Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Pre-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from pre-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality. Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear. This study supports the concept that higher-risk patients benefit more from pre-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: A Danish nationwide cohort study JAMA Intern Med. 2014;174(3):336-344.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Pre-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from pre-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality. Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear. This study supports the concept that higher-risk patients benefit more from pre-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: A Danish nationwide cohort study JAMA Intern Med. 2014;174(3):336-344.

Clinical question: In patients with ischemic heart disease (IHD) undergoing non-cardiac surgery, do pre-operative beta blockers reduce post-operative major cardiovascular events (MACE) or mortality at 30 days?

Background: Pre-operative beta blocker use has become more restricted, as evidence about which patients derive benefit has become clearer. Opinions and practice vary regarding whether all patients with IHD, or only certain populations within this group, benefit from pre-operative beta blockers.

Study design: Retrospective, national registry-based cohort study.

Setting: Denmark, 2004-2009.

Synopsis: No benefit was found for the overall cohort of 28,263 patients. Patients with IHD and heart failure (n=7990) had lower risk of MACE (HR=0.75, 95% CI, 0.70-0.87) and mortality (HR=0.80, 95% CI, 0.70-0.92). Patients with IHD and myocardial infarction within two years (n=1664) had lower risk of MACE (HR=0.54, 95% CI, 0.37-0.78) but not mortality. Beta blocker dose and compliance were unknown. Whether patients had symptoms or inducible ischemia was not clear. This study supports the concept that higher-risk patients benefit more from pre-operative beta blockers, but it is not high-grade evidence.

Bottom line: Not all patients with IHD benefit from pre-operative beta blockers; those with concomitant heart failure or recent MI have a lower risk of MACE and/or mortality at 30 days with beta blockers.

Citation: Andersson C, Merie C, Jorgensen M, et al. Association of ß-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing non-cardiac surgery: A Danish nationwide cohort study JAMA Intern Med. 2014;174(3):336-344.

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

PHILADELPHIA – Eteplirsen safely maintained its beneficial effect on walking speeds for certain patients with Duchenne muscular dystrophy for more than 2 years and was the first drug to show stabilized diaphragm function over the same period.

The investigational gene therapy drug had a stabilizing effect on patients’ walking speed over the course of 120 weeks regardless of whether they started it earlier or later in the open-label extension of the initial 24-week, randomized trial, but those who started treatment earlier maintained a higher walking speed, Dr. Jerry R. Mendell said at the annual meeting of the American Academy of Neurology.

Coinvestigator Dr. Edward M. Kaye of Sarepta Therapeutics, the study sponsor, presented in-depth safety and pharmacokinetics data that showed no significant treatment-related adverse events with eteplirsen in the small study. No patients have discontinued or disrupted treatment, and no laboratory evidence of toxicity has been seen to date.

The initial 24-week, double-blind, randomized, placebo-controlled study involved four patients who were given the equivalent of 30 mg/kg eteplirsen weekly, four given 50 mg/kg eteplirsen weekly, and four given placebo. At the start of the open-label extension study, two of the placebo-treated patients were transitioned to 30 mg/kg weekly and two to 50 mg/kg weekly.

All patients underwent muscle biopsy at baseline, followed by biopsies at 12 weeks in two of the high-dose patients and in two of the placebo-treated patients, and at 24 weeks in the four patients taking 30 mg/kg weekly and in two placebo-treated patients.

"This design permitted a comparison between high dose over a shorter time interval and low dose over a longer time interval," said Dr. Mendell of the Center for Gene Therapy at Nationwide Children’s Hospital, Columbus, Ohio.

All patients underwent a biopsy at 1 year (48 weeks) in the open-label extension (Ann. Neurol. 2013;74:637-47).

By 48 weeks, the mean percentage of dystrophin-positive muscle fibers was 34% in the placebo/30 mg/kg delayed-treatment group, 43% in the placebo/50 mg/kg delayed-treatment group, 42% in the 50-mg/kg group, and 52% in the 30-mg/kg group.

Distance traveled on the 6-minute walk test began to diverge between active and placebo-treated patients at 12 weeks and stabilized at 24 weeks among those who received active treatment, but continued to decline until 36 weeks for placebo-treated patients who started treatment at 24 weeks.

At 120 weeks, the patients who had received continuous treatment with eteplirsen declined by a mean of 14 m on the 6-minute walk test since baseline, compared with a decline of 79 m in those who underwent delayed treatment with eteplirsen. In comparison, studies of the natural history of Duchenne muscular dystrophy (DMD) have shown steady declines on the 6-minute walk test, ranging from 30 to 115 m at 1 year and 97 to 125 m at 2 years.

