For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

 

 

CHALLENGES OF VACCINATION

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

 

 

Is there a best screening protocol?

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

 

 

CHALLENGES OF VACCINATION

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

 

 

Is there a best screening protocol?

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

 

 

CHALLENGES OF VACCINATION

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

 

 

Is there a best screening protocol?

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

A 45-year-old comes to the emergency department because of abdominal pain for the last few months. She has been belching and hiccuping, and she has lost 20 pounds.

A 45-year-old comes to the emergency department, where a CT scan shows a large mass in her stomach. There also are enlarged lymph nodes nearby and far away, and the wall of her abdomen is studded with smaller tumors.

A 45-year-old comes to the emergency department and is told she needs to be admitted to the hospital to work this up. It’s likely cancer, she is told, but the only way to confirm the diagnosis is with a biopsy. They do a procedure in which they insert a camera through her mouth and down her esophagus, and they take a sample of the large mass in her stomach. It is cancer – and it’s widely metastatic.

The resident on her team sends me a text. She wants to know: “What do you do in cases like this?”

Except she is not asking for my advice on medical management. The same day the patient is told it’s cancer, she has a confession. She has no insurance.

I read the text, then turn to the oncology case manager sitting next to me. We talk it through and the answer is as I suspected.

“She can be seen in the county clinic,” I text back, and give the name of an oncologist there. “Or, she can apply for emergency Medi-Cal to follow up at our hospital. But that process can take over a month to get approval.”

Except the case manager looks into it further. Actually, she does not qualify for emergency Medi-Cal because she invoked it earlier that year when she had an infection.

When it’s an emergency, hospitals tend to handle this kind of situation well. I’ve seen hospitals absorb the costs of major medical interventions when a person is acutely ill. They call it a charity case, and they cover all the costs of acute illness and treatment when the patient cannot.

But what this person needs is different. The treatment she needs is not emergent. What she needs is a regular oncologist who can give chemotherapy, monitor for side effects, check her blood counts, get regular scans to monitor the disease, and have conversations with her to navigate the bigger questions. What she needs is an ongoing relationship.

That is harder for a hospital to absorb.

I think back to a year ago, when I was volunteering at the free clinic. A 77-year-old man came in complaining of increased urinary frequency. I did a rectal exam, and I felt it: a large, irregular prostate mass. I thought of all I would normally do, down the algorithm of treatment – I’d order a PSA blood test, arrange for him to have a biopsy, likely get a CT scan, then get him back in the clinic to start treatment. But there, I could not do any of that. There, I was lucky when I could get someone a $4 medication. There, all I could do was hand him the truth. “I am concerned you have prostate cancer,” I said.

I remember how he began crying tears of joy. “God bless you,” he said, grabbing my hand. God bless me? For what? For handing him a problem but no solution? For sharing a suspicion of a diagnosis that could kill him but being unable to intervene? Is it really better knowing?

I deliver a lot of bad news in oncology, but I usually get to blame the disease. The cancer is aggressive. The cancer is causing your pain.

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

A 45-year-old comes to the emergency department because of abdominal pain for the last few months. She has been belching and hiccuping, and she has lost 20 pounds.

A 45-year-old comes to the emergency department, where a CT scan shows a large mass in her stomach. There also are enlarged lymph nodes nearby and far away, and the wall of her abdomen is studded with smaller tumors.

A 45-year-old comes to the emergency department and is told she needs to be admitted to the hospital to work this up. It’s likely cancer, she is told, but the only way to confirm the diagnosis is with a biopsy. They do a procedure in which they insert a camera through her mouth and down her esophagus, and they take a sample of the large mass in her stomach. It is cancer – and it’s widely metastatic.

The resident on her team sends me a text. She wants to know: “What do you do in cases like this?”

Except she is not asking for my advice on medical management. The same day the patient is told it’s cancer, she has a confession. She has no insurance.

I read the text, then turn to the oncology case manager sitting next to me. We talk it through and the answer is as I suspected.

“She can be seen in the county clinic,” I text back, and give the name of an oncologist there. “Or, she can apply for emergency Medi-Cal to follow up at our hospital. But that process can take over a month to get approval.”

Except the case manager looks into it further. Actually, she does not qualify for emergency Medi-Cal because she invoked it earlier that year when she had an infection.

When it’s an emergency, hospitals tend to handle this kind of situation well. I’ve seen hospitals absorb the costs of major medical interventions when a person is acutely ill. They call it a charity case, and they cover all the costs of acute illness and treatment when the patient cannot.

But what this person needs is different. The treatment she needs is not emergent. What she needs is a regular oncologist who can give chemotherapy, monitor for side effects, check her blood counts, get regular scans to monitor the disease, and have conversations with her to navigate the bigger questions. What she needs is an ongoing relationship.

That is harder for a hospital to absorb.

I think back to a year ago, when I was volunteering at the free clinic. A 77-year-old man came in complaining of increased urinary frequency. I did a rectal exam, and I felt it: a large, irregular prostate mass. I thought of all I would normally do, down the algorithm of treatment – I’d order a PSA blood test, arrange for him to have a biopsy, likely get a CT scan, then get him back in the clinic to start treatment. But there, I could not do any of that. There, I was lucky when I could get someone a $4 medication. There, all I could do was hand him the truth. “I am concerned you have prostate cancer,” I said.

I remember how he began crying tears of joy. “God bless you,” he said, grabbing my hand. God bless me? For what? For handing him a problem but no solution? For sharing a suspicion of a diagnosis that could kill him but being unable to intervene? Is it really better knowing?

I deliver a lot of bad news in oncology, but I usually get to blame the disease. The cancer is aggressive. The cancer is causing your pain.

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

A 45-year-old comes to the emergency department because of abdominal pain for the last few months. She has been belching and hiccuping, and she has lost 20 pounds.

A 45-year-old comes to the emergency department, where a CT scan shows a large mass in her stomach. There also are enlarged lymph nodes nearby and far away, and the wall of her abdomen is studded with smaller tumors.

A 45-year-old comes to the emergency department and is told she needs to be admitted to the hospital to work this up. It’s likely cancer, she is told, but the only way to confirm the diagnosis is with a biopsy. They do a procedure in which they insert a camera through her mouth and down her esophagus, and they take a sample of the large mass in her stomach. It is cancer – and it’s widely metastatic.

The resident on her team sends me a text. She wants to know: “What do you do in cases like this?”

Except she is not asking for my advice on medical management. The same day the patient is told it’s cancer, she has a confession. She has no insurance.

I read the text, then turn to the oncology case manager sitting next to me. We talk it through and the answer is as I suspected.

“She can be seen in the county clinic,” I text back, and give the name of an oncologist there. “Or, she can apply for emergency Medi-Cal to follow up at our hospital. But that process can take over a month to get approval.”

Except the case manager looks into it further. Actually, she does not qualify for emergency Medi-Cal because she invoked it earlier that year when she had an infection.

When it’s an emergency, hospitals tend to handle this kind of situation well. I’ve seen hospitals absorb the costs of major medical interventions when a person is acutely ill. They call it a charity case, and they cover all the costs of acute illness and treatment when the patient cannot.

But what this person needs is different. The treatment she needs is not emergent. What she needs is a regular oncologist who can give chemotherapy, monitor for side effects, check her blood counts, get regular scans to monitor the disease, and have conversations with her to navigate the bigger questions. What she needs is an ongoing relationship.

That is harder for a hospital to absorb.

I think back to a year ago, when I was volunteering at the free clinic. A 77-year-old man came in complaining of increased urinary frequency. I did a rectal exam, and I felt it: a large, irregular prostate mass. I thought of all I would normally do, down the algorithm of treatment – I’d order a PSA blood test, arrange for him to have a biopsy, likely get a CT scan, then get him back in the clinic to start treatment. But there, I could not do any of that. There, I was lucky when I could get someone a $4 medication. There, all I could do was hand him the truth. “I am concerned you have prostate cancer,” I said.

I remember how he began crying tears of joy. “God bless you,” he said, grabbing my hand. God bless me? For what? For handing him a problem but no solution? For sharing a suspicion of a diagnosis that could kill him but being unable to intervene? Is it really better knowing?

