocyte-associated limitation of the technology, adipocytes are “now being isolated by single nucleus RNA sequencing.”

“This [sequencing] technology has helped us identify multiple cell states within a cell type; and most of these cell states may have different biological functions, which probably can be investigated by spatial transcriptomic methods,” she said.

Spatial transcriptomics also continue to be used for validation of the new gene markers identified in the course of this research, she noted.
 

The breast tumor microenvironment

At the Garvan Institute, current work is focusing more on defining the landscape of the breast tumor microenvironment at single-cell resolution, according to Dr. Swarbrick, a senior research fellow and head of the Tumour Progression Laboratory there.

vitanovski/Thinkstock.com

“Breast cancers ... are complex cellular ecosystems, and it’s really the sum of the interactions between the cell types that play major roles in determining the etiology of disease and its response to therapy,” he said. “So I think that going forward toward a new age of diagnostics and therapeutics, there’s wonderful potential in capitalizing on the tumor microenvironment for new developments, but this has to be built on a really deep understanding of the tumor microenvironment, and – I might say – a new taxonomy of the breast cellular environment.”

vitanovski/ThinkStock

Fibroblasts

A notable finding of this project was the presence of “not one, but two populations of fibroblasts,” Dr. Swarbrick said, noting that fibroblasts are typically discussed as a single entity.

“This is arguing that there are at least two major types present within the breast, and almost every case has these populations present at roughly equal amounts,” he said.

This is of particular interest, because it has been shown in prior studies that targeting fibroblasts can have therapeutic outcomes.

“So we think this is a very important population within the tumor microenvironment,” he added.

With respect to gene expression features, CAF-1 is dominated by signatures of extracellular matrix deposition and remodeling, which “look like the classic myofibroblasts that we typically think of when we study cancer-associated fibroblasts.”

“In contrast, the CAF-2 population ... have what appears to be quite a predominant secretory function, so we see a lot of cytokines being produced by these cells, but we also see a very high level of expression of a number immune checkpoint ligands,” he said, adding that his team is actively pursuing whether these cells may be undergoing signaling events with infiltrating lymphocytes in the tumor microenvironment.

The signatures for both CAF types are prognostic within large breast cancer data sets, suggesting that they do actually have an important role in disease, he noted.

Markers for these cells include ACTA2, which was previously known to be a marker, and which is almost exclusively restricted to CAF-1, and the cell surface protein CD34 – a progenitor marker in many different cellular systems, “which is actually beautifully expressed on the CAF-2 population” as demonstrated using CITE-seq.

“So we’re now using this as a way to prospectively identify these cells, pull them out of tumors, and conduct biologic assays to learn more about them,” he said.
 

The immune milieu

“We’re in the age of immunotherapy, and this is an area of huge interest, but we have a long way to go in making it as effective as possible for breast cancer patients,” Dr. Swarbrick said. “I believe part of that is through a very deep understanding of the taxonomy.”

RNA data alone are useful but insufficient to fully identify subsets of immune cells due to a “relatively low-resolution ability to resolve T cells.”

“But because we’re now using the panel of 125 antibodies in parallel, we can now start to use protein levels to split up these populations and we can start to now identify, with higher resolution, more unique populations within the environment,” he said, noting that the availability of protein data not only helps identify subtypes, but is also therapeutically important as it allows for certainty regarding whether the protein target of therapeutic antibodies is expressed on the surface of cells.

Ultimately the hope is that this effort to build a multi-omic breast cancer atlas will continue to drive new discoveries in personalized medicine for breast cancer, Dr. Swarbrick concluded, adding that the field is moving fast, and it will be very important for labs like his and the Navin Lab to communicate to avoid needlessly duplicating efforts.

“I think it’s going to be really exciting to start to put some of these [findings] together,” he said.

The MD Anderson project is funded by the Chan Zuckerberg Initiative as part of its work in supporting the Human Cell Atlas project. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.

[email protected]

SOURCE: Seth T et al. SABCS 2018, Abstract GS1-02; Swarbrick A et al. SABCS 2018, Abstract GS1-01

David Henry, MD, is the host of Blood & Cancer, the official podcast of MDedge Hematology/Oncology. In this episode, Nick and Dr. Henry discuss advances and excitement in oncology, as well as the opportunities that podcasting provides and tips for dealing with burnout.

Apple Podcasts
Google Podcasts
Spotify

David Henry, MD, is the host of Blood & Cancer, the official podcast of MDedge Hematology/Oncology. In this episode, Nick and Dr. Henry discuss advances and excitement in oncology, as well as the opportunities that podcasting provides and tips for dealing with burnout.

Apple Podcasts
Google Podcasts
Spotify

David Henry, MD, is the host of Blood & Cancer, the official podcast of MDedge Hematology/Oncology. In this episode, Nick and Dr. Henry discuss advances and excitement in oncology, as well as the opportunities that podcasting provides and tips for dealing with burnout.

Apple Podcasts
Google Podcasts
Spotify

In highly active individuals, high levels of coronary artery calcification do not appear to confer an elevated mortality risk, a large, observational study suggests.

Aquir/ThinkStock

There was an increased risk of elevated levels of coronary artery calcification (CAC) in men with levels of exercise training comparable with that seen in master marathon runners, the study authors reported. However, elevated CAC in highly active men didn’t translate into a significant increase in all-cause or cardiovascular disease mortality risk in the study.

That result is contrary to the hypothesis that high activity levels would increase mortality risk in individuals with CAC, according to senior author Benjamin D. Levine, MD, of Texas Health Presbyterian Hospital in Dallas, and his coauthors.

“Our findings should reassure patients and their health care professionals that it appears these highly active individuals can safely continue their exercise programs,” Dr. Levine and his coauthors wrote in JAMA Cardiology.

The present analysis focused on 21,758 generally healthy men without prevalent cardiovascular disease. They were enrolled in the Cooper Center Longitudinal Study, a prospective, longitudinal study designed to assess linkages between physical activity, cardiorespiratory fitness, and health. The mean age of these men was 52 years at baseline; the mean duration of follow-up was 10.4 years.

Out of 21,758 male participants, 1,561 reported very high levels of physical activity, or at least 3,000 metabolic equivalent of task (MET) minutes per week, while 3,750 reported 1,500-2,999 MET minutes per week, and 16,477 reported low levels of physical activity, or less than 1,500 MET minutes per week.

The adjusted risk of elevated CAC, defined as at least 100 Agatston units, was 11% higher in the individuals reporting very high physical activity levels, the investigators found.

Presence of elevated CAC nearly doubled the risk of death in men with low levels of exercise, with a hazard ratio of 1.93 (95% confidence interval, 1.34-2.78), the investigators found. By contrast, there was no significant increase in all-cause mortality in the most active group (HR, 0.77; 95% CI, 0.52-1.15).

Taken together, these findings seem to provide evidence that high activity levels do not increase mortality risk, the investigators wrote, noting that the study is believed to have the “best available” mortality data in a large CAC population that includes measurement of physical activity.

The research was supported in partly through the National Space Biomedical Research Institute. One study author reported disclosures related to Abbott, AstraZeneca, and the American Heart Association.
 

SOURCE: Levine BD et al. JAMA Cardiol. 2019 Jan 30. doi: 10.1001/jamacardio.2018.4628.

In highly active individuals, high levels of coronary artery calcification do not appear to confer an elevated mortality risk, a large, observational study suggests.

Aquir/ThinkStock

There was an increased risk of elevated levels of coronary artery calcification (CAC) in men with levels of exercise training comparable with that seen in master marathon runners, the study authors reported. However, elevated CAC in highly active men didn’t translate into a significant increase in all-cause or cardiovascular disease mortality risk in the study.

That result is contrary to the hypothesis that high activity levels would increase mortality risk in individuals with CAC, according to senior author Benjamin D. Levine, MD, of Texas Health Presbyterian Hospital in Dallas, and his coauthors.

“Our findings should reassure patients and their health care professionals that it appears these highly active individuals can safely continue their exercise programs,” Dr. Levine and his coauthors wrote in JAMA Cardiology.