There was "remarkable stability" in diaphragm function over the course of treatment with eteplirsen, "which is quite different from the natural history of untreated patients," Dr. Mendell said. In all 12 patients, maximal expiratory pressure remained stable, going from a mean of 90% of predicted at baseline to 95% at 120 weeks. The same was true for maximal inspiratory pressure, moving from 79% of expected at baseline to 80% at 120 weeks. In contrast, the natural history of untreated DMD shows that pulmonary function declines substantially over time: by 3.9%/year for maximal inspiratory pressure after starting at 90% of predicted at 9 years of age, and by 3.6%/year after starting at 45% of predicted at 9 years of age (Pediatr. Pulmonol. 2014;49:473-81).

Eteplirsen was created to help patients with a deletion of exon 51 in dystrophin, which causes a nonfunctional dystrophin protein. The drug is a charge-neutral phosphorodiamidate morpholino oligomer (PMO) that targets the 13% of DMD patients with this mutation by directing alternative splicing of the dystrophin gene through its ability to bind to exon 51 of dystrophin pre-mRNA. This restores transcription and translation of a truncated, yet functional, dystrophin protein, such as those found in Becker muscular dystrophy.

The neutral charge of eteplirsen helps it to avoid binding to serum proteins, which is one of the problems that have occurred with phosphorothioate antisense oligonucleotide-based drugs. Phosphorothioate antisense drugs have also been linked to immune activation, hepatotoxicity, thrombocytopenia, coagulopathy, renal toxicity, and proteinuria. But Dr. Kaye reported that eteplirsen is mainly excreted by the kidneys, has a half-life of about 3 hours, and showed no evidence of those problems. Only 13 of 453 urine protein assessments tested positive, but all were low, transient, and resolved spontaneously.

"The reason that this is important is there has actually been very little human data until recently, despite the fact that [PMOs have] been around for over 30 years. Most of the work has been done in animals and in research laboratories, and it’s only until recently that people have been exposed to the drug," Dr. Kaye said.

The study was funded by Sarepta Therapeutics. Dr. Kaye and two coauthors are employees of the company. Dr. Mendell had no relevant disclosures.

[email protected]

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The radiograph demonstrates no acute osseous injury, such as fracture or dislocation. Of interest and note is increased sclerosis within both femoral heads, more so on the left versus the right side. Given the patient’s young age, such findings could be related to early avascular necrosis. His clinical symptoms certainly correlate. MRI or bone scan, as well as orthopedic evaluation, is warranted in such a case. 

Fortunately, subsequent MRI of both hips did not show any avascular necrosis but rather osteoarthritic changes. The MRI of his spinal column was negative as well.

ANSWER

The correct interpretation of this ECG includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats with sinus arrest. An intraventricular conduction defect is also present. 

Sinus bradycardia is indicated by the normal PQRST complexes at a rate of less than 60 beats/min. A marked sinus arrhythmia is ­evidenced by more than one pause (between third and fourth beats and seventh and eighth beats on the lead I rhythm strip) on the ECG. 

Sinus arrest occurs when the sinus node fails to conduct (absence of P wave during the interval of the pause). A normal QRS complex without a preceding P wave indicates a junctional escape beat. Finally, an intraventricular conduction defect is documented by a QRS duration ≥ 110 ms in the absence of a right or left bundle branch block.

ANSWER

The correct interpretation of this ECG includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats with sinus arrest. An intraventricular conduction defect is also present. 

Sinus bradycardia is indicated by the normal PQRST complexes at a rate of less than 60 beats/min. A marked sinus arrhythmia is ­evidenced by more than one pause (between third and fourth beats and seventh and eighth beats on the lead I rhythm strip) on the ECG. 

Sinus arrest occurs when the sinus node fails to conduct (absence of P wave during the interval of the pause). A normal QRS complex without a preceding P wave indicates a junctional escape beat. Finally, an intraventricular conduction defect is documented by a QRS duration ≥ 110 ms in the absence of a right or left bundle branch block.

ANSWER

The correct interpretation of this ECG includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats with sinus arrest. An intraventricular conduction defect is also present. 

Sinus bradycardia is indicated by the normal PQRST complexes at a rate of less than 60 beats/min. A marked sinus arrhythmia is ­evidenced by more than one pause (between third and fourth beats and seventh and eighth beats on the lead I rhythm strip) on the ECG. 

Sinus arrest occurs when the sinus node fails to conduct (absence of P wave during the interval of the pause). A normal QRS complex without a preceding P wave indicates a junctional escape beat. Finally, an intraventricular conduction defect is documented by a QRS duration ≥ 110 ms in the absence of a right or left bundle branch block.

