The outlet ventricular septal defect is a cornerstone of the outflow tract defects and exists on a continuum that is anatomically different from the isolated central perimembranous VSD, according to the results of an observational study of 277 preserved heart specimens with isolated outlet ventricular septal defect without subpulmonary stenosis.

“In all of the specimens studied, the VSD always opened in the outlet of the right ventricle, cradled between the two limbs of the septal band, irrespective of the presence or absence of a fibrous continuity between the aortic and tricuspid valves, and the presence of an outlet septum,” according to the report published in the March issue of the Journal of Thoracic and Cardiovascular Surgery by Dr. Meriem Mostefa-Kara of the Paris Descartes University and her colleagues.

Copyright © 2015 by AATS

The 277 specimens comprised 19 with isolated ventricular septal defect; 71 with tetralogy of Fallot (TOF); 51 with TOF with pulmonary atresia (PA); 54 with common arterial trunk (CAT); 65 with double-outlet right ventricle (DORV), with subaortic, doubly committed, or subpulmonary ventricular septal defect; and 17 with interrupted aortic arch (IAA) type B (doi:10.1016/j.jtcvs.2014.11.087).

Previous studies have shown that all malalignment defects include a VSD because of the malalignment and the absence of fusion between the outlet septum and the rest of the ventricular septum, and all authors agree that this VSD is cradled between the two limbs of the septal band, according to the researchers.

They found such an outlet VSD in all of the heart specimens studied, Dr. Mostefa-Kara and her colleagues added. In addition, they found that its anatomic variants were distributed differently according to the defect involved. This was especially true when focusing of the posteroinferior rim and particularly on the aortic-tricuspid fibrous continuity. In addition, this continuity occurred with different frequency among the various outflow tract defects studied.

They found the highest rate of continuity in isolated outlet VSD, then decreasing progressively from TOF to TOF-PA, then DORV, becoming “exceedingly rare” in CAT and absent in IAA type B.

The researchers also analyzed 26 hearts with isolated central perimembranous VSD from their anatomic collection and compared these with the outlet VSD hearts. All 26 of these VSDs were located behind the septal leaflet of the tricuspid valve, under the posteroinferior limb of the septal band, and NOT between the two limbs of the septal band as was the case with the outlet VSDs.

This led them to state that there was a “blatant anatomical difference between the these two types of VSDs,” and pointed out the risk of confusion. “The presence of a fibrous continuity at the posteroinferior rim of the VSD is important for the surgeon, because it makes the conduction axis vulnerable during surgery and therefore must be described specifically in the preoperative assessment of the defect,” they warned.

“This anatomic approach places the outlet VSD as a cornerstone of the outflow tract defects, anatomically different from the isolated central perimembranous VSD. This may help us to better understand the anatomy of the VSDs and to clarify their classification and terminology,” Dr. Mostefa-Kara and her colleagues concluded.

The study was sponsored by the French Society of Cardiology. The authors reported having no relevant disclosures.

[email protected]

The outlet ventricular septal defect is a cornerstone of the outflow tract defects and exists on a continuum that is anatomically different from the isolated central perimembranous VSD, according to the results of an observational study of 277 preserved heart specimens with isolated outlet ventricular septal defect without subpulmonary stenosis.

“In all of the specimens studied, the VSD always opened in the outlet of the right ventricle, cradled between the two limbs of the septal band, irrespective of the presence or absence of a fibrous continuity between the aortic and tricuspid valves, and the presence of an outlet septum,” according to the report published in the March issue of the Journal of Thoracic and Cardiovascular Surgery by Dr. Meriem Mostefa-Kara of the Paris Descartes University and her colleagues.

Copyright © 2015 by AATS

The 277 specimens comprised 19 with isolated ventricular septal defect; 71 with tetralogy of Fallot (TOF); 51 with TOF with pulmonary atresia (PA); 54 with common arterial trunk (CAT); 65 with double-outlet right ventricle (DORV), with subaortic, doubly committed, or subpulmonary ventricular septal defect; and 17 with interrupted aortic arch (IAA) type B (doi:10.1016/j.jtcvs.2014.11.087).