The present analysis focused on 21,758 generally healthy men without prevalent cardiovascular disease. They were enrolled in the Cooper Center Longitudinal Study, a prospective, longitudinal study designed to assess linkages between physical activity, cardiorespiratory fitness, and health. The mean age of these men was 52 years at baseline; the mean duration of follow-up was 10.4 years.

Out of 21,758 male participants, 1,561 reported very high levels of physical activity, or at least 3,000 metabolic equivalent of task (MET) minutes per week, while 3,750 reported 1,500-2,999 MET minutes per week, and 16,477 reported low levels of physical activity, or less than 1,500 MET minutes per week.

The adjusted risk of elevated CAC, defined as at least 100 Agatston units, was 11% higher in the individuals reporting very high physical activity levels, the investigators found.

Presence of elevated CAC nearly doubled the risk of death in men with low levels of exercise, with a hazard ratio of 1.93 (95% confidence interval, 1.34-2.78), the investigators found. By contrast, there was no significant increase in all-cause mortality in the most active group (HR, 0.77; 95% CI, 0.52-1.15).

Taken together, these findings seem to provide evidence that high activity levels do not increase mortality risk, the investigators wrote, noting that the study is believed to have the “best available” mortality data in a large CAC population that includes measurement of physical activity.

The research was supported in partly through the National Space Biomedical Research Institute. One study author reported disclosures related to Abbott, AstraZeneca, and the American Heart Association.
 

SOURCE: Levine BD et al. JAMA Cardiol. 2019 Jan 30. doi: 10.1001/jamacardio.2018.4628.

In highly active individuals, high levels of coronary artery calcification do not appear to confer an elevated mortality risk, a large, observational study suggests.

Aquir/ThinkStock

There was an increased risk of elevated levels of coronary artery calcification (CAC) in men with levels of exercise training comparable with that seen in master marathon runners, the study authors reported. However, elevated CAC in highly active men didn’t translate into a significant increase in all-cause or cardiovascular disease mortality risk in the study.

That result is contrary to the hypothesis that high activity levels would increase mortality risk in individuals with CAC, according to senior author Benjamin D. Levine, MD, of Texas Health Presbyterian Hospital in Dallas, and his coauthors.

“Our findings should reassure patients and their health care professionals that it appears these highly active individuals can safely continue their exercise programs,” Dr. Levine and his coauthors wrote in JAMA Cardiology.

The present analysis focused on 21,758 generally healthy men without prevalent cardiovascular disease. They were enrolled in the Cooper Center Longitudinal Study, a prospective, longitudinal study designed to assess linkages between physical activity, cardiorespiratory fitness, and health. The mean age of these men was 52 years at baseline; the mean duration of follow-up was 10.4 years.

Out of 21,758 male participants, 1,561 reported very high levels of physical activity, or at least 3,000 metabolic equivalent of task (MET) minutes per week, while 3,750 reported 1,500-2,999 MET minutes per week, and 16,477 reported low levels of physical activity, or less than 1,500 MET minutes per week.

The adjusted risk of elevated CAC, defined as at least 100 Agatston units, was 11% higher in the individuals reporting very high physical activity levels, the investigators found.

Presence of elevated CAC nearly doubled the risk of death in men with low levels of exercise, with a hazard ratio of 1.93 (95% confidence interval, 1.34-2.78), the investigators found. By contrast, there was no significant increase in all-cause mortality in the most active group (HR, 0.77; 95% CI, 0.52-1.15).

Taken together, these findings seem to provide evidence that high activity levels do not increase mortality risk, the investigators wrote, noting that the study is believed to have the “best available” mortality data in a large CAC population that includes measurement of physical activity.

The research was supported in partly through the National Space Biomedical Research Institute. One study author reported disclosures related to Abbott, AstraZeneca, and the American Heart Association.
 

SOURCE: Levine BD et al. JAMA Cardiol. 2019 Jan 30. doi: 10.1001/jamacardio.2018.4628.

Brooklyn, N.Y. – A risk calculator for bipolar disorder that has reached late stages of development might merit a trial to test whether treating prodromal symptoms delays or prevents the disease from developing in young patients, an expert said at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Clinicians often are confronted with children who have prodromal symptoms of bipolar disorder, but only about half of those children eventually convert to full disease expression. As a result, treatment is not routine practice, said Boris Birmaher, MD, Endowed Chair, Early Onset Bipolar Disease, at the University of Pittsburgh.

A risk calculator that more effectively identifies those at highest risk of converting might be a tool that could allow early intervention to be tested. Such a calculator has been in development for some years, and the most recent research suggests that it is nearing a degree of accuracy that is clinically meaningful (J Am Acad Child Adolesc Psychiatry. 2018;57:755-63).

“The accuracy of this risk calculator at this moment is 70%,” Dr. Birmaher reported.

Accuracy might improve further with the identification and incorporation of more predictive variables. High-risk features for conversion include a parent with bipolar disorder, particularly one with childhood onset, and specific clinical features, such as prominent episodes of mania.

“Once replicated, the risk calculator will be instrumental to predict personalized risk to develop bipolar disease,” Dr. Birmaher said. He compared it to risk calculators now in use in other fields of medicine, such as cancer and cardiovascular disease, which generate information used by patients and their physicians for treatment decisions.

In the most recent study with the risk calculator, which has been the topic of several previous publications, 140 children with a diagnosis of bipolar disorder not otherwise specified (BP-NOS) were assessed every 7 months for a median of 11.5 years. BP-NOS is the diagnosis of a prodromal syndrome that includes mood lability and other features of bipolar disorder but not at levels reaching DSM-5 diagnostic criteria. The primary outcome of the study was conversion from BP-NOS to bipolar I or II, which are DSM-5 categories.

At the end of follow-up, 53.6% of the population had converted to bipolar I or II, which is consistent with previous risk estimates in this population. In specific patients, the correlation between predicted and observed conversions was “excellent.” Furthermore, the risk calculator was reported to have provided “good” discrimination between converters and nonconverters.

The risk calculator already is accessible online (http://www.cabsresearch.pitt.edu/bpriskcalculator/). Dr. Birmaher invited clinicians to visit and “play around” with its features, but he also issued a warning. “Be careful because we need to further validate this, which we are doing now, to see if it’s truly accurate or not. If it is, it would be a very good tool for us,” he said.

There are many potential clinical applications of the risk calculator, but Dr. Birmaher emphasized its possible value in selecting at-risk patients for therapy studies. Although several therapy trials already have been conducted in high-risk children on the basis of clinical presentation alone, such as a double-blind trial in BP-NOS patients that associated aripiprazole with a reduction in mania (J Child Adolesc Psychopharmacol. 2017;27:864-74), Dr. Birmaher sees the risk calculator as potentially more precise in identifying candidates.

Brooklyn, N.Y. – A risk calculator for bipolar disorder that has reached late stages of development might merit a trial to test whether treating prodromal symptoms delays or prevents the disease from developing in young patients, an expert said at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Clinicians often are confronted with children who have prodromal symptoms of bipolar disorder, but only about half of those children eventually convert to full disease expression. As a result, treatment is not routine practice, said Boris Birmaher, MD, Endowed Chair, Early Onset Bipolar Disease, at the University of Pittsburgh.

A risk calculator that more effectively identifies those at highest risk of converting might be a tool that could allow early intervention to be tested. Such a calculator has been in development for some years, and the most recent research suggests that it is nearing a degree of accuracy that is clinically meaningful (J Am Acad Child Adolesc Psychiatry. 2018;57:755-63).

“The accuracy of this risk calculator at this moment is 70%,” Dr. Birmaher reported.

Accuracy might improve further with the identification and incorporation of more predictive variables. High-risk features for conversion include a parent with bipolar disorder, particularly one with childhood onset, and specific clinical features, such as prominent episodes of mania.

“Once replicated, the risk calculator will be instrumental to predict personalized risk to develop bipolar disease,” Dr. Birmaher said. He compared it to risk calculators now in use in other fields of medicine, such as cancer and cardiovascular disease, which generate information used by patients and their physicians for treatment decisions.