I deliver a lot of bad news in oncology, but I usually get to blame the disease. The cancer is aggressive. The cancer is causing your pain.

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

Recall that melatonin displays multiple biological functions, acting as an antioxidant, cytokine, neurotransmitter, and global regulator of the circadian clock, the latter for which it is best known.^1-3 At the cutaneous level, melatonin exhibits antioxidant (direct, as a radical scavenger; indirect, through upregulating antioxidant enzymes), anti-inflammatory, photoprotective, tissue regenerative, and cytoprotective activity, particularly in its capacity to preserve mitochondrial function.^4-8

Melatonin also protects skin homeostasis,⁶ and, consequently, is believed to act against carcinogenesis and potentially other deleterious dysfunctions such as hyperproliferative/inflammatory conditions.⁵ Notably, functional melatonin receptors are expressed in human skin and hair follicles, where melatonin is also produced, further buttressing the critical role that melatonin plays in skin health.⁵ Melatonin also displays immunomodulatory, thermoregulatory, and antitumor functions.⁹ The topical application of melatonin has been demonstrated to diminish markers of reactive oxygen species as well as reverse manifestations of cutaneous aging.⁵

Melatonin is both produced by and metabolized in the skin. The hormone and its metabolites (6-hydroxymelatonin, N¹-acetyl-N²-formyl-5-methoxykynuramine [AFMK], N-acetyl-serotonin, and 5-methoxytryptamine) reduce UVB-induced oxidative cell damage in human keratinocytes and melanocytes, and also act as radioprotectors.⁶

Melatonin has been shown to protect human dermal fibroblasts from UVA- and UVB-induced damage.⁹ In addition, melatonin and its metabolites have been demonstrated to suppress the growth of cultured human melanomas, and high doses of melatonin used in clinical trials in late metastatic melanoma stages have enhanced the efficacy of or diminished the side effects of chemotherapy/chemo-immunotherapy.⁹

UVB and melatonin in the lab

In a 2018 hairless mouse study in which animals were irradiated by UVB for 8 weeks, Park et al. showed that melatonin displays anti-wrinkle activity by suppressing reactive oxygen species- and sonic hedgehog-mediated inflammatory proteins. Melatonin also protected against transepidermal water loss and prevented epidermal thickness as well as dermal collagen degradation.¹⁰

Also that year, Skobowiat et al. found that the topical application of melatonin and its active derivatives (N1-acetyl-N2-formyl-5-methoxykynurenine and N-acetylserotonin) yielded photoprotective effects pre- and post-UVB treatment in human and porcine skin ex vivo. They concluded that their results justify additional investigation of the clinical applications of melatonin and its metabolites for its potential to exert protective effects against UVB in human subjects.⁸

Although the preponderance of previous work identifies melatonin as a strong antioxidant, Kocyigit et al. reported in 2018 on new in vitro studies suggesting that melatonin dose-dependently exerts cytotoxic and apoptotic activity on several cell types, including both human epidermoid carcinoma and normal skin fibroblasts. Their findings showed that melatonin exhibited proliferative effects on cancerous and normal cells at low doses and cytotoxic effects at high doses.¹¹
 

Melatonin as a sunscreen ingredient

Further supporting its use in the topical armamentarium for skin health, melatonin is a key ingredient in a sunscreen formulation, the creation of which was driven by the need to protect the skin of military personnel facing lengthy UV exposure. Specifically, the formulation containing avobenzone, octinoxate, oxybenzone, and titanium dioxide along with melatonin and pumpkin seed oil underwent a preclinical safety evaluation in 2017, as reported by Bora et al. The formulation was found to be nonmutagenic, nontoxic, and safe in animal models and is deemed ready to test for its efficacy in humans.¹² Melatonin is also among a host of systemic treatment options for skin lightening.¹³

Oral and topical melatonin in human studies

In a 2017 study on the impact of melatonin treatment on the skin of former smokers, Sagan et al. assessed oxidative damage to membrane lipids in blood serum and in epidermis exfoliated during microdermabrasion (at baseline, 2 weeks after, and 4 weeks after treatment) in postmenopausal women. Never smokers (n = 44) and former smokers (n = 46) were divided into control, melatonin topical, antioxidant topical, and melatonin oral treatment groups. The investigators found that after only 2 weeks, melatonin oral treatment significantly reversed the elevated serum lipid peroxidation in former smokers. Oral melatonin increased elasticity, moisture, and sebum levels after 4 weeks of treatment and topical melatonin increased sebum level. They concluded that the use of exogenous melatonin reverses the effects of oxidative damage to membrane lipids and ameliorates cutaneous biophysical traits in postmenopausal women who once smoked. The researchers added that melatonin use for all former smokers is warranted and that topically applied melatonin merits consideration for improving the effects of facial microdermabrasion.¹⁴

In a systematic literature review in 2017, Scheuer identified 20 studies (4 human and 16 experimental) indicating that melatonin exerts a protective effect against artificial UV-induced erythema when applied pre-exposure.⁷ Also that year, Scheuer and colleagues conducted randomized, double-blind, placebo-controlled work demonstrating that topical melatonin (12.5%) significantly reduced erythema resulting from natural sunlight, and in a separate randomized, double-blind, placebo-controlled crossover study that the same concentration of a full body application of melatonin exhibited no significant impact on cognition and should be considered safe for dermal application.⁷ Scheuer added that additional longitudinal research is needed to ascertain effects of topical melatonin usage over time.

Early in 2018, Milani and Sparavigna reported on a randomized, split-face, assessor-blinded, prospective 3-month study of 22 women (mean age 55 years) with moderate to severe facial skin aging; the study was designed to test the efficacy of melatonin-based day and night creams. All of the women completed the proof-of-concept trial in which crow’s feet were found to be significantly diminished on the sides of the face treated with the creams compared with the nontreated skin.

Image Source/getty images

Conclusion

The majority of research on the potent hormone melatonin over nearly the last quarter century indicates that this dynamic substance provides multifaceted benefits in performing several biological functions. Topical melatonin is available over the counter. Its expanded use in skin care warrants greater attention as we learn more about this versatile endogenous substance.

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 dermnews@mdedge.com.

References

1. Zmijewski MA et al. Dermatoendocrinol. 2011 Jan;3(1):3-10.

2. Slominski A et al. Trends Endocrinol Metab. 2008 Jan;19(1):17-24.

3. Slominski A et al. J Cell Physiol. 2003 Jul;196(1):144-53.

4. Milani M et al. Clin Cosmet Investig Dermatol. 2018 Jan 24;11:51-7.

5. Day D et al. J Drugs Dermatol. 2018 Sep 1;17(9):966-9.

6. Slominski AT et al. Cell Mol Life Sci. 2017 Nov;74(21):3913-25.

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

8. Skobowiat C et al. J Pineal Res. 2018 Sep;65(2):e12501.

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

10. Park EK et al. Int J Mol Sci. 2018 Jul 8;19(7). pii: E1995.

11. Kocyigit A et al. Mutat Res. 2018 May-Jun;829-30:50-60.

12. Bora NS et al. Regul Toxicol Pharmacol. 2017 Oct;89:1-12.

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

14. Sagan D et al. Ann Agric Environ Med. 2017 Dec 23;24(4):659-66.

Recall that melatonin displays multiple biological functions, acting as an antioxidant, cytokine, neurotransmitter, and global regulator of the circadian clock, the latter for which it is best known.^1-3 At the cutaneous level, melatonin exhibits antioxidant (direct, as a radical scavenger; indirect, through upregulating antioxidant enzymes), anti-inflammatory, photoprotective, tissue regenerative, and cytoprotective activity, particularly in its capacity to preserve mitochondrial function.^4-8

Melatonin also protects skin homeostasis,⁶ and, consequently, is believed to act against carcinogenesis and potentially other deleterious dysfunctions such as hyperproliferative/inflammatory conditions.⁵ Notably, functional melatonin receptors are expressed in human skin and hair follicles, where melatonin is also produced, further buttressing the critical role that melatonin plays in skin health.⁵ Melatonin also displays immunomodulatory, thermoregulatory, and antitumor functions.⁹ The topical application of melatonin has been demonstrated to diminish markers of reactive oxygen species as well as reverse manifestations of cutaneous aging.⁵