ANSWER

For a number of reasons (discussed more fully below), the correct answer is to follow up with the pathologist (choice “c”); the biopsying provider, who is the only person to have seen the lesion, is responsible for resolving any discordance between the report and the clinical presentation/appearance.

Simply accepting the report as fact and notifying the patient of the result (choice “a”) is unacceptable. Removing more tissue from the base of the site (choice “b”) is not likely to provide any useful clinical information. Watching the site for change (choice “d”) ignores the possibility that the original lesion has already spread.

DISCUSSION

Skin tags, also known as fibroepithelioma or acrochorda, are extremely common, benign lesions encountered daily by almost all medical providers. Melanoma in tag form is decidedly unusual, but far from unknown. Around 80% of melanomas are essentially flat (macular), and about 10% are nodular. The rest, from a morphologic standpoint, are all over the map. They can be red, blue, and even white. Contrary to popular misconception, they rarely itch, and you probably wouldn’t want to depend on your dog to alert you to their presence.

My point? Although we conceive of melanomas as looking a certain way (a useful and nec­essary view), the reality is that their morphologic presentations are astonishingly diverse. They include pedunculated tags.

This means that unless we have a very good reason to do otherwise, we should send almost every skin lesion we remove for pathologic examination. Simple, small tags, warts, and the like can be safely discarded. But anything of substance, or anything that appears to be the least bit odd, must be submitted to pathology.

Furthermore, the pathology reports must be carefully read and the results connected to the particular lesion. This case illustrates that necessity nicely. With its black tip, this lesion was more than a little worrisome. When no mention was made of the pigmentary changes, a call to the pathologist was in order.

In this case, the pathologist was more than happy to order new and deeper cuts to be made in the specimen. Within two days, he issued a new report, which showed benign nevoid changes that explained the dark pigment and failed to show any atypia. Then, and only then, were we able to give the results to the patient.

This principle can be extrapolated to results from other types of tests. They are not to be accepted blindly by the ordering provider, who is in the unique position of having seen the patient.

ANSWER

For a number of reasons (discussed more fully below), the correct answer is to follow up with the pathologist (choice “c”); the biopsying provider, who is the only person to have seen the lesion, is responsible for resolving any discordance between the report and the clinical presentation/appearance.

Simply accepting the report as fact and notifying the patient of the result (choice “a”) is unacceptable. Removing more tissue from the base of the site (choice “b”) is not likely to provide any useful clinical information. Watching the site for change (choice “d”) ignores the possibility that the original lesion has already spread.

DISCUSSION

Skin tags, also known as fibroepithelioma or acrochorda, are extremely common, benign lesions encountered daily by almost all medical providers. Melanoma in tag form is decidedly unusual, but far from unknown. Around 80% of melanomas are essentially flat (macular), and about 10% are nodular. The rest, from a morphologic standpoint, are all over the map. They can be red, blue, and even white. Contrary to popular misconception, they rarely itch, and you probably wouldn’t want to depend on your dog to alert you to their presence.

My point? Although we conceive of melanomas as looking a certain way (a useful and nec­essary view), the reality is that their morphologic presentations are astonishingly diverse. They include pedunculated tags.

This means that unless we have a very good reason to do otherwise, we should send almost every skin lesion we remove for pathologic examination. Simple, small tags, warts, and the like can be safely discarded. But anything of substance, or anything that appears to be the least bit odd, must be submitted to pathology.

Furthermore, the pathology reports must be carefully read and the results connected to the particular lesion. This case illustrates that necessity nicely. With its black tip, this lesion was more than a little worrisome. When no mention was made of the pigmentary changes, a call to the pathologist was in order.

In this case, the pathologist was more than happy to order new and deeper cuts to be made in the specimen. Within two days, he issued a new report, which showed benign nevoid changes that explained the dark pigment and failed to show any atypia. Then, and only then, were we able to give the results to the patient.

This principle can be extrapolated to results from other types of tests. They are not to be accepted blindly by the ordering provider, who is in the unique position of having seen the patient.

ANSWER

For a number of reasons (discussed more fully below), the correct answer is to follow up with the pathologist (choice “c”); the biopsying provider, who is the only person to have seen the lesion, is responsible for resolving any discordance between the report and the clinical presentation/appearance.

Simply accepting the report as fact and notifying the patient of the result (choice “a”) is unacceptable. Removing more tissue from the base of the site (choice “b”) is not likely to provide any useful clinical information. Watching the site for change (choice “d”) ignores the possibility that the original lesion has already spread.