In the most recent study with the risk calculator, which has been the topic of several previous publications, 140 children with a diagnosis of bipolar disorder not otherwise specified (BP-NOS) were assessed every 7 months for a median of 11.5 years. BP-NOS is the diagnosis of a prodromal syndrome that includes mood lability and other features of bipolar disorder but not at levels reaching DSM-5 diagnostic criteria. The primary outcome of the study was conversion from BP-NOS to bipolar I or II, which are DSM-5 categories.

At the end of follow-up, 53.6% of the population had converted to bipolar I or II, which is consistent with previous risk estimates in this population. In specific patients, the correlation between predicted and observed conversions was “excellent.” Furthermore, the risk calculator was reported to have provided “good” discrimination between converters and nonconverters.

The risk calculator already is accessible online (http://www.cabsresearch.pitt.edu/bpriskcalculator/). Dr. Birmaher invited clinicians to visit and “play around” with its features, but he also issued a warning. “Be careful because we need to further validate this, which we are doing now, to see if it’s truly accurate or not. If it is, it would be a very good tool for us,” he said.

There are many potential clinical applications of the risk calculator, but Dr. Birmaher emphasized its possible value in selecting at-risk patients for therapy studies. Although several therapy trials already have been conducted in high-risk children on the basis of clinical presentation alone, such as a double-blind trial in BP-NOS patients that associated aripiprazole with a reduction in mania (J Child Adolesc Psychopharmacol. 2017;27:864-74), Dr. Birmaher sees the risk calculator as potentially more precise in identifying candidates.

Brooklyn, N.Y. – A risk calculator for bipolar disorder that has reached late stages of development might merit a trial to test whether treating prodromal symptoms delays or prevents the disease from developing in young patients, an expert said at a pediatric psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Clinicians often are confronted with children who have prodromal symptoms of bipolar disorder, but only about half of those children eventually convert to full disease expression. As a result, treatment is not routine practice, said Boris Birmaher, MD, Endowed Chair, Early Onset Bipolar Disease, at the University of Pittsburgh.

A risk calculator that more effectively identifies those at highest risk of converting might be a tool that could allow early intervention to be tested. Such a calculator has been in development for some years, and the most recent research suggests that it is nearing a degree of accuracy that is clinically meaningful (J Am Acad Child Adolesc Psychiatry. 2018;57:755-63).

“The accuracy of this risk calculator at this moment is 70%,” Dr. Birmaher reported.

Accuracy might improve further with the identification and incorporation of more predictive variables. High-risk features for conversion include a parent with bipolar disorder, particularly one with childhood onset, and specific clinical features, such as prominent episodes of mania.

“Once replicated, the risk calculator will be instrumental to predict personalized risk to develop bipolar disease,” Dr. Birmaher said. He compared it to risk calculators now in use in other fields of medicine, such as cancer and cardiovascular disease, which generate information used by patients and their physicians for treatment decisions.

In the most recent study with the risk calculator, which has been the topic of several previous publications, 140 children with a diagnosis of bipolar disorder not otherwise specified (BP-NOS) were assessed every 7 months for a median of 11.5 years. BP-NOS is the diagnosis of a prodromal syndrome that includes mood lability and other features of bipolar disorder but not at levels reaching DSM-5 diagnostic criteria. The primary outcome of the study was conversion from BP-NOS to bipolar I or II, which are DSM-5 categories.

At the end of follow-up, 53.6% of the population had converted to bipolar I or II, which is consistent with previous risk estimates in this population. In specific patients, the correlation between predicted and observed conversions was “excellent.” Furthermore, the risk calculator was reported to have provided “good” discrimination between converters and nonconverters.

The risk calculator already is accessible online (http://www.cabsresearch.pitt.edu/bpriskcalculator/). Dr. Birmaher invited clinicians to visit and “play around” with its features, but he also issued a warning. “Be careful because we need to further validate this, which we are doing now, to see if it’s truly accurate or not. If it is, it would be a very good tool for us,” he said.

There are many potential clinical applications of the risk calculator, but Dr. Birmaher emphasized its possible value in selecting at-risk patients for therapy studies. Although several therapy trials already have been conducted in high-risk children on the basis of clinical presentation alone, such as a double-blind trial in BP-NOS patients that associated aripiprazole with a reduction in mania (J Child Adolesc Psychopharmacol. 2017;27:864-74), Dr. Birmaher sees the risk calculator as potentially more precise in identifying candidates.

“How come you retired?” I asked.

Pattanaphong Khuankaew/EyeEm/gettyimages

A few years my junior, Marty had taught in public school forever. “It was the MCAS,” he said. That’s the Massachusetts Comprehensive Assessment System, a standardized test meant to gauge student performance and teacher competence.

“They demanded that my students test at a fifth-grade level,” Marty said. “But they were all at a second-grade level.

“Plus, I had been teaching for thirty years, and some kid right out of college was telling me how to do my job. So I left.”

Of course, this tale will sound familiar to physicians. Pay for performance. Bean counters calling the shots. Dismissal of clinical experience as useless and self-serving.

A recent book lays it all out: Jerry Z. Muller’s The Tyranny of Metrics. This book is punchy, witty, and succinct – you can read it in a day. A historian of economics and culture, Muller shows the extent of what I had guessed at from chats with people in different fields. The cult of metrics has taken over many parts of society: teaching, medicine, the police, the military, business, philanthropy. In all of these, if you don’t count it, it doesn’t count.

Metrics, it is assumed, are “hard” and “objective.” They must “replace judgment based on experience with standardized measurement.” Their promise is transparency, efficiency, accountability.

Muller began to study this when he became chair of his academic department. He thought his job was to nurture scholars and help students learn, only to find much of his time taken up with feeding often worthless data to remote administrators. He traces the metrical impulse, at root, to lack of trust. It’s not only doctors whom society doesn’t trust, but experts of all kinds.

Principal agents ... “employed in institutions are not to be trusted … their activity must be monitored and measured ... those measures need to be transparent to those without firsthand knowledge of the institutions ... and ... pecuniary rewards and punishments are the best way to motivate ‘agents.’ ”

What this analysis ignores, argues Muller, is that professionals respond not just to “extrinsic motivation[s]” (money) but to intrinsic ones: commitment to profession and clients, doing the right thing, making people happier and better, being recognized and honored by peers, doing interesting and stimulating work. When society denigrates and dismisses those considerations, professionals become demoralized. They leave, or they learn to game the system.

Muller gives many examples. Punish hospitals for readmissions within 30 days of discharge? Fine – readmit patients under “observation status” and call them outpatients. Dock hospitals for deaths within 30 days of leaving? Keep the respirator on for an extra day, and let the patient die on day 31. Risky case? Don’t operate. “Juking the stats” – arresting many small-fry drug pushers instead of focusing on the kingpins. Does U.S. News and World Report rank a college higher for classes with under 20 students? Schedule seminars with a maximum of 19. (My example, not Muller’s.) Teach to the MCAS (unless, like Marty, you decide that’s hopeless and just quit). Buff the numbers.

You know the drill. And if you need to learn it to succeed – or not be judged a failure – you’ll learn it.

Studies show that “pay for performance” often doesn’t work. Metric advocates ignore these and call for more studies. In Muller’s words, “Metric fixation, which aspires to imitate science, too often resembles faith.”

Muller argues with balance and nuance. He affirms that objective measurement has helped sweep away old dogmas no one had ever tested and culled markedly substandard teachers. But he shows that over the past 30 years just counting what you know how to count, counting things that cannot be counted, and privileging belief over disconfirming evidence has conferred on metrics “elements of a cult,” whose baleful effects doctors and others toiling in their professional vineyards know too well.

Faith in metrics will wane and its cult will pass away, though likely well after we have done so ourselves. At some point, so-called situated knowledge – what people who actually do something know – will again be valued.

In the meantime, please rate this column highly (give it a 6 on a scale of 1-5), and confirm that there are no barriers to your implementing its wisdom, which comes unsullied by any financial conflicts of interest.

And check out Muller’s book. You have nothing to lose but your chains.

Measurement without meaning is tyranny!
 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].

“How come you retired?” I asked.

Pattanaphong Khuankaew/EyeEm/gettyimages

A few years my junior, Marty had taught in public school forever. “It was the MCAS,” he said. That’s the Massachusetts Comprehensive Assessment System, a standardized test meant to gauge student performance and teacher competence.