Melatonin is both produced by and metabolized in the skin. The hormone and its metabolites (6-hydroxymelatonin, N¹-acetyl-N²-formyl-5-methoxykynuramine [AFMK], N-acetyl-serotonin, and 5-methoxytryptamine) reduce UVB-induced oxidative cell damage in human keratinocytes and melanocytes, and also act as radioprotectors.⁶

Melatonin has been shown to protect human dermal fibroblasts from UVA- and UVB-induced damage.⁹ In addition, melatonin and its metabolites have been demonstrated to suppress the growth of cultured human melanomas, and high doses of melatonin used in clinical trials in late metastatic melanoma stages have enhanced the efficacy of or diminished the side effects of chemotherapy/chemo-immunotherapy.⁹

UVB and melatonin in the lab

In a 2018 hairless mouse study in which animals were irradiated by UVB for 8 weeks, Park et al. showed that melatonin displays anti-wrinkle activity by suppressing reactive oxygen species- and sonic hedgehog-mediated inflammatory proteins. Melatonin also protected against transepidermal water loss and prevented epidermal thickness as well as dermal collagen degradation.¹⁰

Also that year, Skobowiat et al. found that the topical application of melatonin and its active derivatives (N1-acetyl-N2-formyl-5-methoxykynurenine and N-acetylserotonin) yielded photoprotective effects pre- and post-UVB treatment in human and porcine skin ex vivo. They concluded that their results justify additional investigation of the clinical applications of melatonin and its metabolites for its potential to exert protective effects against UVB in human subjects.⁸

Although the preponderance of previous work identifies melatonin as a strong antioxidant, Kocyigit et al. reported in 2018 on new in vitro studies suggesting that melatonin dose-dependently exerts cytotoxic and apoptotic activity on several cell types, including both human epidermoid carcinoma and normal skin fibroblasts. Their findings showed that melatonin exhibited proliferative effects on cancerous and normal cells at low doses and cytotoxic effects at high doses.¹¹
 

Melatonin as a sunscreen ingredient

Further supporting its use in the topical armamentarium for skin health, melatonin is a key ingredient in a sunscreen formulation, the creation of which was driven by the need to protect the skin of military personnel facing lengthy UV exposure. Specifically, the formulation containing avobenzone, octinoxate, oxybenzone, and titanium dioxide along with melatonin and pumpkin seed oil underwent a preclinical safety evaluation in 2017, as reported by Bora et al. The formulation was found to be nonmutagenic, nontoxic, and safe in animal models and is deemed ready to test for its efficacy in humans.¹² Melatonin is also among a host of systemic treatment options for skin lightening.¹³

Oral and topical melatonin in human studies

In a 2017 study on the impact of melatonin treatment on the skin of former smokers, Sagan et al. assessed oxidative damage to membrane lipids in blood serum and in epidermis exfoliated during microdermabrasion (at baseline, 2 weeks after, and 4 weeks after treatment) in postmenopausal women. Never smokers (n = 44) and former smokers (n = 46) were divided into control, melatonin topical, antioxidant topical, and melatonin oral treatment groups. The investigators found that after only 2 weeks, melatonin oral treatment significantly reversed the elevated serum lipid peroxidation in former smokers. Oral melatonin increased elasticity, moisture, and sebum levels after 4 weeks of treatment and topical melatonin increased sebum level. They concluded that the use of exogenous melatonin reverses the effects of oxidative damage to membrane lipids and ameliorates cutaneous biophysical traits in postmenopausal women who once smoked. The researchers added that melatonin use for all former smokers is warranted and that topically applied melatonin merits consideration for improving the effects of facial microdermabrasion.¹⁴

In a systematic literature review in 2017, Scheuer identified 20 studies (4 human and 16 experimental) indicating that melatonin exerts a protective effect against artificial UV-induced erythema when applied pre-exposure.⁷ Also that year, Scheuer and colleagues conducted randomized, double-blind, placebo-controlled work demonstrating that topical melatonin (12.5%) significantly reduced erythema resulting from natural sunlight, and in a separate randomized, double-blind, placebo-controlled crossover study that the same concentration of a full body application of melatonin exhibited no significant impact on cognition and should be considered safe for dermal application.⁷ Scheuer added that additional longitudinal research is needed to ascertain effects of topical melatonin usage over time.

Early in 2018, Milani and Sparavigna reported on a randomized, split-face, assessor-blinded, prospective 3-month study of 22 women (mean age 55 years) with moderate to severe facial skin aging; the study was designed to test the efficacy of melatonin-based day and night creams. All of the women completed the proof-of-concept trial in which crow’s feet were found to be significantly diminished on the sides of the face treated with the creams compared with the nontreated skin.

Image Source/getty images

Conclusion

The majority of research on the potent hormone melatonin over nearly the last quarter century indicates that this dynamic substance provides multifaceted benefits in performing several biological functions. Topical melatonin is available over the counter. Its expanded use in skin care warrants greater attention as we learn more about this versatile endogenous substance.

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 dermnews@mdedge.com.

References

1. Zmijewski MA et al. Dermatoendocrinol. 2011 Jan;3(1):3-10.

2. Slominski A et al. Trends Endocrinol Metab. 2008 Jan;19(1):17-24.

3. Slominski A et al. J Cell Physiol. 2003 Jul;196(1):144-53.

4. Milani M et al. Clin Cosmet Investig Dermatol. 2018 Jan 24;11:51-7.

5. Day D et al. J Drugs Dermatol. 2018 Sep 1;17(9):966-9.

6. Slominski AT et al. Cell Mol Life Sci. 2017 Nov;74(21):3913-25.

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

8. Skobowiat C et al. J Pineal Res. 2018 Sep;65(2):e12501.

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

10. Park EK et al. Int J Mol Sci. 2018 Jul 8;19(7). pii: E1995.

11. Kocyigit A et al. Mutat Res. 2018 May-Jun;829-30:50-60.

12. Bora NS et al. Regul Toxicol Pharmacol. 2017 Oct;89:1-12.

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

14. Sagan D et al. Ann Agric Environ Med. 2017 Dec 23;24(4):659-66.

Recall that melatonin displays multiple biological functions, acting as an antioxidant, cytokine, neurotransmitter, and global regulator of the circadian clock, the latter for which it is best known.^1-3 At the cutaneous level, melatonin exhibits antioxidant (direct, as a radical scavenger; indirect, through upregulating antioxidant enzymes), anti-inflammatory, photoprotective, tissue regenerative, and cytoprotective activity, particularly in its capacity to preserve mitochondrial function.^4-8

Melatonin also protects skin homeostasis,⁶ and, consequently, is believed to act against carcinogenesis and potentially other deleterious dysfunctions such as hyperproliferative/inflammatory conditions.⁵ Notably, functional melatonin receptors are expressed in human skin and hair follicles, where melatonin is also produced, further buttressing the critical role that melatonin plays in skin health.⁵ Melatonin also displays immunomodulatory, thermoregulatory, and antitumor functions.⁹ The topical application of melatonin has been demonstrated to diminish markers of reactive oxygen species as well as reverse manifestations of cutaneous aging.⁵

Melatonin is both produced by and metabolized in the skin. The hormone and its metabolites (6-hydroxymelatonin, N¹-acetyl-N²-formyl-5-methoxykynuramine [AFMK], N-acetyl-serotonin, and 5-methoxytryptamine) reduce UVB-induced oxidative cell damage in human keratinocytes and melanocytes, and also act as radioprotectors.⁶

Melatonin has been shown to protect human dermal fibroblasts from UVA- and UVB-induced damage.⁹ In addition, melatonin and its metabolites have been demonstrated to suppress the growth of cultured human melanomas, and high doses of melatonin used in clinical trials in late metastatic melanoma stages have enhanced the efficacy of or diminished the side effects of chemotherapy/chemo-immunotherapy.⁹

UVB and melatonin in the lab

In a 2018 hairless mouse study in which animals were irradiated by UVB for 8 weeks, Park et al. showed that melatonin displays anti-wrinkle activity by suppressing reactive oxygen species- and sonic hedgehog-mediated inflammatory proteins. Melatonin also protected against transepidermal water loss and prevented epidermal thickness as well as dermal collagen degradation.¹⁰