DISCUSSION

Skin tags, also known as fibroepithelioma or acrochorda, are extremely common, benign lesions encountered daily by almost all medical providers. Melanoma in tag form is decidedly unusual, but far from unknown. Around 80% of melanomas are essentially flat (macular), and about 10% are nodular. The rest, from a morphologic standpoint, are all over the map. They can be red, blue, and even white. Contrary to popular misconception, they rarely itch, and you probably wouldn’t want to depend on your dog to alert you to their presence.

My point? Although we conceive of melanomas as looking a certain way (a useful and nec­essary view), the reality is that their morphologic presentations are astonishingly diverse. They include pedunculated tags.

This means that unless we have a very good reason to do otherwise, we should send almost every skin lesion we remove for pathologic examination. Simple, small tags, warts, and the like can be safely discarded. But anything of substance, or anything that appears to be the least bit odd, must be submitted to pathology.

Furthermore, the pathology reports must be carefully read and the results connected to the particular lesion. This case illustrates that necessity nicely. With its black tip, this lesion was more than a little worrisome. When no mention was made of the pigmentary changes, a call to the pathologist was in order.

In this case, the pathologist was more than happy to order new and deeper cuts to be made in the specimen. Within two days, he issued a new report, which showed benign nevoid changes that explained the dark pigment and failed to show any atypia. Then, and only then, were we able to give the results to the patient.

This principle can be extrapolated to results from other types of tests. They are not to be accepted blindly by the ordering provider, who is in the unique position of having seen the patient.

When 95 women from Wright-Patterson Air Force Base in Ohio were surveyed about their views of noninvasive prenatal testing (NIPT) versus invasive screening, more than 60% of respondents said they would choose NIPT or no invasive testing if ultrasound screening, a quad screen, or conventional first-trimester screening revealed an abnormality. One-third of respondents said they would likely undergo invasive testing if NIPT results were abnormal, and more than 50% of women in this group reported that the results might influence their decision to continue the pregnancy.

The survey results were presented as a poster at the 2014 American College of Obstetricians and Gynecologists (ACOG) annual clinical meeting in Chicago.¹

All patients attended a group prenatal genetic counseling session led by a single provider in early pregnancy before completing the survey.

The military population surveyed in this study “as a whole is a little bit skewed in race and education,” said Jacqueline Vidosh, MD, a coauthor of the study. That population was predominantly white, with the majority of women having completed at least some college.”

“The nice thing about a military population, however, is that you capture geographical differences, which is a lot harder to do on a small scale,” said Dr. Vidosh.

Andrea Shields, MD, provided the genetic counseling education for the study.

“My class lasted anywhere from 75 minutes to about 90 minutes,” she said, “so it was a considerable time that we took, but it wasn’t specifically devoted to NIPT. That portion took about 10 minutes. But it was introducing them to prenatal diagnosis and screening that took a while, so I think there has to be a large focus on education for any type of prenatal test. Pretest education is extremely important, especially when we’re trying to introduce this technology.”

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When 95 women from Wright-Patterson Air Force Base in Ohio were surveyed about their views of noninvasive prenatal testing (NIPT) versus invasive screening, more than 60% of respondents said they would choose NIPT or no invasive testing if ultrasound screening, a quad screen, or conventional first-trimester screening revealed an abnormality. One-third of respondents said they would likely undergo invasive testing if NIPT results were abnormal, and more than 50% of women in this group reported that the results might influence their decision to continue the pregnancy.

The survey results were presented as a poster at the 2014 American College of Obstetricians and Gynecologists (ACOG) annual clinical meeting in Chicago.¹

All patients attended a group prenatal genetic counseling session led by a single provider in early pregnancy before completing the survey.

The military population surveyed in this study “as a whole is a little bit skewed in race and education,” said Jacqueline Vidosh, MD, a coauthor of the study. That population was predominantly white, with the majority of women having completed at least some college.”

“The nice thing about a military population, however, is that you capture geographical differences, which is a lot harder to do on a small scale,” said Dr. Vidosh.

Andrea Shields, MD, provided the genetic counseling education for the study.

“My class lasted anywhere from 75 minutes to about 90 minutes,” she said, “so it was a considerable time that we took, but it wasn’t specifically devoted to NIPT. That portion took about 10 minutes. But it was introducing them to prenatal diagnosis and screening that took a while, so I think there has to be a large focus on education for any type of prenatal test. Pretest education is extremely important, especially when we’re trying to introduce this technology.”

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING

Ospemifene found to have minimal effects on the endometrium at 52 weeks

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

When 95 women from Wright-Patterson Air Force Base in Ohio were surveyed about their views of noninvasive prenatal testing (NIPT) versus invasive screening, more than 60% of respondents said they would choose NIPT or no invasive testing if ultrasound screening, a quad screen, or conventional first-trimester screening revealed an abnormality. One-third of respondents said they would likely undergo invasive testing if NIPT results were abnormal, and more than 50% of women in this group reported that the results might influence their decision to continue the pregnancy.