“They demanded that my students test at a fifth-grade level,” Marty said. “But they were all at a second-grade level.

“Plus, I had been teaching for thirty years, and some kid right out of college was telling me how to do my job. So I left.”

Of course, this tale will sound familiar to physicians. Pay for performance. Bean counters calling the shots. Dismissal of clinical experience as useless and self-serving.

A recent book lays it all out: Jerry Z. Muller’s The Tyranny of Metrics. This book is punchy, witty, and succinct – you can read it in a day. A historian of economics and culture, Muller shows the extent of what I had guessed at from chats with people in different fields. The cult of metrics has taken over many parts of society: teaching, medicine, the police, the military, business, philanthropy. In all of these, if you don’t count it, it doesn’t count.

Metrics, it is assumed, are “hard” and “objective.” They must “replace judgment based on experience with standardized measurement.” Their promise is transparency, efficiency, accountability.

Muller began to study this when he became chair of his academic department. He thought his job was to nurture scholars and help students learn, only to find much of his time taken up with feeding often worthless data to remote administrators. He traces the metrical impulse, at root, to lack of trust. It’s not only doctors whom society doesn’t trust, but experts of all kinds.

Principal agents ... “employed in institutions are not to be trusted … their activity must be monitored and measured ... those measures need to be transparent to those without firsthand knowledge of the institutions ... and ... pecuniary rewards and punishments are the best way to motivate ‘agents.’ ”

What this analysis ignores, argues Muller, is that professionals respond not just to “extrinsic motivation[s]” (money) but to intrinsic ones: commitment to profession and clients, doing the right thing, making people happier and better, being recognized and honored by peers, doing interesting and stimulating work. When society denigrates and dismisses those considerations, professionals become demoralized. They leave, or they learn to game the system.

Muller gives many examples. Punish hospitals for readmissions within 30 days of discharge? Fine – readmit patients under “observation status” and call them outpatients. Dock hospitals for deaths within 30 days of leaving? Keep the respirator on for an extra day, and let the patient die on day 31. Risky case? Don’t operate. “Juking the stats” – arresting many small-fry drug pushers instead of focusing on the kingpins. Does U.S. News and World Report rank a college higher for classes with under 20 students? Schedule seminars with a maximum of 19. (My example, not Muller’s.) Teach to the MCAS (unless, like Marty, you decide that’s hopeless and just quit). Buff the numbers.

You know the drill. And if you need to learn it to succeed – or not be judged a failure – you’ll learn it.

Studies show that “pay for performance” often doesn’t work. Metric advocates ignore these and call for more studies. In Muller’s words, “Metric fixation, which aspires to imitate science, too often resembles faith.”

Muller argues with balance and nuance. He affirms that objective measurement has helped sweep away old dogmas no one had ever tested and culled markedly substandard teachers. But he shows that over the past 30 years just counting what you know how to count, counting things that cannot be counted, and privileging belief over disconfirming evidence has conferred on metrics “elements of a cult,” whose baleful effects doctors and others toiling in their professional vineyards know too well.

Faith in metrics will wane and its cult will pass away, though likely well after we have done so ourselves. At some point, so-called situated knowledge – what people who actually do something know – will again be valued.

In the meantime, please rate this column highly (give it a 6 on a scale of 1-5), and confirm that there are no barriers to your implementing its wisdom, which comes unsullied by any financial conflicts of interest.

And check out Muller’s book. You have nothing to lose but your chains.

Measurement without meaning is tyranny!
 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].

“How come you retired?” I asked.

Pattanaphong Khuankaew/EyeEm/gettyimages

A few years my junior, Marty had taught in public school forever. “It was the MCAS,” he said. That’s the Massachusetts Comprehensive Assessment System, a standardized test meant to gauge student performance and teacher competence.

“They demanded that my students test at a fifth-grade level,” Marty said. “But they were all at a second-grade level.

“Plus, I had been teaching for thirty years, and some kid right out of college was telling me how to do my job. So I left.”

Of course, this tale will sound familiar to physicians. Pay for performance. Bean counters calling the shots. Dismissal of clinical experience as useless and self-serving.

A recent book lays it all out: Jerry Z. Muller’s The Tyranny of Metrics. This book is punchy, witty, and succinct – you can read it in a day. A historian of economics and culture, Muller shows the extent of what I had guessed at from chats with people in different fields. The cult of metrics has taken over many parts of society: teaching, medicine, the police, the military, business, philanthropy. In all of these, if you don’t count it, it doesn’t count.

Metrics, it is assumed, are “hard” and “objective.” They must “replace judgment based on experience with standardized measurement.” Their promise is transparency, efficiency, accountability.

Muller began to study this when he became chair of his academic department. He thought his job was to nurture scholars and help students learn, only to find much of his time taken up with feeding often worthless data to remote administrators. He traces the metrical impulse, at root, to lack of trust. It’s not only doctors whom society doesn’t trust, but experts of all kinds.

Principal agents ... “employed in institutions are not to be trusted … their activity must be monitored and measured ... those measures need to be transparent to those without firsthand knowledge of the institutions ... and ... pecuniary rewards and punishments are the best way to motivate ‘agents.’ ”

What this analysis ignores, argues Muller, is that professionals respond not just to “extrinsic motivation[s]” (money) but to intrinsic ones: commitment to profession and clients, doing the right thing, making people happier and better, being recognized and honored by peers, doing interesting and stimulating work. When society denigrates and dismisses those considerations, professionals become demoralized. They leave, or they learn to game the system.

Muller gives many examples. Punish hospitals for readmissions within 30 days of discharge? Fine – readmit patients under “observation status” and call them outpatients. Dock hospitals for deaths within 30 days of leaving? Keep the respirator on for an extra day, and let the patient die on day 31. Risky case? Don’t operate. “Juking the stats” – arresting many small-fry drug pushers instead of focusing on the kingpins. Does U.S. News and World Report rank a college higher for classes with under 20 students? Schedule seminars with a maximum of 19. (My example, not Muller’s.) Teach to the MCAS (unless, like Marty, you decide that’s hopeless and just quit). Buff the numbers.

You know the drill. And if you need to learn it to succeed – or not be judged a failure – you’ll learn it.

Studies show that “pay for performance” often doesn’t work. Metric advocates ignore these and call for more studies. In Muller’s words, “Metric fixation, which aspires to imitate science, too often resembles faith.”

Muller argues with balance and nuance. He affirms that objective measurement has helped sweep away old dogmas no one had ever tested and culled markedly substandard teachers. But he shows that over the past 30 years just counting what you know how to count, counting things that cannot be counted, and privileging belief over disconfirming evidence has conferred on metrics “elements of a cult,” whose baleful effects doctors and others toiling in their professional vineyards know too well.

Faith in metrics will wane and its cult will pass away, though likely well after we have done so ourselves. At some point, so-called situated knowledge – what people who actually do something know – will again be valued.

In the meantime, please rate this column highly (give it a 6 on a scale of 1-5), and confirm that there are no barriers to your implementing its wisdom, which comes unsullied by any financial conflicts of interest.

And check out Muller’s book. You have nothing to lose but your chains.

Measurement without meaning is tyranny!
 

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at [email protected].

I cared for my first patient with leukemia my first month as a doctor. Actually, he would protest that characterization. Marty didn’t have leukemia anymore. After chemotherapy and a bone marrow transplant, he was a few years out with no evidence of disease. While his hematologist was hesitant to use the word “cured” until more time had passed, he had been in a lasting remission.

Except that was the chart version of Marty’s story, not his own. He was profoundly depressed, he confided in me during our first meeting. The part missing from his chart was the toll this entire saga had taken on his emotional well-being and personal life. He was diagnosed as a college sophomore, left school for treatment, and then never went back. He was pulled from his friends and his life.

“I never thought I would be the guy living in my parents’ basement,” he told me. “No job. No friends. No girlfriend.”

And, the graft-versus-host disease was still affecting him. His skin chronically itched. The light bothered his eyes, so he couldn’t drive long distances. Insecure about his skin and his vision, he self-imposed limitations on his activities, which in turn limited his hobbies.