Also that year, Skobowiat et al. found that the topical application of melatonin and its active derivatives (N1-acetyl-N2-formyl-5-methoxykynurenine and N-acetylserotonin) yielded photoprotective effects pre- and post-UVB treatment in human and porcine skin ex vivo. They concluded that their results justify additional investigation of the clinical applications of melatonin and its metabolites for its potential to exert protective effects against UVB in human subjects.⁸

Although the preponderance of previous work identifies melatonin as a strong antioxidant, Kocyigit et al. reported in 2018 on new in vitro studies suggesting that melatonin dose-dependently exerts cytotoxic and apoptotic activity on several cell types, including both human epidermoid carcinoma and normal skin fibroblasts. Their findings showed that melatonin exhibited proliferative effects on cancerous and normal cells at low doses and cytotoxic effects at high doses.¹¹
 

Melatonin as a sunscreen ingredient

Further supporting its use in the topical armamentarium for skin health, melatonin is a key ingredient in a sunscreen formulation, the creation of which was driven by the need to protect the skin of military personnel facing lengthy UV exposure. Specifically, the formulation containing avobenzone, octinoxate, oxybenzone, and titanium dioxide along with melatonin and pumpkin seed oil underwent a preclinical safety evaluation in 2017, as reported by Bora et al. The formulation was found to be nonmutagenic, nontoxic, and safe in animal models and is deemed ready to test for its efficacy in humans.¹² Melatonin is also among a host of systemic treatment options for skin lightening.¹³

Oral and topical melatonin in human studies

In a 2017 study on the impact of melatonin treatment on the skin of former smokers, Sagan et al. assessed oxidative damage to membrane lipids in blood serum and in epidermis exfoliated during microdermabrasion (at baseline, 2 weeks after, and 4 weeks after treatment) in postmenopausal women. Never smokers (n = 44) and former smokers (n = 46) were divided into control, melatonin topical, antioxidant topical, and melatonin oral treatment groups. The investigators found that after only 2 weeks, melatonin oral treatment significantly reversed the elevated serum lipid peroxidation in former smokers. Oral melatonin increased elasticity, moisture, and sebum levels after 4 weeks of treatment and topical melatonin increased sebum level. They concluded that the use of exogenous melatonin reverses the effects of oxidative damage to membrane lipids and ameliorates cutaneous biophysical traits in postmenopausal women who once smoked. The researchers added that melatonin use for all former smokers is warranted and that topically applied melatonin merits consideration for improving the effects of facial microdermabrasion.¹⁴

In a systematic literature review in 2017, Scheuer identified 20 studies (4 human and 16 experimental) indicating that melatonin exerts a protective effect against artificial UV-induced erythema when applied pre-exposure.⁷ Also that year, Scheuer and colleagues conducted randomized, double-blind, placebo-controlled work demonstrating that topical melatonin (12.5%) significantly reduced erythema resulting from natural sunlight, and in a separate randomized, double-blind, placebo-controlled crossover study that the same concentration of a full body application of melatonin exhibited no significant impact on cognition and should be considered safe for dermal application.⁷ Scheuer added that additional longitudinal research is needed to ascertain effects of topical melatonin usage over time.

Early in 2018, Milani and Sparavigna reported on a randomized, split-face, assessor-blinded, prospective 3-month study of 22 women (mean age 55 years) with moderate to severe facial skin aging; the study was designed to test the efficacy of melatonin-based day and night creams. All of the women completed the proof-of-concept trial in which crow’s feet were found to be significantly diminished on the sides of the face treated with the creams compared with the nontreated skin.

Image Source/getty images

Conclusion

The majority of research on the potent hormone melatonin over nearly the last quarter century indicates that this dynamic substance provides multifaceted benefits in performing several biological functions. Topical melatonin is available over the counter. Its expanded use in skin care warrants greater attention as we learn more about this versatile endogenous substance.

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 dermnews@mdedge.com.

References

1. Zmijewski MA et al. Dermatoendocrinol. 2011 Jan;3(1):3-10.

2. Slominski A et al. Trends Endocrinol Metab. 2008 Jan;19(1):17-24.

3. Slominski A et al. J Cell Physiol. 2003 Jul;196(1):144-53.

4. Milani M et al. Clin Cosmet Investig Dermatol. 2018 Jan 24;11:51-7.

5. Day D et al. J Drugs Dermatol. 2018 Sep 1;17(9):966-9.

6. Slominski AT et al. Cell Mol Life Sci. 2017 Nov;74(21):3913-25.

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

8. Skobowiat C et al. J Pineal Res. 2018 Sep;65(2):e12501.

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

10. Park EK et al. Int J Mol Sci. 2018 Jul 8;19(7). pii: E1995.

11. Kocyigit A et al. Mutat Res. 2018 May-Jun;829-30:50-60.

12. Bora NS et al. Regul Toxicol Pharmacol. 2017 Oct;89:1-12.

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

14. Sagan D et al. Ann Agric Environ Med. 2017 Dec 23;24(4):659-66.

The complete blood cell count (CBC) is one of the most frequently ordered laboratory tests in both the inpatient and outpatient settings. Not long ago, the CBC required peering through a microscope and counting the red blood cells, white blood cells, and platelets. These 3 numbers are still the primary purpose of the test.

Now, with automated counters, the CBC report also contains other numbers that delineate characteristics of each cell type. For example:

The mean corpuscular volume is the average volume of red blood cells. Providers use it to classify anemia as either microcytic, normocytic, or macrocytic, each with its own differential diagnosis.

The differential white blood cell count provides absolute counts and relative percentages of each type of leukocyte. For example, the absolute neutrophil count is an important measure of immunocompetence.

But other values in the CBC may be overlooked, even though they can provide important information. Here, we highlight 3 of them:

• The red blood cell distribution width (RDW)
• The mean platelet volume (MPV)
• The nucleated red blood cell (NRBC) count.

In addition to describing their diagnostic utility, we also discuss emerging evidence of their potential prognostic significance in hematologic and nonhematologic disorders. By incorporating an awareness of their value in clinical practice, providers can maximize the usefulness of the CBC.

RED BLOOD CELL DISTRIBUTION WIDTH

The RDW is a measure of variation (anisocytosis) in the size of the circulating red cells. The term “width” is misleading, as the value is not derived from the width of the red blood cell, but rather from the width of the distribution curve of the corpuscular volume (Figure 1). Therefore, a normal RDW means that the cells are all about the same size, while a high RDW means they vary widely in size.

The RDW can be calculated either as a coefficient of variation, with a reference range of 11% to 16% depending on the laboratory, or, less often, as a standard deviation, with a reference range of 39 to 46 fL.

The RDW can differentiate between causes of anemia

A high RDW is often found in nutritional deficiencies of iron, vitamin B₁₂, and folate. This information is helpful in differentiating the cause of microcytic anemia, as a high RDW suggests iron-deficiency anemia while a normal RDW suggests thalassemia.¹ In iron deficiency, the RDW often rises before the mean corpuscular volume falls, serving as an early diagnostic clue.

The RDW can also be high after recent hemorrhage or rapid hemolysis, as the acute drop in hemoglobin results in increased production of reticulocytes, which are larger than mature erythrocytes.

Because a range of disorders can elevate the RDW, reviewing the peripheral blood smear is an important next step in the diagnostic evaluation, specifically looking for reticulocytes, microspherocytes, and other abnormal red blood cells contributing to the RDW elevation.

A normal RDW is less diagnostically useful. It indicates the red blood cells are of uniform size, but they may be uniformly small or large depending on how long the anemia has persisted. Since red cells circulate for only about 120 days, patients who have severe iron-deficiency anemia for months to years are expected to have a normal rather than a high RDW, as their red cells of normal size have all been replaced by microcytes.

A low RDW is not consistently associated with any hematologic disorder.