The survey results were presented as a poster at the 2014 American College of Obstetricians and Gynecologists (ACOG) annual clinical meeting in Chicago.¹

All patients attended a group prenatal genetic counseling session led by a single provider in early pregnancy before completing the survey.

The military population surveyed in this study “as a whole is a little bit skewed in race and education,” said Jacqueline Vidosh, MD, a coauthor of the study. That population was predominantly white, with the majority of women having completed at least some college.”

“The nice thing about a military population, however, is that you capture geographical differences, which is a lot harder to do on a small scale,” said Dr. Vidosh.

Andrea Shields, MD, provided the genetic counseling education for the study.

“My class lasted anywhere from 75 minutes to about 90 minutes,” she said, “so it was a considerable time that we took, but it wasn’t specifically devoted to NIPT. That portion took about 10 minutes. But it was introducing them to prenatal diagnosis and screening that took a while, so I think there has to be a large focus on education for any type of prenatal test. Pretest education is extremely important, especially when we’re trying to introduce this technology.”

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING

Ospemifene found to have minimal effects on the endometrium at 52 weeks

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

Shoulder dystocia is a leading cause of litigation in obstetrics, and the delivery note is an indispensable tool in the defense of a case. When investigators from the University of Southern California analyzed 66 delivery notes to determine how many of 20 intrapartum elements were covered, they found that an average of 11 (58%) were documented. No note included all 20 element.

The study was presented as a poster at the 2014 American College of Obstetricians and Gynecologists annual clinical meeting in Chicago.¹

The 20 elements and their frequency of documentation were:

• date – 96%
• time – 96%
• maneuvers used to achieve delivery – 91%
• order of maneuvers – 89%
• maternal gravidity and parity – 86%
• mode of delivery – 86%
• Apgar scores – 80%
• type of perineal laceration – 80%
• infant birth weight – 77%
• resident provider – 75%
• head-to-body interval – 58%
• cord gases – 53%
• attending provider – 46%
• whether episiotomy was performed – 39%
• application of gentle downward traction – 31%
• movement of the infant’s extremities after delivery – 30%
• which shoulder was anterior – 21%
• whether the patient was informed of the shoulder dystocia – 4%
• adequacy of maternal pelvis – 2%
• lack of fundal pressure – 1%.

Investigators recommended that providers implement use of a standard form to improve recording of critical elements.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING

Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Ospemifene found to have minimal effects on the endometrium at 52 weeks

Why it’s important to open the sexual health dialogue

Shoulder dystocia is a leading cause of litigation in obstetrics, and the delivery note is an indispensable tool in the defense of a case. When investigators from the University of Southern California analyzed 66 delivery notes to determine how many of 20 intrapartum elements were covered, they found that an average of 11 (58%) were documented. No note included all 20 element.

The study was presented as a poster at the 2014 American College of Obstetricians and Gynecologists annual clinical meeting in Chicago.¹

The 20 elements and their frequency of documentation were:

• date – 96%
• time – 96%
• maneuvers used to achieve delivery – 91%
• order of maneuvers – 89%
• maternal gravidity and parity – 86%
• mode of delivery – 86%
• Apgar scores – 80%
• type of perineal laceration – 80%
• infant birth weight – 77%
• resident provider – 75%
• head-to-body interval – 58%
• cord gases – 53%
• attending provider – 46%
• whether episiotomy was performed – 39%
• application of gentle downward traction – 31%
• movement of the infant’s extremities after delivery – 30%
• which shoulder was anterior – 21%
• whether the patient was informed of the shoulder dystocia – 4%
• adequacy of maternal pelvis – 2%
• lack of fundal pressure – 1%.

Investigators recommended that providers implement use of a standard form to improve recording of critical elements.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING

Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Ospemifene found to have minimal effects on the endometrium at 52 weeks

Why it’s important to open the sexual health dialogue

Shoulder dystocia is a leading cause of litigation in obstetrics, and the delivery note is an indispensable tool in the defense of a case. When investigators from the University of Southern California analyzed 66 delivery notes to determine how many of 20 intrapartum elements were covered, they found that an average of 11 (58%) were documented. No note included all 20 element.