In medical literature, what Marty was going through is chalked up to issues in survivorship. Many patients experience some version of this story. And it’s often not the hematologist or oncologist, but primary care physicians, who are responsible for managing this challenging aftermath.

Primary care physicians are responsible for a lot. After a certain duration of remission, I’ve noticed we tell some of our hematology and oncology patients, “Congratulations! You’ve graduated our clinic. We are happy to see you back if you’d like. But really, your primary care physician can manage your health now.”

In addition to depression, there was anxiety, understandably centered on the tenuousness of his health. I remember how Marty would send urgent emails and call the office after each blood test. If anything came back abnormal, there came a slew of questions. The meaning behind them was clear: The questions were filled with a fear that it could be the leukemia coming back.

What he didn’t know was that I was scared, too. After all, I was an internal medicine resident, not a hematologist. Was I checking the right labs? Was I taking his concerns seriously enough? Behind the scenes, I checked myself by running things by his bone marrow transplant doctor on a regular basis. She guided me on guiding him.

I often thought that I couldn’t imagine what he was feeling. We were the same age, but our day-to-day concerns took a drastically different tone. We both took a deep interest in his blood work, but while I felt angst over taking responsibility for them, he worried about whether they signaled an impending death.

“If the leukemia does come back,” he told me one day, “I don’t think I want to treat it. I can’t deal with all that again.”

There were many times he wanted to give up, he told me, and it was only for his parents that he pushed through. But now, he said, if it came back and the odds of curing it were that much smaller, he couldn’t do it for his parents again. He would take his savings, travel the world, and not look back.

I listened. I felt I understood his values at that point. I could not disagree.

Looking back, I realize some of my best help to Marty was through paperwork. It wasn’t glamorous, but it was what Marty needed. The passport to putting his life back together included many notes from a doctor: One to get him back into school, another to live in a dorm room, another for accommodations for his vision during exams, another to participate in sports.

At the time, I still was in newfound awe of the power of my signature; suddenly, signing MD at the end of documents persuaded schools, employers, and others to provide necessary services for my patients. I couldn’t think of a better use of my signature than to help Marty get his life back.

At the end of my residency, when I broke the news that I wouldn’t be a primary care physician anymore, I tried to soften it by sharing that I would be staying at Stanford for a fellowship in hematology and oncology. I’d be around. When I casually suggested he could come by anytime to say hello, he said no, and I then realized my blunder. He didn’t want to see me in a cancer center. He had done his time there. That was not the place he wanted to be a patient, ever again.

This month Marty turned 30, and so did I. He occasionally sends me updates from school, which I always enjoy receiving. He is on a sports team; he is pursuing a degree in economics; he has friends. And, he remains in remission. It took a long time, but he is happy.

During our last visit together, Marty gave me a stuffed animal with the name of the college I had helped him go back to. It’s sitting on my bookshelf. It reminds me how to be there for patients during the aftermath, a time that can be easily overlooked as the hardest. It reminds me what matters.

Minor details of this story have been changed to protect privacy.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

I cared for my first patient with leukemia my first month as a doctor. Actually, he would protest that characterization. Marty didn’t have leukemia anymore. After chemotherapy and a bone marrow transplant, he was a few years out with no evidence of disease. While his hematologist was hesitant to use the word “cured” until more time had passed, he had been in a lasting remission.

Except that was the chart version of Marty’s story, not his own. He was profoundly depressed, he confided in me during our first meeting. The part missing from his chart was the toll this entire saga had taken on his emotional well-being and personal life. He was diagnosed as a college sophomore, left school for treatment, and then never went back. He was pulled from his friends and his life.

“I never thought I would be the guy living in my parents’ basement,” he told me. “No job. No friends. No girlfriend.”

And, the graft-versus-host disease was still affecting him. His skin chronically itched. The light bothered his eyes, so he couldn’t drive long distances. Insecure about his skin and his vision, he self-imposed limitations on his activities, which in turn limited his hobbies.

In medical literature, what Marty was going through is chalked up to issues in survivorship. Many patients experience some version of this story. And it’s often not the hematologist or oncologist, but primary care physicians, who are responsible for managing this challenging aftermath.

Primary care physicians are responsible for a lot. After a certain duration of remission, I’ve noticed we tell some of our hematology and oncology patients, “Congratulations! You’ve graduated our clinic. We are happy to see you back if you’d like. But really, your primary care physician can manage your health now.”

In addition to depression, there was anxiety, understandably centered on the tenuousness of his health. I remember how Marty would send urgent emails and call the office after each blood test. If anything came back abnormal, there came a slew of questions. The meaning behind them was clear: The questions were filled with a fear that it could be the leukemia coming back.

What he didn’t know was that I was scared, too. After all, I was an internal medicine resident, not a hematologist. Was I checking the right labs? Was I taking his concerns seriously enough? Behind the scenes, I checked myself by running things by his bone marrow transplant doctor on a regular basis. She guided me on guiding him.

I often thought that I couldn’t imagine what he was feeling. We were the same age, but our day-to-day concerns took a drastically different tone. We both took a deep interest in his blood work, but while I felt angst over taking responsibility for them, he worried about whether they signaled an impending death.

“If the leukemia does come back,” he told me one day, “I don’t think I want to treat it. I can’t deal with all that again.”

There were many times he wanted to give up, he told me, and it was only for his parents that he pushed through. But now, he said, if it came back and the odds of curing it were that much smaller, he couldn’t do it for his parents again. He would take his savings, travel the world, and not look back.

I listened. I felt I understood his values at that point. I could not disagree.

Looking back, I realize some of my best help to Marty was through paperwork. It wasn’t glamorous, but it was what Marty needed. The passport to putting his life back together included many notes from a doctor: One to get him back into school, another to live in a dorm room, another for accommodations for his vision during exams, another to participate in sports.

At the time, I still was in newfound awe of the power of my signature; suddenly, signing MD at the end of documents persuaded schools, employers, and others to provide necessary services for my patients. I couldn’t think of a better use of my signature than to help Marty get his life back.

At the end of my residency, when I broke the news that I wouldn’t be a primary care physician anymore, I tried to soften it by sharing that I would be staying at Stanford for a fellowship in hematology and oncology. I’d be around. When I casually suggested he could come by anytime to say hello, he said no, and I then realized my blunder. He didn’t want to see me in a cancer center. He had done his time there. That was not the place he wanted to be a patient, ever again.

This month Marty turned 30, and so did I. He occasionally sends me updates from school, which I always enjoy receiving. He is on a sports team; he is pursuing a degree in economics; he has friends. And, he remains in remission. It took a long time, but he is happy.

During our last visit together, Marty gave me a stuffed animal with the name of the college I had helped him go back to. It’s sitting on my bookshelf. It reminds me how to be there for patients during the aftermath, a time that can be easily overlooked as the hardest. It reminds me what matters.

Minor details of this story have been changed to protect privacy.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

I cared for my first patient with leukemia my first month as a doctor. Actually, he would protest that characterization. Marty didn’t have leukemia anymore. After chemotherapy and a bone marrow transplant, he was a few years out with no evidence of disease. While his hematologist was hesitant to use the word “cured” until more time had passed, he had been in a lasting remission.

Except that was the chart version of Marty’s story, not his own. He was profoundly depressed, he confided in me during our first meeting. The part missing from his chart was the toll this entire saga had taken on his emotional well-being and personal life. He was diagnosed as a college sophomore, left school for treatment, and then never went back. He was pulled from his friends and his life.

“I never thought I would be the guy living in my parents’ basement,” he told me. “No job. No friends. No girlfriend.”

And, the graft-versus-host disease was still affecting him. His skin chronically itched. The light bothered his eyes, so he couldn’t drive long distances. Insecure about his skin and his vision, he self-imposed limitations on his activities, which in turn limited his hobbies.

In medical literature, what Marty was going through is chalked up to issues in survivorship. Many patients experience some version of this story. And it’s often not the hematologist or oncologist, but primary care physicians, who are responsible for managing this challenging aftermath.

Primary care physicians are responsible for a lot. After a certain duration of remission, I’ve noticed we tell some of our hematology and oncology patients, “Congratulations! You’ve graduated our clinic. We are happy to see you back if you’d like. But really, your primary care physician can manage your health now.”