RDW may have prognostic value

Emerging data suggest that the RDW may also have prognostic value in nonhematologic diseases. In a retrospective study of 15,852 adult participants in the Third National Health and Nutrition Examination Survey (1988–1994), a higher RDW was associated with a higher risk of death, with the all-cause mortality rate increasing by 23% for every 1% increment in RDW.²

This correlation is particularly prominent in cardiac disorders. In 2 large retrospective studies of patients with symptomatic heart failure, a higher RDW was a strong predictor of morbidity and death (hazard ratio 1.17 per 1-standard deviation increase, P < .001), even stronger than more commonly used variables such as ejection fraction, New York Heart Association functional class, and renal function.³

In a retrospective analysis of 4,111 patients with myocardial infarction, the degree of RDW elevation correlated with the risk of repeat nonfatal myocardial infarction, coronary death, new symptomatic heart failure, and stroke.⁴

It is hypothesized that high RDW may reflect poor cell membrane integrity from altered cholesterol content, which in turn has deleterious effects on multiple organ systems and is therefore associated with adverse outcomes.⁵

Currently, using the RDW to assess prognosis remains investigational, and how best to interpret it in daily practice requires further study.

 

 

MEAN PLATELET VOLUME

The MPV, ie, the average size of platelets, is reported in femtoliters (fL). Because the MPV varies depending on the instrument used, each laboratory has a unique reference range, usually about 8 to 12 fL. The MPV must be interpreted in conjunction with the platelet count; the product of the MPV and platelet count is called the total platelet mass.

Using the MPV to find the cause of thrombocytopenia

The MPV can be used to help narrow the differential diagnosis of thrombocytopenia. For example, it is high in thrombocytopenia resulting from peripheral destruction, as in immune thrombocytopenic purpura. This is because as platelets are lost, thrombopoietin production increases and new, larger platelets are released from healthy megakaryocytes in an attempt to increase the total platelet mass.

In contrast, the MPV is low in patients with thrombocytopenia due to megakaryocyte hypoplasia, as malfunctioning megakaryocytes cannot maintain the total platelet mass, and any platelets produced remain small. This distinction can be obscured in the setting of splenomegaly, as larger platelets are more easily sequestered in the spleen and the MPV may therefore be low or normal.

The MPV can also be used to differentiate congenital thrombocytopenic disorders, which can be characterized by either a high MPV (eg, gray platelet syndrome, Bernard-Soulier syndrome) or a low MPV (eg, Wiskott-Aldrich syndrome) (Figure 2).

MPV may have prognostic value

Evidence suggests that the MPV also has potential prognostic value, particularly in vascular disease, as larger platelets are hypothesized to have increased hemostatic potential.

In a large meta-analysis of patients with coronary artery disease, a high MPV was associated with worse outcomes; the risk of death or myocardial infarction was 17% higher in those with a high MPV (the threshold ranged from 8.4 to 11.7 fL in the different studies) than in those with a low MPV.⁶

In a study of 213 patients with non-ST-segment elevation myocardial infarction, the risk of significant coronary artery disease was 4.18 times higher in patients with a high MPV and a high troponin level than in patients with a normal MPV and a high troponin.⁷ The authors suggested that a high MPV may help identify patients at highest risk of significant coronary artery disease who would benefit from invasive studies (ie, coronary angiography).

This correlation has also been observed in other forms of vascular disease. In 261 patients who underwent carotid angioplasty and stenting, an MPV higher than 10.1 fL was associated with a risk of in-stent restenosis more than 3 times higher.⁸

The MPV has also been found to be higher in patients with type 2 diabetes than in controls, particularly in those with microvascular complications such as retinopathy or microalbuminuria.⁹

Conversely, in patients with cancer, a low MPV appears to be associated with a poor prognosis. In a retrospective analysis of 236 patients with esophageal cancer, those who had an MPV of 7.4 fL or less had significantly shorter overall survival than patients with an MPV higher than 7.4 fL.¹⁰

A low MPV has also been associated with an increased risk of venous thromoboembolism in patients with cancer. In a prospective observational cohort study of 1,544 patients, the 2-year probability of venous thromboembolism was 9% in patients with an MPV less than 10.8 fL, compared with 5.5% in those with higher MPV values. The 2-year overall survival rate was also higher in patients with high MPV than in those with low MPV, at 64.7% vs 55.7%, respectively (P = .001).¹¹

But the MPV is far from a perfect clinical metric. Since its measurement is subject to significant laboratory variation, an abnormal value should always be confirmed with evaluation of a peripheral blood smear. Furthermore, it is unclear why a high MPV portends poor prognosis in patients without cancer, whereas the opposite is true in patients with cancer. Therefore, its role in prognostication remains investigational, and further studies are essential to determine its appropriate usefulness in clinical practice.¹²

NUCLEATED RED BLOOD CELL COUNT

NRBCs are immature red blood cell precursors not present in the circulation of healthy adults. During erythropoiesis, the common myeloid progenitor cell first differentiates into a proerythroblast; subsequently, the chromatin in the nucleus of the proerythroblast gradually condenses until it becomes an orthochromatic erythroblast, also known as a nucleated red cell (Figure 2). Once the nucleus is expelled, the cell is known as a reticulocyte, which ultimately becomes a mature erythrocyte.

Healthy newborns have circulating NRBCs that rapidly disappear within a few weeks of birth. However, NRBCs can return to the circulation in a variety of disease states.

Causes of NRBCs

Brisk hemolysis or rapid blood loss can cause NRBCs to be released into the blood as erythropoiesis increases in an attempt to compensate for acute anemia.

Damage or stress to the bone marrow also causes NRBCs to be released into the peripheral blood, as is often the case in hematologic diseases. In a study of 478 patients with hematologic diseases, the frequency of NRBC positivity at diagnosis was highest in patients with chronic myeloid leukemia (100%), acute leukemia (62%), and myelodysplastic syndromes (45%).¹³ NRBCs also appeared at higher frequencies during chemotherapy in other hematologic conditions, such as hemophagocytic lymphohistiocytosis.

The mechanism by which NRBCs are expelled from the bone marrow is unclear, though studies have suggested that inflammation or hypoxia or both cause increased hematopoietic stress, resulting in the release of immature red cells. Increased concentrations of inflammatory cytokines (interleukin 6 and interleukin 3) and erythropoietin in the plasma and decreased arterial oxygen partial tension have been reported in patients with circulating NRBCs.^14,15

Because they are associated with hematologic disorders, the finding of NRBCs should prompt evaluation of a peripheral smear to assess for abnormalities in other cell lines.

The NRBC count and prognosis

In critically ill patients, peripheral NRBCs can also indicate life-threatening conditions.

In a study of 421 adult intensive care patients, the in-hospital mortality rate was 42% in those with peripheral NRBCs vs 5.9% in those without them.¹⁶ Further, the higher the NRBC count and the more days that NRBCs were reported in the CBC, the higher the risk of death.

In adults with acute respiratory distress syndrome, the finding of any NRBCs in the peripheral blood was an independent risk factor for death, and an NRBC count higher than 220 cells/µL was associated with a more than 3-fold higher risk of death.¹⁷

Daily screening in patients in surgical intensive care units revealed that NRBCs appeared an average of 9 days before death, consistent with an early marker of impending decline.¹⁸

In another study,¹⁹ the risk of death within 90 days of hospital discharge was higher in NRBC-positive patients, reaching 21.9% in those who had a count higher than 200 cells/µL. The risk of unplanned hospital readmission within 30 days was also increased.

Leukoerythroblastosis

The combination of NRBCs and immature white blood cells (eg, myelocytes, metamyelocytes) is called leukoerythroblastosis.

Leukoerythroblastosis is classically seen in myelophthisic anemias in which hematopoietic cells in the marrow are displaced by fibrosis, tumor, or other space-occupying processes, but it can also occur in any situation of acute marrow stress, including critical illness.

In addition, leukoerythroblastosis appears in a rare complication of sickle cell hemoglobinopathies: bone marrow necrosis with fat embolism syndrome.^20,21 As the marrow necroses, fat emboli are released in the systemic circulation causing micro- and macrovascular occlusions and multiorgan failure. The largest case series in the literature reports 58 patients with bone marrow necrosis with fat embolism syndrome.²²

At our institution, we have seen 18 patients with this condition in the past 8 years, with the frequency of diagnosis increasing with heightened awareness of the disorder. We have found that leukoerythroblastosis is often an early marker of this unrecognized syndrome and can prompt emergency red cell exchange, which is considered to be lifesaving in this condition.²²

These examples and many others show that the presence of NRBCs in the CBC can serve as an important clinical warning.