The study was presented as a poster at the 2014 American College of Obstetricians and Gynecologists annual clinical meeting in Chicago.¹

The 20 elements and their frequency of documentation were:

• date – 96%
• time – 96%
• maneuvers used to achieve delivery – 91%
• order of maneuvers – 89%
• maternal gravidity and parity – 86%
• mode of delivery – 86%
• Apgar scores – 80%
• type of perineal laceration – 80%
• infant birth weight – 77%
• resident provider – 75%
• head-to-body interval – 58%
• cord gases – 53%
• attending provider – 46%
• whether episiotomy was performed – 39%
• application of gentle downward traction – 31%
• movement of the infant’s extremities after delivery – 30%
• which shoulder was anterior – 21%
• whether the patient was informed of the shoulder dystocia – 4%
• adequacy of maternal pelvis – 2%
• lack of fundal pressure – 1%.

Investigators recommended that providers implement use of a standard form to improve recording of critical elements.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING

Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Ospemifene found to have minimal effects on the endometrium at 52 weeks

Why it’s important to open the sexual health dialogue

Ospemifene was FDA-approved in 2013 to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. This nonestrogenenic drug has tissue selective agonist/antagonist effects—a selective estrogen-receptor modulator (SERM). Tamoxifen, a first-generation SERM, increases the risk of endometrial cancer. However, the second-generation SERM raloxifene is not associated with this increased risk. In preclinical studies and clinical trials, ospemifene has been shown to exert positive effects on the vaginal epithelium and minimal effects on the endometrium.

Steven R. Goldstein, MD, from New York University School of Medicine, and colleagues set out to determine the endometrial safety of ospemifene in six Phase 2/3 clinical trials of postemenopausal women with up to 52 weeks of exposure to ospemifene 60 mg/day versus placebo.

Endometrial safety of the study drug was assessed in a total of 1,349 women with an intact uterus (851 in the ospemifene group vs 543 in the placebo group).

Results
Endometrial biopsies obtained at 52 weeks revealed a rate of endometrial hyperplasia of 0.3%.

Of 342 biopsied women, “there was a single case of a woman with simple hyperplasia,” says Dr. Goldstein. “She was 52 years old, had become menopausal at age 49 and had been taking hormone therapy for about 2 years before entering the trial. After 4 months of ospemifene, she had an episode of bleeding and was diagnosed with proliferative endometrium. The study drug was stopped with a plan to follow up in 3 months; 89 days later she had another episode of bleeding and was diagnosed with simple hyperplasia. She was treated with a single course of progestogen, the hyperplasia resolved, and then she was noted to have a benign polyp.”

No complex hyperplasias or carcinomas were found.

Ospemifene participants with histologic findings other than inactive, atrophic, or insufficient was 3.5% at 52 weeks, and this finding was similar to baseline endometrial biopsy results for placebo (4.0%).

The incidence of active and disordered type endometrial proliferation was less than 1% of participants treated with ospemifene. The vaginal bleeding incidence was similar in the treatment and placebo groups.

“This data tells me that this drug is clearly acting like its cousin raloxifene in the uterus, with virtually no active proliferation and no true hyperplasia. The FDA guidance for any of these products is less than 1% hyperplasia in 1 year, and there was a single case out of 342 biopsies, says Dr. Goldstein.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING
Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

Ospemifene was FDA-approved in 2013 to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. This nonestrogenenic drug has tissue selective agonist/antagonist effects—a selective estrogen-receptor modulator (SERM). Tamoxifen, a first-generation SERM, increases the risk of endometrial cancer. However, the second-generation SERM raloxifene is not associated with this increased risk. In preclinical studies and clinical trials, ospemifene has been shown to exert positive effects on the vaginal epithelium and minimal effects on the endometrium.

Steven R. Goldstein, MD, from New York University School of Medicine, and colleagues set out to determine the endometrial safety of ospemifene in six Phase 2/3 clinical trials of postemenopausal women with up to 52 weeks of exposure to ospemifene 60 mg/day versus placebo.

Endometrial safety of the study drug was assessed in a total of 1,349 women with an intact uterus (851 in the ospemifene group vs 543 in the placebo group).

Results
Endometrial biopsies obtained at 52 weeks revealed a rate of endometrial hyperplasia of 0.3%.

Of 342 biopsied women, “there was a single case of a woman with simple hyperplasia,” says Dr. Goldstein. “She was 52 years old, had become menopausal at age 49 and had been taking hormone therapy for about 2 years before entering the trial. After 4 months of ospemifene, she had an episode of bleeding and was diagnosed with proliferative endometrium. The study drug was stopped with a plan to follow up in 3 months; 89 days later she had another episode of bleeding and was diagnosed with simple hyperplasia. She was treated with a single course of progestogen, the hyperplasia resolved, and then she was noted to have a benign polyp.”

No complex hyperplasias or carcinomas were found.