In addition to depression, there was anxiety, understandably centered on the tenuousness of his health. I remember how Marty would send urgent emails and call the office after each blood test. If anything came back abnormal, there came a slew of questions. The meaning behind them was clear: The questions were filled with a fear that it could be the leukemia coming back.

What he didn’t know was that I was scared, too. After all, I was an internal medicine resident, not a hematologist. Was I checking the right labs? Was I taking his concerns seriously enough? Behind the scenes, I checked myself by running things by his bone marrow transplant doctor on a regular basis. She guided me on guiding him.

I often thought that I couldn’t imagine what he was feeling. We were the same age, but our day-to-day concerns took a drastically different tone. We both took a deep interest in his blood work, but while I felt angst over taking responsibility for them, he worried about whether they signaled an impending death.

“If the leukemia does come back,” he told me one day, “I don’t think I want to treat it. I can’t deal with all that again.”

There were many times he wanted to give up, he told me, and it was only for his parents that he pushed through. But now, he said, if it came back and the odds of curing it were that much smaller, he couldn’t do it for his parents again. He would take his savings, travel the world, and not look back.

I listened. I felt I understood his values at that point. I could not disagree.

Looking back, I realize some of my best help to Marty was through paperwork. It wasn’t glamorous, but it was what Marty needed. The passport to putting his life back together included many notes from a doctor: One to get him back into school, another to live in a dorm room, another for accommodations for his vision during exams, another to participate in sports.

At the time, I still was in newfound awe of the power of my signature; suddenly, signing MD at the end of documents persuaded schools, employers, and others to provide necessary services for my patients. I couldn’t think of a better use of my signature than to help Marty get his life back.

At the end of my residency, when I broke the news that I wouldn’t be a primary care physician anymore, I tried to soften it by sharing that I would be staying at Stanford for a fellowship in hematology and oncology. I’d be around. When I casually suggested he could come by anytime to say hello, he said no, and I then realized my blunder. He didn’t want to see me in a cancer center. He had done his time there. That was not the place he wanted to be a patient, ever again.

This month Marty turned 30, and so did I. He occasionally sends me updates from school, which I always enjoy receiving. He is on a sports team; he is pursuing a degree in economics; he has friends. And, he remains in remission. It took a long time, but he is happy.

During our last visit together, Marty gave me a stuffed animal with the name of the college I had helped him go back to. It’s sitting on my bookshelf. It reminds me how to be there for patients during the aftermath, a time that can be easily overlooked as the hardest. It reminds me what matters.

Minor details of this story have been changed to protect privacy.
 

Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.

Found in various plant and animal species, including humans, melatonin (N-acetyl-5-methoxytryptamine) is best known for its daily fluctuations in circulating levels that regulate circadian rhythms. But this ancient serotonin derivative, stimulated by beta-adrenergic receptors, is the primary neuroendocrine product of the pineal gland (discovered as such in 1917) in humans and a dynamic compound with diverse roles in human health levels of which decrease with age.^1,2 Over the last quarter of a century, we have arrived at a much greater understanding of the varied biological functions of this highly lipophilic hormone, which is now recognized as the strongest endogenous antioxidant, particularly potent against hydroxyl radicals, the most harmful of reactive oxygen species, and known to protect mitochondria and DNA from direct oxidative harm.^2-4 Directly or via its circadian impact, melatonin also affects skin as well as core body temperature.¹ This column is a brief review of some early studies on melatonin and some of the cutaneous conditions for which exogenous melatonin shows promise. Next month’s column will address some more of the activities of this dynamic hormone while concentrating on the interaction of melatonin and ultraviolet radiation.

Dr_Microbe/Getty Images

Early studies

In the mid-1990s, Bangha et al. performed several studies in healthy human volunteers that demonstrated that topically applied melatonin suppressed UVB-induced erythema (with one study showing pre- and posttreatment as effective and a subsequent one showing only pretreatment as effective), and also found that melatonin appears to have the potential to accumulate in the stratum corneum with extended release into the blood system through cutaneous delivery.^5-7

A randomized, double-blind study by Dreher et al. in 12 healthy adults (6 women and 6 men, all white, aged 29-49 years) considered the short-term photoprotective effects of topically applied vitamin C, vitamin E, and melatonin, alone or in combination, 30 minutes after UV exposure. A dose-dependent photoprotective effect was associated with melatonin, and photoprotective properties were enhanced when melatonin in was combined with vitamins C and E.⁸

The following year, Dreher et al. evaluated the short-term photoprotective effects of the same compounds in a randomized, double-blind, placebo-controlled human study. Each antioxidant was topically applied alone or in combination after UV exposure in a single application (immediately or 30 minutes after UV exposure) or in multiple applications 30 minutes, 1 hour, and 2 hours after UV exposure (totaling three applications). Interestingly, no photoprotective effects were seen. The researchers concluded that given the speed of cutaneous damage from UV radiation, antioxidants likely must be delivered at the appropriate site in sufficient doses at the outset of and during active oxidative harm.⁹

In 2004, Fischer et al. conducted a clinical study of 15 healthy volunteers to test the skin penetration activity of melatonin 0.01% in a cream and 0.01% and 0.03% in a solution. During a 24-hour period, researchers obtained blood samples for melatonin measurement prior to application at 9 a.m. as well as 1, 4, 8, and 24 hours after application. Preapplication serum melatonin levels ranged from 0.6 to 15.9 pg/mL. The mean serum value 24 hours later after application of the 0.01% melatonin cream was 9.0 pg/mL. For the 0.01% solution group, the mean melatonin level was 12.7 pg/mL 24 hours after application. Melatonin levels also substantially rose just 1 and 8 hours later in the 0.03% solution group, with cumulative melatonin measured as 7.1 pg/mL in the 0.01% cream group, 8.6 pg/mL in the 0.01% solution participants, and 15.7 pg/mL in the 0.03% group. The investigators concluded that as a strong lipophilic compound melatonin penetrates the skin with serum blood levels increasing in a dose- and galenic-dependent manner without prompting spikes above the physiological range.¹⁰

Wound healing and atopic dermatitis

In 2006, Sener et al. reported that topically applied and systemically administered melatonin was successful as a pressure ulcer treatment in rats.¹¹ Four years later, in a study using a chronic wound model in rats with pinealectomy that suppressed basal melatonin, Ozler et al. found that systemic and topical melatonin treatment were equally effective in imparting wound healing effects.¹²

A study in mice conducted by Kim et al. at around the same time showed that topically applied melatonin, by reducing total IgE in serum and interleukin-4 and interferon-gamma production by activated CD4(+) T cells, inhibits atopic dermatitis–like skin lesion development engendered by 2,4-dinitrofluorobenzene (DNFB) treatment in NC/Nga mice.¹³

More recently, Abbaszadeh et al. have suggested that melatonin has the potential to enhance the therapeutic ratio in radiation oncology, and to be more effective at reducing skin damage in this setting when used in optimal and non-toxic doses.²

Pigmentation disorders

Melatonin and serotonin are thought to have potential to ameliorate or attenuate the spread of vitiligo.¹ In addition, melatonin appears to have potential in the realm of hyperpigmentation treatment. Investigators have found that the combination of topical melatonin 5% and a daily dose of 3 g of oral melatonin over 120 days significantly reduces Melasma Area Severity Index scores in comparison to placebo; the improvement is attributed primarily to the use of topical melatonin.^14,15

Androgenetic alopecia

In 2018, Hatem et al. designed nanostructured lipid carriers to better deliver melatonin in antioxidant oils to treat androgenic alopecia. They found that the carriers achieved a sustained release of 6 hours and raised the skin deposition of melatonin 4.5-fold in the stratum corneum, 7-fold in the epidermis, and 6.8-fold in the dermis compared with a melatonin solution. The nanostructured lipid carriers also improved on clinical results, compared to the melatonin formula, by increasing hair density and thickness and reducing hair loss in patients with androgenic alopecia.¹⁶

Conclusion

Studies in humans have shown that melatonin has particular relevance in dermatology given its demonstrated anti-inflammatory, antioxidant, and anti-aging activity through systemic administration and, particularly, topical application. Demonstrated to be safe and effective, topically applied melatonin appears to warrant serious consideration as a skin-protective, anti-aging tool in the dermatologic armamentarium.