OLD TESTS CAN STILL BE USEFUL

The CBC provides much more than simple cell counts; it is a rich collection of information related to each blood cell. These days, with new diagnostic tests and prognostic tools based on molecular analysis, it is important to not overlook the value of the tests clinicians have been ordering for generations.

The RDW, MPV, and NRBC count will not likely provide definitive or flawless diagnostic or prognostic information, but when understood and used correctly, they provide readily available, cost-effective, and useful data that can supplement and guide clinical decision-making. By understanding the CBC more fully, providers can maximize the truly complete nature of this routine laboratory test.

The complete blood cell count (CBC) is one of the most frequently ordered laboratory tests in both the inpatient and outpatient settings. Not long ago, the CBC required peering through a microscope and counting the red blood cells, white blood cells, and platelets. These 3 numbers are still the primary purpose of the test.

Now, with automated counters, the CBC report also contains other numbers that delineate characteristics of each cell type. For example:

The mean corpuscular volume is the average volume of red blood cells. Providers use it to classify anemia as either microcytic, normocytic, or macrocytic, each with its own differential diagnosis.

The differential white blood cell count provides absolute counts and relative percentages of each type of leukocyte. For example, the absolute neutrophil count is an important measure of immunocompetence.

But other values in the CBC may be overlooked, even though they can provide important information. Here, we highlight 3 of them:

• The red blood cell distribution width (RDW)
• The mean platelet volume (MPV)
• The nucleated red blood cell (NRBC) count.

In addition to describing their diagnostic utility, we also discuss emerging evidence of their potential prognostic significance in hematologic and nonhematologic disorders. By incorporating an awareness of their value in clinical practice, providers can maximize the usefulness of the CBC.

RED BLOOD CELL DISTRIBUTION WIDTH

The RDW is a measure of variation (anisocytosis) in the size of the circulating red cells. The term “width” is misleading, as the value is not derived from the width of the red blood cell, but rather from the width of the distribution curve of the corpuscular volume (Figure 1). Therefore, a normal RDW means that the cells are all about the same size, while a high RDW means they vary widely in size.

The RDW can be calculated either as a coefficient of variation, with a reference range of 11% to 16% depending on the laboratory, or, less often, as a standard deviation, with a reference range of 39 to 46 fL.

The RDW can differentiate between causes of anemia

A high RDW is often found in nutritional deficiencies of iron, vitamin B₁₂, and folate. This information is helpful in differentiating the cause of microcytic anemia, as a high RDW suggests iron-deficiency anemia while a normal RDW suggests thalassemia.¹ In iron deficiency, the RDW often rises before the mean corpuscular volume falls, serving as an early diagnostic clue.

The RDW can also be high after recent hemorrhage or rapid hemolysis, as the acute drop in hemoglobin results in increased production of reticulocytes, which are larger than mature erythrocytes.

Because a range of disorders can elevate the RDW, reviewing the peripheral blood smear is an important next step in the diagnostic evaluation, specifically looking for reticulocytes, microspherocytes, and other abnormal red blood cells contributing to the RDW elevation.

A normal RDW is less diagnostically useful. It indicates the red blood cells are of uniform size, but they may be uniformly small or large depending on how long the anemia has persisted. Since red cells circulate for only about 120 days, patients who have severe iron-deficiency anemia for months to years are expected to have a normal rather than a high RDW, as their red cells of normal size have all been replaced by microcytes.

A low RDW is not consistently associated with any hematologic disorder.

RDW may have prognostic value

Emerging data suggest that the RDW may also have prognostic value in nonhematologic diseases. In a retrospective study of 15,852 adult participants in the Third National Health and Nutrition Examination Survey (1988–1994), a higher RDW was associated with a higher risk of death, with the all-cause mortality rate increasing by 23% for every 1% increment in RDW.²

This correlation is particularly prominent in cardiac disorders. In 2 large retrospective studies of patients with symptomatic heart failure, a higher RDW was a strong predictor of morbidity and death (hazard ratio 1.17 per 1-standard deviation increase, P < .001), even stronger than more commonly used variables such as ejection fraction, New York Heart Association functional class, and renal function.³

In a retrospective analysis of 4,111 patients with myocardial infarction, the degree of RDW elevation correlated with the risk of repeat nonfatal myocardial infarction, coronary death, new symptomatic heart failure, and stroke.⁴

It is hypothesized that high RDW may reflect poor cell membrane integrity from altered cholesterol content, which in turn has deleterious effects on multiple organ systems and is therefore associated with adverse outcomes.⁵

Currently, using the RDW to assess prognosis remains investigational, and how best to interpret it in daily practice requires further study.

 

 

MEAN PLATELET VOLUME

The MPV, ie, the average size of platelets, is reported in femtoliters (fL). Because the MPV varies depending on the instrument used, each laboratory has a unique reference range, usually about 8 to 12 fL. The MPV must be interpreted in conjunction with the platelet count; the product of the MPV and platelet count is called the total platelet mass.

Using the MPV to find the cause of thrombocytopenia

The MPV can be used to help narrow the differential diagnosis of thrombocytopenia. For example, it is high in thrombocytopenia resulting from peripheral destruction, as in immune thrombocytopenic purpura. This is because as platelets are lost, thrombopoietin production increases and new, larger platelets are released from healthy megakaryocytes in an attempt to increase the total platelet mass.

In contrast, the MPV is low in patients with thrombocytopenia due to megakaryocyte hypoplasia, as malfunctioning megakaryocytes cannot maintain the total platelet mass, and any platelets produced remain small. This distinction can be obscured in the setting of splenomegaly, as larger platelets are more easily sequestered in the spleen and the MPV may therefore be low or normal.

The MPV can also be used to differentiate congenital thrombocytopenic disorders, which can be characterized by either a high MPV (eg, gray platelet syndrome, Bernard-Soulier syndrome) or a low MPV (eg, Wiskott-Aldrich syndrome) (Figure 2).

MPV may have prognostic value

Evidence suggests that the MPV also has potential prognostic value, particularly in vascular disease, as larger platelets are hypothesized to have increased hemostatic potential.

In a large meta-analysis of patients with coronary artery disease, a high MPV was associated with worse outcomes; the risk of death or myocardial infarction was 17% higher in those with a high MPV (the threshold ranged from 8.4 to 11.7 fL in the different studies) than in those with a low MPV.⁶

In a study of 213 patients with non-ST-segment elevation myocardial infarction, the risk of significant coronary artery disease was 4.18 times higher in patients with a high MPV and a high troponin level than in patients with a normal MPV and a high troponin.⁷ The authors suggested that a high MPV may help identify patients at highest risk of significant coronary artery disease who would benefit from invasive studies (ie, coronary angiography).

This correlation has also been observed in other forms of vascular disease. In 261 patients who underwent carotid angioplasty and stenting, an MPV higher than 10.1 fL was associated with a risk of in-stent restenosis more than 3 times higher.⁸

The MPV has also been found to be higher in patients with type 2 diabetes than in controls, particularly in those with microvascular complications such as retinopathy or microalbuminuria.⁹

Conversely, in patients with cancer, a low MPV appears to be associated with a poor prognosis. In a retrospective analysis of 236 patients with esophageal cancer, those who had an MPV of 7.4 fL or less had significantly shorter overall survival than patients with an MPV higher than 7.4 fL.¹⁰

A low MPV has also been associated with an increased risk of venous thromoboembolism in patients with cancer. In a prospective observational cohort study of 1,544 patients, the 2-year probability of venous thromboembolism was 9% in patients with an MPV less than 10.8 fL, compared with 5.5% in those with higher MPV values. The 2-year overall survival rate was also higher in patients with high MPV than in those with low MPV, at 64.7% vs 55.7%, respectively (P = .001).¹¹

But the MPV is far from a perfect clinical metric. Since its measurement is subject to significant laboratory variation, an abnormal value should always be confirmed with evaluation of a peripheral blood smear. Furthermore, it is unclear why a high MPV portends poor prognosis in patients without cancer, whereas the opposite is true in patients with cancer. Therefore, its role in prognostication remains investigational, and further studies are essential to determine its appropriate usefulness in clinical practice.¹²

NUCLEATED RED BLOOD CELL COUNT

NRBCs are immature red blood cell precursors not present in the circulation of healthy adults. During erythropoiesis, the common myeloid progenitor cell first differentiates into a proerythroblast; subsequently, the chromatin in the nucleus of the proerythroblast gradually condenses until it becomes an orthochromatic erythroblast, also known as a nucleated red cell (Figure 2). Once the nucleus is expelled, the cell is known as a reticulocyte, which ultimately becomes a mature erythrocyte.