Ospemifene participants with histologic findings other than inactive, atrophic, or insufficient was 3.5% at 52 weeks, and this finding was similar to baseline endometrial biopsy results for placebo (4.0%).

The incidence of active and disordered type endometrial proliferation was less than 1% of participants treated with ospemifene. The vaginal bleeding incidence was similar in the treatment and placebo groups.

“This data tells me that this drug is clearly acting like its cousin raloxifene in the uterus, with virtually no active proliferation and no true hyperplasia. The FDA guidance for any of these products is less than 1% hyperplasia in 1 year, and there was a single case out of 342 biopsies, says Dr. Goldstein.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING
Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

Ospemifene was FDA-approved in 2013 to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. This nonestrogenenic drug has tissue selective agonist/antagonist effects—a selective estrogen-receptor modulator (SERM). Tamoxifen, a first-generation SERM, increases the risk of endometrial cancer. However, the second-generation SERM raloxifene is not associated with this increased risk. In preclinical studies and clinical trials, ospemifene has been shown to exert positive effects on the vaginal epithelium and minimal effects on the endometrium.

Steven R. Goldstein, MD, from New York University School of Medicine, and colleagues set out to determine the endometrial safety of ospemifene in six Phase 2/3 clinical trials of postemenopausal women with up to 52 weeks of exposure to ospemifene 60 mg/day versus placebo.

Endometrial safety of the study drug was assessed in a total of 1,349 women with an intact uterus (851 in the ospemifene group vs 543 in the placebo group).

Results
Endometrial biopsies obtained at 52 weeks revealed a rate of endometrial hyperplasia of 0.3%.

Of 342 biopsied women, “there was a single case of a woman with simple hyperplasia,” says Dr. Goldstein. “She was 52 years old, had become menopausal at age 49 and had been taking hormone therapy for about 2 years before entering the trial. After 4 months of ospemifene, she had an episode of bleeding and was diagnosed with proliferative endometrium. The study drug was stopped with a plan to follow up in 3 months; 89 days later she had another episode of bleeding and was diagnosed with simple hyperplasia. She was treated with a single course of progestogen, the hyperplasia resolved, and then she was noted to have a benign polyp.”

No complex hyperplasias or carcinomas were found.

Ospemifene participants with histologic findings other than inactive, atrophic, or insufficient was 3.5% at 52 weeks, and this finding was similar to baseline endometrial biopsy results for placebo (4.0%).

The incidence of active and disordered type endometrial proliferation was less than 1% of participants treated with ospemifene. The vaginal bleeding incidence was similar in the treatment and placebo groups.

“This data tells me that this drug is clearly acting like its cousin raloxifene in the uterus, with virtually no active proliferation and no true hyperplasia. The FDA guidance for any of these products is less than 1% hyperplasia in 1 year, and there was a single case out of 342 biopsies, says Dr. Goldstein.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING
Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

Blood sample collection

Credit: Jeremy L. Grisham

An analysis of more than 30,000 individuals has revealed several genetic mutations that appear to play roles in hematologic disorders.

Investigators discovered variants that showed correlations with platelet counts, white blood cell (WBC) counts, hemoglobin concentration, and hematocrit levels.

The group believes these findings could have implications for a range of conditions, including cytopenias, myeloproliferative neoplasms, and stroke.

Guillaume Lettre, PhD, of Université de Montréal and the Montreal Heart Institute in Canada, and his colleagues recounted their discoveries in a letter to Nature Genetics.

The investigators analyzed hemoglobin concentration, hematocrit levels, WBC counts, and platelet counts in 31,340 individuals genotyped on an exome array.

This revealed several missense variants in CXCR2 that were associated with a decreased WBC count. And in a resequencing study, the team identified a CXCR2 frameshift mutation that was associated with congenital neutropenia.

The group also discovered several missense and splice-site variants in genes known to regulate hematopoiesis—TFR2, HBB, TUBB1, SH2B3, and EPO.

A TFR2 mutation (rs139178017) was independently associated with higher hematocrit levels and hemoglobin concentration.

An HBB variant (rs33971440) and an EPO variant (rs62483572), on the other hand, were associated with lower hematocrit levels and hemoglobin concentrations. Further analyses confirmed that having these mutations increased a person’s risk of anemia, with odds ratios of 36.1 and 1.7, respectively.

A TUBB1 missense variant (rs41303899) was associated with decreased platelet count, while 2 missense variants of SH2B3 (rs148636776 and rs72650673) were associated with increased platelet counts.

Lastly, a mutation in JAK2 (rs77375493) was associated with increases in platelets, WBCs, hemoglobin, and hematocrit. And further analyses suggested that individuals with this variant had early stage myeloproliferative neoplasms.