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Slominski AT et al. J Invest Dermatol. 2018 Mar;138(3):490-9.

2. Abbaszadeh A et al. J Biomed Phys Eng. 2017 Jun;7(2):127-136.

3. Fischer T et al. Hautarzt. 1999 Jan;50(1):5-11.

4. Scheuer C. Dan Med J. 2017 Jun;64(6). pii:B5358.

5. Bangha E et al. Arch Dermatol Res. 1996 Aug;288(9):522-6.

6. Bangha E et al. Dermatology. 1997;195(3):248-52.

7. Bangha E et al. Skin Pharmacol. 1997;10(5-6):298-302.

8. Dreher F et al. Br J Dermatol. 1998 Aug;139(2):332-9.

9. Dreher F et al. Dermatology. 1999;198(1):52-5.

10. Fischer TW et al. Skin Pharmacol Physiol. 2004 Jul-Aug;17(4):190-4.

11. Sener G et al. J Pineal Res. 2006 Apr;40(3):280-7.

12. Ozler M et al. Scand J Clin Lab Invest. 2010 Oct;70(6):447-52.

13. Kim TH et al. J Pineal Res. 2009 Nov;47(4):324-9.

14. Juhasz MLW et al. J Cosmet Dermatol. 2018 Dec;17(6):1144-57.

15. Hamadi SA, Mohammed MM, Aljaf AN, et al. The role of topical and oral melatonin in management of melasma patients. J Arab Univ Basic Appl Sci. 2009;8:30‐42.

16. Hatem S et al. Expert Opin Drug Deliv. 2018 Oct;15(10):927-35.

Found in various plant and animal species, including humans, melatonin (N-acetyl-5-methoxytryptamine) is best known for its daily fluctuations in circulating levels that regulate circadian rhythms. But this ancient serotonin derivative, stimulated by beta-adrenergic receptors, is the primary neuroendocrine product of the pineal gland (discovered as such in 1917) in humans and a dynamic compound with diverse roles in human health levels of which decrease with age.^1,2 Over the last quarter of a century, we have arrived at a much greater understanding of the varied biological functions of this highly lipophilic hormone, which is now recognized as the strongest endogenous antioxidant, particularly potent against hydroxyl radicals, the most harmful of reactive oxygen species, and known to protect mitochondria and DNA from direct oxidative harm.^2-4 Directly or via its circadian impact, melatonin also affects skin as well as core body temperature.¹ This column is a brief review of some early studies on melatonin and some of the cutaneous conditions for which exogenous melatonin shows promise. Next month’s column will address some more of the activities of this dynamic hormone while concentrating on the interaction of melatonin and ultraviolet radiation.

Dr_Microbe/Getty Images

Early studies

In the mid-1990s, Bangha et al. performed several studies in healthy human volunteers that demonstrated that topically applied melatonin suppressed UVB-induced erythema (with one study showing pre- and posttreatment as effective and a subsequent one showing only pretreatment as effective), and also found that melatonin appears to have the potential to accumulate in the stratum corneum with extended release into the blood system through cutaneous delivery.^5-7

A randomized, double-blind study by Dreher et al. in 12 healthy adults (6 women and 6 men, all white, aged 29-49 years) considered the short-term photoprotective effects of topically applied vitamin C, vitamin E, and melatonin, alone or in combination, 30 minutes after UV exposure. A dose-dependent photoprotective effect was associated with melatonin, and photoprotective properties were enhanced when melatonin in was combined with vitamins C and E.⁸

The following year, Dreher et al. evaluated the short-term photoprotective effects of the same compounds in a randomized, double-blind, placebo-controlled human study. Each antioxidant was topically applied alone or in combination after UV exposure in a single application (immediately or 30 minutes after UV exposure) or in multiple applications 30 minutes, 1 hour, and 2 hours after UV exposure (totaling three applications). Interestingly, no photoprotective effects were seen. The researchers concluded that given the speed of cutaneous damage from UV radiation, antioxidants likely must be delivered at the appropriate site in sufficient doses at the outset of and during active oxidative harm.⁹

In 2004, Fischer et al. conducted a clinical study of 15 healthy volunteers to test the skin penetration activity of melatonin 0.01% in a cream and 0.01% and 0.03% in a solution. During a 24-hour period, researchers obtained blood samples for melatonin measurement prior to application at 9 a.m. as well as 1, 4, 8, and 24 hours after application. Preapplication serum melatonin levels ranged from 0.6 to 15.9 pg/mL. The mean serum value 24 hours later after application of the 0.01% melatonin cream was 9.0 pg/mL. For the 0.01% solution group, the mean melatonin level was 12.7 pg/mL 24 hours after application. Melatonin levels also substantially rose just 1 and 8 hours later in the 0.03% solution group, with cumulative melatonin measured as 7.1 pg/mL in the 0.01% cream group, 8.6 pg/mL in the 0.01% solution participants, and 15.7 pg/mL in the 0.03% group. The investigators concluded that as a strong lipophilic compound melatonin penetrates the skin with serum blood levels increasing in a dose- and galenic-dependent manner without prompting spikes above the physiological range.¹⁰

Wound healing and atopic dermatitis

In 2006, Sener et al. reported that topically applied and systemically administered melatonin was successful as a pressure ulcer treatment in rats.¹¹ Four years later, in a study using a chronic wound model in rats with pinealectomy that suppressed basal melatonin, Ozler et al. found that systemic and topical melatonin treatment were equally effective in imparting wound healing effects.¹²

A study in mice conducted by Kim et al. at around the same time showed that topically applied melatonin, by reducing total IgE in serum and interleukin-4 and interferon-gamma production by activated CD4(+) T cells, inhibits atopic dermatitis–like skin lesion development engendered by 2,4-dinitrofluorobenzene (DNFB) treatment in NC/Nga mice.¹³

More recently, Abbaszadeh et al. have suggested that melatonin has the potential to enhance the therapeutic ratio in radiation oncology, and to be more effective at reducing skin damage in this setting when used in optimal and non-toxic doses.²

Pigmentation disorders

Melatonin and serotonin are thought to have potential to ameliorate or attenuate the spread of vitiligo.¹ In addition, melatonin appears to have potential in the realm of hyperpigmentation treatment. Investigators have found that the combination of topical melatonin 5% and a daily dose of 3 g of oral melatonin over 120 days significantly reduces Melasma Area Severity Index scores in comparison to placebo; the improvement is attributed primarily to the use of topical melatonin.^14,15

Androgenetic alopecia

In 2018, Hatem et al. designed nanostructured lipid carriers to better deliver melatonin in antioxidant oils to treat androgenic alopecia. They found that the carriers achieved a sustained release of 6 hours and raised the skin deposition of melatonin 4.5-fold in the stratum corneum, 7-fold in the epidermis, and 6.8-fold in the dermis compared with a melatonin solution. The nanostructured lipid carriers also improved on clinical results, compared to the melatonin formula, by increasing hair density and thickness and reducing hair loss in patients with androgenic alopecia.¹⁶

Conclusion

Studies in humans have shown that melatonin has particular relevance in dermatology given its demonstrated anti-inflammatory, antioxidant, and anti-aging activity through systemic administration and, particularly, topical application. Demonstrated to be safe and effective, topically applied melatonin appears to warrant serious consideration as a skin-protective, anti-aging tool in the dermatologic armamentarium.

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Slominski AT et al. J Invest Dermatol. 2018 Mar;138(3):490-9.