Healthy newborns have circulating NRBCs that rapidly disappear within a few weeks of birth. However, NRBCs can return to the circulation in a variety of disease states.

Causes of NRBCs

Brisk hemolysis or rapid blood loss can cause NRBCs to be released into the blood as erythropoiesis increases in an attempt to compensate for acute anemia.

Damage or stress to the bone marrow also causes NRBCs to be released into the peripheral blood, as is often the case in hematologic diseases. In a study of 478 patients with hematologic diseases, the frequency of NRBC positivity at diagnosis was highest in patients with chronic myeloid leukemia (100%), acute leukemia (62%), and myelodysplastic syndromes (45%).¹³ NRBCs also appeared at higher frequencies during chemotherapy in other hematologic conditions, such as hemophagocytic lymphohistiocytosis.

The mechanism by which NRBCs are expelled from the bone marrow is unclear, though studies have suggested that inflammation or hypoxia or both cause increased hematopoietic stress, resulting in the release of immature red cells. Increased concentrations of inflammatory cytokines (interleukin 6 and interleukin 3) and erythropoietin in the plasma and decreased arterial oxygen partial tension have been reported in patients with circulating NRBCs.^14,15

Because they are associated with hematologic disorders, the finding of NRBCs should prompt evaluation of a peripheral smear to assess for abnormalities in other cell lines.

The NRBC count and prognosis

In critically ill patients, peripheral NRBCs can also indicate life-threatening conditions.

In a study of 421 adult intensive care patients, the in-hospital mortality rate was 42% in those with peripheral NRBCs vs 5.9% in those without them.¹⁶ Further, the higher the NRBC count and the more days that NRBCs were reported in the CBC, the higher the risk of death.

In adults with acute respiratory distress syndrome, the finding of any NRBCs in the peripheral blood was an independent risk factor for death, and an NRBC count higher than 220 cells/µL was associated with a more than 3-fold higher risk of death.¹⁷

Daily screening in patients in surgical intensive care units revealed that NRBCs appeared an average of 9 days before death, consistent with an early marker of impending decline.¹⁸

In another study,¹⁹ the risk of death within 90 days of hospital discharge was higher in NRBC-positive patients, reaching 21.9% in those who had a count higher than 200 cells/µL. The risk of unplanned hospital readmission within 30 days was also increased.

Leukoerythroblastosis

The combination of NRBCs and immature white blood cells (eg, myelocytes, metamyelocytes) is called leukoerythroblastosis.

Leukoerythroblastosis is classically seen in myelophthisic anemias in which hematopoietic cells in the marrow are displaced by fibrosis, tumor, or other space-occupying processes, but it can also occur in any situation of acute marrow stress, including critical illness.

In addition, leukoerythroblastosis appears in a rare complication of sickle cell hemoglobinopathies: bone marrow necrosis with fat embolism syndrome.^20,21 As the marrow necroses, fat emboli are released in the systemic circulation causing micro- and macrovascular occlusions and multiorgan failure. The largest case series in the literature reports 58 patients with bone marrow necrosis with fat embolism syndrome.²²

At our institution, we have seen 18 patients with this condition in the past 8 years, with the frequency of diagnosis increasing with heightened awareness of the disorder. We have found that leukoerythroblastosis is often an early marker of this unrecognized syndrome and can prompt emergency red cell exchange, which is considered to be lifesaving in this condition.²²

These examples and many others show that the presence of NRBCs in the CBC can serve as an important clinical warning.

OLD TESTS CAN STILL BE USEFUL

The CBC provides much more than simple cell counts; it is a rich collection of information related to each blood cell. These days, with new diagnostic tests and prognostic tools based on molecular analysis, it is important to not overlook the value of the tests clinicians have been ordering for generations.

The RDW, MPV, and NRBC count will not likely provide definitive or flawless diagnostic or prognostic information, but when understood and used correctly, they provide readily available, cost-effective, and useful data that can supplement and guide clinical decision-making. By understanding the CBC more fully, providers can maximize the truly complete nature of this routine laboratory test.

The complete blood cell count (CBC) is one of the most frequently ordered laboratory tests in both the inpatient and outpatient settings. Not long ago, the CBC required peering through a microscope and counting the red blood cells, white blood cells, and platelets. These 3 numbers are still the primary purpose of the test.

Now, with automated counters, the CBC report also contains other numbers that delineate characteristics of each cell type. For example:

The mean corpuscular volume is the average volume of red blood cells. Providers use it to classify anemia as either microcytic, normocytic, or macrocytic, each with its own differential diagnosis.

The differential white blood cell count provides absolute counts and relative percentages of each type of leukocyte. For example, the absolute neutrophil count is an important measure of immunocompetence.

But other values in the CBC may be overlooked, even though they can provide important information. Here, we highlight 3 of them:

• The red blood cell distribution width (RDW)
• The mean platelet volume (MPV)
• The nucleated red blood cell (NRBC) count.

In addition to describing their diagnostic utility, we also discuss emerging evidence of their potential prognostic significance in hematologic and nonhematologic disorders. By incorporating an awareness of their value in clinical practice, providers can maximize the usefulness of the CBC.

RED BLOOD CELL DISTRIBUTION WIDTH

The RDW is a measure of variation (anisocytosis) in the size of the circulating red cells. The term “width” is misleading, as the value is not derived from the width of the red blood cell, but rather from the width of the distribution curve of the corpuscular volume (Figure 1). Therefore, a normal RDW means that the cells are all about the same size, while a high RDW means they vary widely in size.

The RDW can be calculated either as a coefficient of variation, with a reference range of 11% to 16% depending on the laboratory, or, less often, as a standard deviation, with a reference range of 39 to 46 fL.

The RDW can differentiate between causes of anemia

A high RDW is often found in nutritional deficiencies of iron, vitamin B₁₂, and folate. This information is helpful in differentiating the cause of microcytic anemia, as a high RDW suggests iron-deficiency anemia while a normal RDW suggests thalassemia.¹ In iron deficiency, the RDW often rises before the mean corpuscular volume falls, serving as an early diagnostic clue.

The RDW can also be high after recent hemorrhage or rapid hemolysis, as the acute drop in hemoglobin results in increased production of reticulocytes, which are larger than mature erythrocytes.

Because a range of disorders can elevate the RDW, reviewing the peripheral blood smear is an important next step in the diagnostic evaluation, specifically looking for reticulocytes, microspherocytes, and other abnormal red blood cells contributing to the RDW elevation.

A normal RDW is less diagnostically useful. It indicates the red blood cells are of uniform size, but they may be uniformly small or large depending on how long the anemia has persisted. Since red cells circulate for only about 120 days, patients who have severe iron-deficiency anemia for months to years are expected to have a normal rather than a high RDW, as their red cells of normal size have all been replaced by microcytes.

A low RDW is not consistently associated with any hematologic disorder.

RDW may have prognostic value

Emerging data suggest that the RDW may also have prognostic value in nonhematologic diseases. In a retrospective study of 15,852 adult participants in the Third National Health and Nutrition Examination Survey (1988–1994), a higher RDW was associated with a higher risk of death, with the all-cause mortality rate increasing by 23% for every 1% increment in RDW.²

This correlation is particularly prominent in cardiac disorders. In 2 large retrospective studies of patients with symptomatic heart failure, a higher RDW was a strong predictor of morbidity and death (hazard ratio 1.17 per 1-standard deviation increase, P < .001), even stronger than more commonly used variables such as ejection fraction, New York Heart Association functional class, and renal function.³

In a retrospective analysis of 4,111 patients with myocardial infarction, the degree of RDW elevation correlated with the risk of repeat nonfatal myocardial infarction, coronary death, new symptomatic heart failure, and stroke.⁴

It is hypothesized that high RDW may reflect poor cell membrane integrity from altered cholesterol content, which in turn has deleterious effects on multiple organ systems and is therefore associated with adverse outcomes.⁵

Currently, using the RDW to assess prognosis remains investigational, and how best to interpret it in daily practice requires further study.