“[T]hese donors also had a higher risk of having a stroke during their lifetime,” said study author Jean-Claude Tardif, MD, of Université de Montréal and the Montreal Heart Institute.

He and his colleagues believe these findings are encouraging, as they provide additional insight into hematologic disorders. But the results also suggest the experimental approach used in this study can be applied to other diseases as well.

Blood sample collection

Credit: Jeremy L. Grisham

An analysis of more than 30,000 individuals has revealed several genetic mutations that appear to play roles in hematologic disorders.

Investigators discovered variants that showed correlations with platelet counts, white blood cell (WBC) counts, hemoglobin concentration, and hematocrit levels.

The group believes these findings could have implications for a range of conditions, including cytopenias, myeloproliferative neoplasms, and stroke.

Guillaume Lettre, PhD, of Université de Montréal and the Montreal Heart Institute in Canada, and his colleagues recounted their discoveries in a letter to Nature Genetics.

The investigators analyzed hemoglobin concentration, hematocrit levels, WBC counts, and platelet counts in 31,340 individuals genotyped on an exome array.

This revealed several missense variants in CXCR2 that were associated with a decreased WBC count. And in a resequencing study, the team identified a CXCR2 frameshift mutation that was associated with congenital neutropenia.

The group also discovered several missense and splice-site variants in genes known to regulate hematopoiesis—TFR2, HBB, TUBB1, SH2B3, and EPO.

A TFR2 mutation (rs139178017) was independently associated with higher hematocrit levels and hemoglobin concentration.

An HBB variant (rs33971440) and an EPO variant (rs62483572), on the other hand, were associated with lower hematocrit levels and hemoglobin concentrations. Further analyses confirmed that having these mutations increased a person’s risk of anemia, with odds ratios of 36.1 and 1.7, respectively.

A TUBB1 missense variant (rs41303899) was associated with decreased platelet count, while 2 missense variants of SH2B3 (rs148636776 and rs72650673) were associated with increased platelet counts.

Lastly, a mutation in JAK2 (rs77375493) was associated with increases in platelets, WBCs, hemoglobin, and hematocrit. And further analyses suggested that individuals with this variant had early stage myeloproliferative neoplasms.

“[T]hese donors also had a higher risk of having a stroke during their lifetime,” said study author Jean-Claude Tardif, MD, of Université de Montréal and the Montreal Heart Institute.

He and his colleagues believe these findings are encouraging, as they provide additional insight into hematologic disorders. But the results also suggest the experimental approach used in this study can be applied to other diseases as well.

Blood sample collection

Credit: Jeremy L. Grisham

An analysis of more than 30,000 individuals has revealed several genetic mutations that appear to play roles in hematologic disorders.

Investigators discovered variants that showed correlations with platelet counts, white blood cell (WBC) counts, hemoglobin concentration, and hematocrit levels.

The group believes these findings could have implications for a range of conditions, including cytopenias, myeloproliferative neoplasms, and stroke.

Guillaume Lettre, PhD, of Université de Montréal and the Montreal Heart Institute in Canada, and his colleagues recounted their discoveries in a letter to Nature Genetics.

The investigators analyzed hemoglobin concentration, hematocrit levels, WBC counts, and platelet counts in 31,340 individuals genotyped on an exome array.

This revealed several missense variants in CXCR2 that were associated with a decreased WBC count. And in a resequencing study, the team identified a CXCR2 frameshift mutation that was associated with congenital neutropenia.

The group also discovered several missense and splice-site variants in genes known to regulate hematopoiesis—TFR2, HBB, TUBB1, SH2B3, and EPO.

A TFR2 mutation (rs139178017) was independently associated with higher hematocrit levels and hemoglobin concentration.

An HBB variant (rs33971440) and an EPO variant (rs62483572), on the other hand, were associated with lower hematocrit levels and hemoglobin concentrations. Further analyses confirmed that having these mutations increased a person’s risk of anemia, with odds ratios of 36.1 and 1.7, respectively.

A TUBB1 missense variant (rs41303899) was associated with decreased platelet count, while 2 missense variants of SH2B3 (rs148636776 and rs72650673) were associated with increased platelet counts.

Lastly, a mutation in JAK2 (rs77375493) was associated with increases in platelets, WBCs, hemoglobin, and hematocrit. And further analyses suggested that individuals with this variant had early stage myeloproliferative neoplasms.

“[T]hese donors also had a higher risk of having a stroke during their lifetime,” said study author Jean-Claude Tardif, MD, of Université de Montréal and the Montreal Heart Institute.

He and his colleagues believe these findings are encouraging, as they provide additional insight into hematologic disorders. But the results also suggest the experimental approach used in this study can be applied to other diseases as well.