2. Abbaszadeh A et al. J Biomed Phys Eng. 2017 Jun;7(2):127-136.

3. Fischer T et al. Hautarzt. 1999 Jan;50(1):5-11.

4. Scheuer C. Dan Med J. 2017 Jun;64(6). pii:B5358.

5. Bangha E et al. Arch Dermatol Res. 1996 Aug;288(9):522-6.

6. Bangha E et al. Dermatology. 1997;195(3):248-52.

7. Bangha E et al. Skin Pharmacol. 1997;10(5-6):298-302.

8. Dreher F et al. Br J Dermatol. 1998 Aug;139(2):332-9.

9. Dreher F et al. Dermatology. 1999;198(1):52-5.

10. Fischer TW et al. Skin Pharmacol Physiol. 2004 Jul-Aug;17(4):190-4.

11. Sener G et al. J Pineal Res. 2006 Apr;40(3):280-7.

12. Ozler M et al. Scand J Clin Lab Invest. 2010 Oct;70(6):447-52.

13. Kim TH et al. J Pineal Res. 2009 Nov;47(4):324-9.

14. Juhasz MLW et al. J Cosmet Dermatol. 2018 Dec;17(6):1144-57.

15. Hamadi SA, Mohammed MM, Aljaf AN, et al. The role of topical and oral melatonin in management of melasma patients. J Arab Univ Basic Appl Sci. 2009;8:30‐42.

16. Hatem S et al. Expert Opin Drug Deliv. 2018 Oct;15(10):927-35.

Found in various plant and animal species, including humans, melatonin (N-acetyl-5-methoxytryptamine) is best known for its daily fluctuations in circulating levels that regulate circadian rhythms. But this ancient serotonin derivative, stimulated by beta-adrenergic receptors, is the primary neuroendocrine product of the pineal gland (discovered as such in 1917) in humans and a dynamic compound with diverse roles in human health levels of which decrease with age.^1,2 Over the last quarter of a century, we have arrived at a much greater understanding of the varied biological functions of this highly lipophilic hormone, which is now recognized as the strongest endogenous antioxidant, particularly potent against hydroxyl radicals, the most harmful of reactive oxygen species, and known to protect mitochondria and DNA from direct oxidative harm.^2-4 Directly or via its circadian impact, melatonin also affects skin as well as core body temperature.¹ This column is a brief review of some early studies on melatonin and some of the cutaneous conditions for which exogenous melatonin shows promise. Next month’s column will address some more of the activities of this dynamic hormone while concentrating on the interaction of melatonin and ultraviolet radiation.

Dr_Microbe/Getty Images

Early studies

In the mid-1990s, Bangha et al. performed several studies in healthy human volunteers that demonstrated that topically applied melatonin suppressed UVB-induced erythema (with one study showing pre- and posttreatment as effective and a subsequent one showing only pretreatment as effective), and also found that melatonin appears to have the potential to accumulate in the stratum corneum with extended release into the blood system through cutaneous delivery.^5-7

A randomized, double-blind study by Dreher et al. in 12 healthy adults (6 women and 6 men, all white, aged 29-49 years) considered the short-term photoprotective effects of topically applied vitamin C, vitamin E, and melatonin, alone or in combination, 30 minutes after UV exposure. A dose-dependent photoprotective effect was associated with melatonin, and photoprotective properties were enhanced when melatonin in was combined with vitamins C and E.⁸

The following year, Dreher et al. evaluated the short-term photoprotective effects of the same compounds in a randomized, double-blind, placebo-controlled human study. Each antioxidant was topically applied alone or in combination after UV exposure in a single application (immediately or 30 minutes after UV exposure) or in multiple applications 30 minutes, 1 hour, and 2 hours after UV exposure (totaling three applications). Interestingly, no photoprotective effects were seen. The researchers concluded that given the speed of cutaneous damage from UV radiation, antioxidants likely must be delivered at the appropriate site in sufficient doses at the outset of and during active oxidative harm.⁹

In 2004, Fischer et al. conducted a clinical study of 15 healthy volunteers to test the skin penetration activity of melatonin 0.01% in a cream and 0.01% and 0.03% in a solution. During a 24-hour period, researchers obtained blood samples for melatonin measurement prior to application at 9 a.m. as well as 1, 4, 8, and 24 hours after application. Preapplication serum melatonin levels ranged from 0.6 to 15.9 pg/mL. The mean serum value 24 hours later after application of the 0.01% melatonin cream was 9.0 pg/mL. For the 0.01% solution group, the mean melatonin level was 12.7 pg/mL 24 hours after application. Melatonin levels also substantially rose just 1 and 8 hours later in the 0.03% solution group, with cumulative melatonin measured as 7.1 pg/mL in the 0.01% cream group, 8.6 pg/mL in the 0.01% solution participants, and 15.7 pg/mL in the 0.03% group. The investigators concluded that as a strong lipophilic compound melatonin penetrates the skin with serum blood levels increasing in a dose- and galenic-dependent manner without prompting spikes above the physiological range.¹⁰

Wound healing and atopic dermatitis

In 2006, Sener et al. reported that topically applied and systemically administered melatonin was successful as a pressure ulcer treatment in rats.¹¹ Four years later, in a study using a chronic wound model in rats with pinealectomy that suppressed basal melatonin, Ozler et al. found that systemic and topical melatonin treatment were equally effective in imparting wound healing effects.¹²

A study in mice conducted by Kim et al. at around the same time showed that topically applied melatonin, by reducing total IgE in serum and interleukin-4 and interferon-gamma production by activated CD4(+) T cells, inhibits atopic dermatitis–like skin lesion development engendered by 2,4-dinitrofluorobenzene (DNFB) treatment in NC/Nga mice.¹³

More recently, Abbaszadeh et al. have suggested that melatonin has the potential to enhance the therapeutic ratio in radiation oncology, and to be more effective at reducing skin damage in this setting when used in optimal and non-toxic doses.²

Pigmentation disorders

Melatonin and serotonin are thought to have potential to ameliorate or attenuate the spread of vitiligo.¹ In addition, melatonin appears to have potential in the realm of hyperpigmentation treatment. Investigators have found that the combination of topical melatonin 5% and a daily dose of 3 g of oral melatonin over 120 days significantly reduces Melasma Area Severity Index scores in comparison to placebo; the improvement is attributed primarily to the use of topical melatonin.^14,15

Androgenetic alopecia

In 2018, Hatem et al. designed nanostructured lipid carriers to better deliver melatonin in antioxidant oils to treat androgenic alopecia. They found that the carriers achieved a sustained release of 6 hours and raised the skin deposition of melatonin 4.5-fold in the stratum corneum, 7-fold in the epidermis, and 6.8-fold in the dermis compared with a melatonin solution. The nanostructured lipid carriers also improved on clinical results, compared to the melatonin formula, by increasing hair density and thickness and reducing hair loss in patients with androgenic alopecia.¹⁶

Conclusion

Studies in humans have shown that melatonin has particular relevance in dermatology given its demonstrated anti-inflammatory, antioxidant, and anti-aging activity through systemic administration and, particularly, topical application. Demonstrated to be safe and effective, topically applied melatonin appears to warrant serious consideration as a skin-protective, anti-aging tool in the dermatologic armamentarium.

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Slominski AT et al. J Invest Dermatol. 2018 Mar;138(3):490-9.

2. Abbaszadeh A et al. J Biomed Phys Eng. 2017 Jun;7(2):127-136.

3. Fischer T et al. Hautarzt. 1999 Jan;50(1):5-11.

4. Scheuer C. Dan Med J. 2017 Jun;64(6). pii:B5358.

5. Bangha E et al. Arch Dermatol Res. 1996 Aug;288(9):522-6.

6. Bangha E et al. Dermatology. 1997;195(3):248-52.

7. Bangha E et al. Skin Pharmacol. 1997;10(5-6):298-302.

8. Dreher F et al. Br J Dermatol. 1998 Aug;139(2):332-9.

9. Dreher F et al. Dermatology. 1999;198(1):52-5.

10. Fischer TW et al. Skin Pharmacol Physiol. 2004 Jul-Aug;17(4):190-4.

11. Sener G et al. J Pineal Res. 2006 Apr;40(3):280-7.

12. Ozler M et al. Scand J Clin Lab Invest. 2010 Oct;70(6):447-52.

13. Kim TH et al. J Pineal Res. 2009 Nov;47(4):324-9.

14. Juhasz MLW et al. J Cosmet Dermatol. 2018 Dec;17(6):1144-57.

15. Hamadi SA, Mohammed MM, Aljaf AN, et al. The role of topical and oral melatonin in management of melasma patients. J Arab Univ Basic Appl Sci. 2009;8:30‐42.

16. Hatem S et al. Expert Opin Drug Deliv. 2018 Oct;15(10):927-35.

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.