 

 

MEAN PLATELET VOLUME

The MPV, ie, the average size of platelets, is reported in femtoliters (fL). Because the MPV varies depending on the instrument used, each laboratory has a unique reference range, usually about 8 to 12 fL. The MPV must be interpreted in conjunction with the platelet count; the product of the MPV and platelet count is called the total platelet mass.

Using the MPV to find the cause of thrombocytopenia

The MPV can be used to help narrow the differential diagnosis of thrombocytopenia. For example, it is high in thrombocytopenia resulting from peripheral destruction, as in immune thrombocytopenic purpura. This is because as platelets are lost, thrombopoietin production increases and new, larger platelets are released from healthy megakaryocytes in an attempt to increase the total platelet mass.

In contrast, the MPV is low in patients with thrombocytopenia due to megakaryocyte hypoplasia, as malfunctioning megakaryocytes cannot maintain the total platelet mass, and any platelets produced remain small. This distinction can be obscured in the setting of splenomegaly, as larger platelets are more easily sequestered in the spleen and the MPV may therefore be low or normal.

The MPV can also be used to differentiate congenital thrombocytopenic disorders, which can be characterized by either a high MPV (eg, gray platelet syndrome, Bernard-Soulier syndrome) or a low MPV (eg, Wiskott-Aldrich syndrome) (Figure 2).

MPV may have prognostic value

Evidence suggests that the MPV also has potential prognostic value, particularly in vascular disease, as larger platelets are hypothesized to have increased hemostatic potential.

In a large meta-analysis of patients with coronary artery disease, a high MPV was associated with worse outcomes; the risk of death or myocardial infarction was 17% higher in those with a high MPV (the threshold ranged from 8.4 to 11.7 fL in the different studies) than in those with a low MPV.⁶

In a study of 213 patients with non-ST-segment elevation myocardial infarction, the risk of significant coronary artery disease was 4.18 times higher in patients with a high MPV and a high troponin level than in patients with a normal MPV and a high troponin.⁷ The authors suggested that a high MPV may help identify patients at highest risk of significant coronary artery disease who would benefit from invasive studies (ie, coronary angiography).

This correlation has also been observed in other forms of vascular disease. In 261 patients who underwent carotid angioplasty and stenting, an MPV higher than 10.1 fL was associated with a risk of in-stent restenosis more than 3 times higher.⁸

The MPV has also been found to be higher in patients with type 2 diabetes than in controls, particularly in those with microvascular complications such as retinopathy or microalbuminuria.⁹

Conversely, in patients with cancer, a low MPV appears to be associated with a poor prognosis. In a retrospective analysis of 236 patients with esophageal cancer, those who had an MPV of 7.4 fL or less had significantly shorter overall survival than patients with an MPV higher than 7.4 fL.¹⁰

A low MPV has also been associated with an increased risk of venous thromoboembolism in patients with cancer. In a prospective observational cohort study of 1,544 patients, the 2-year probability of venous thromboembolism was 9% in patients with an MPV less than 10.8 fL, compared with 5.5% in those with higher MPV values. The 2-year overall survival rate was also higher in patients with high MPV than in those with low MPV, at 64.7% vs 55.7%, respectively (P = .001).¹¹

But the MPV is far from a perfect clinical metric. Since its measurement is subject to significant laboratory variation, an abnormal value should always be confirmed with evaluation of a peripheral blood smear. Furthermore, it is unclear why a high MPV portends poor prognosis in patients without cancer, whereas the opposite is true in patients with cancer. Therefore, its role in prognostication remains investigational, and further studies are essential to determine its appropriate usefulness in clinical practice.¹²

NUCLEATED RED BLOOD CELL COUNT

NRBCs are immature red blood cell precursors not present in the circulation of healthy adults. During erythropoiesis, the common myeloid progenitor cell first differentiates into a proerythroblast; subsequently, the chromatin in the nucleus of the proerythroblast gradually condenses until it becomes an orthochromatic erythroblast, also known as a nucleated red cell (Figure 2). Once the nucleus is expelled, the cell is known as a reticulocyte, which ultimately becomes a mature erythrocyte.

Healthy newborns have circulating NRBCs that rapidly disappear within a few weeks of birth. However, NRBCs can return to the circulation in a variety of disease states.

Causes of NRBCs

Brisk hemolysis or rapid blood loss can cause NRBCs to be released into the blood as erythropoiesis increases in an attempt to compensate for acute anemia.

Damage or stress to the bone marrow also causes NRBCs to be released into the peripheral blood, as is often the case in hematologic diseases. In a study of 478 patients with hematologic diseases, the frequency of NRBC positivity at diagnosis was highest in patients with chronic myeloid leukemia (100%), acute leukemia (62%), and myelodysplastic syndromes (45%).¹³ NRBCs also appeared at higher frequencies during chemotherapy in other hematologic conditions, such as hemophagocytic lymphohistiocytosis.

The mechanism by which NRBCs are expelled from the bone marrow is unclear, though studies have suggested that inflammation or hypoxia or both cause increased hematopoietic stress, resulting in the release of immature red cells. Increased concentrations of inflammatory cytokines (interleukin 6 and interleukin 3) and erythropoietin in the plasma and decreased arterial oxygen partial tension have been reported in patients with circulating NRBCs.^14,15

Because they are associated with hematologic disorders, the finding of NRBCs should prompt evaluation of a peripheral smear to assess for abnormalities in other cell lines.

The NRBC count and prognosis

In critically ill patients, peripheral NRBCs can also indicate life-threatening conditions.

In a study of 421 adult intensive care patients, the in-hospital mortality rate was 42% in those with peripheral NRBCs vs 5.9% in those without them.¹⁶ Further, the higher the NRBC count and the more days that NRBCs were reported in the CBC, the higher the risk of death.

In adults with acute respiratory distress syndrome, the finding of any NRBCs in the peripheral blood was an independent risk factor for death, and an NRBC count higher than 220 cells/µL was associated with a more than 3-fold higher risk of death.¹⁷

Daily screening in patients in surgical intensive care units revealed that NRBCs appeared an average of 9 days before death, consistent with an early marker of impending decline.¹⁸

In another study,¹⁹ the risk of death within 90 days of hospital discharge was higher in NRBC-positive patients, reaching 21.9% in those who had a count higher than 200 cells/µL. The risk of unplanned hospital readmission within 30 days was also increased.

Leukoerythroblastosis

The combination of NRBCs and immature white blood cells (eg, myelocytes, metamyelocytes) is called leukoerythroblastosis.

Leukoerythroblastosis is classically seen in myelophthisic anemias in which hematopoietic cells in the marrow are displaced by fibrosis, tumor, or other space-occupying processes, but it can also occur in any situation of acute marrow stress, including critical illness.

In addition, leukoerythroblastosis appears in a rare complication of sickle cell hemoglobinopathies: bone marrow necrosis with fat embolism syndrome.^20,21 As the marrow necroses, fat emboli are released in the systemic circulation causing micro- and macrovascular occlusions and multiorgan failure. The largest case series in the literature reports 58 patients with bone marrow necrosis with fat embolism syndrome.²²

At our institution, we have seen 18 patients with this condition in the past 8 years, with the frequency of diagnosis increasing with heightened awareness of the disorder. We have found that leukoerythroblastosis is often an early marker of this unrecognized syndrome and can prompt emergency red cell exchange, which is considered to be lifesaving in this condition.²²

These examples and many others show that the presence of NRBCs in the CBC can serve as an important clinical warning.

OLD TESTS CAN STILL BE USEFUL

The CBC provides much more than simple cell counts; it is a rich collection of information related to each blood cell. These days, with new diagnostic tests and prognostic tools based on molecular analysis, it is important to not overlook the value of the tests clinicians have been ordering for generations.

The RDW, MPV, and NRBC count will not likely provide definitive or flawless diagnostic or prognostic information, but when understood and used correctly, they provide readily available, cost-effective, and useful data that can supplement and guide clinical decision-making. By understanding the CBC more fully, providers can maximize the truly complete nature of this routine laboratory test.