Previous studies have shown that all malalignment defects include a VSD because of the malalignment and the absence of fusion between the outlet septum and the rest of the ventricular septum, and all authors agree that this VSD is cradled between the two limbs of the septal band, according to the researchers.

They found such an outlet VSD in all of the heart specimens studied, Dr. Mostefa-Kara and her colleagues added. In addition, they found that its anatomic variants were distributed differently according to the defect involved. This was especially true when focusing of the posteroinferior rim and particularly on the aortic-tricuspid fibrous continuity. In addition, this continuity occurred with different frequency among the various outflow tract defects studied.

They found the highest rate of continuity in isolated outlet VSD, then decreasing progressively from TOF to TOF-PA, then DORV, becoming “exceedingly rare” in CAT and absent in IAA type B.

The researchers also analyzed 26 hearts with isolated central perimembranous VSD from their anatomic collection and compared these with the outlet VSD hearts. All 26 of these VSDs were located behind the septal leaflet of the tricuspid valve, under the posteroinferior limb of the septal band, and NOT between the two limbs of the septal band as was the case with the outlet VSDs.

This led them to state that there was a “blatant anatomical difference between the these two types of VSDs,” and pointed out the risk of confusion. “The presence of a fibrous continuity at the posteroinferior rim of the VSD is important for the surgeon, because it makes the conduction axis vulnerable during surgery and therefore must be described specifically in the preoperative assessment of the defect,” they warned.

“This anatomic approach places the outlet VSD as a cornerstone of the outflow tract defects, anatomically different from the isolated central perimembranous VSD. This may help us to better understand the anatomy of the VSDs and to clarify their classification and terminology,” Dr. Mostefa-Kara and her colleagues concluded.

The study was sponsored by the French Society of Cardiology. The authors reported having no relevant disclosures.

[email protected]

The outlet ventricular septal defect is a cornerstone of the outflow tract defects and exists on a continuum that is anatomically different from the isolated central perimembranous VSD, according to the results of an observational study of 277 preserved heart specimens with isolated outlet ventricular septal defect without subpulmonary stenosis.

“In all of the specimens studied, the VSD always opened in the outlet of the right ventricle, cradled between the two limbs of the septal band, irrespective of the presence or absence of a fibrous continuity between the aortic and tricuspid valves, and the presence of an outlet septum,” according to the report published in the March issue of the Journal of Thoracic and Cardiovascular Surgery by Dr. Meriem Mostefa-Kara of the Paris Descartes University and her colleagues.

Copyright © 2015 by AATS

The 277 specimens comprised 19 with isolated ventricular septal defect; 71 with tetralogy of Fallot (TOF); 51 with TOF with pulmonary atresia (PA); 54 with common arterial trunk (CAT); 65 with double-outlet right ventricle (DORV), with subaortic, doubly committed, or subpulmonary ventricular septal defect; and 17 with interrupted aortic arch (IAA) type B (doi:10.1016/j.jtcvs.2014.11.087).

Previous studies have shown that all malalignment defects include a VSD because of the malalignment and the absence of fusion between the outlet septum and the rest of the ventricular septum, and all authors agree that this VSD is cradled between the two limbs of the septal band, according to the researchers.

They found such an outlet VSD in all of the heart specimens studied, Dr. Mostefa-Kara and her colleagues added. In addition, they found that its anatomic variants were distributed differently according to the defect involved. This was especially true when focusing of the posteroinferior rim and particularly on the aortic-tricuspid fibrous continuity. In addition, this continuity occurred with different frequency among the various outflow tract defects studied.

They found the highest rate of continuity in isolated outlet VSD, then decreasing progressively from TOF to TOF-PA, then DORV, becoming “exceedingly rare” in CAT and absent in IAA type B.

The researchers also analyzed 26 hearts with isolated central perimembranous VSD from their anatomic collection and compared these with the outlet VSD hearts. All 26 of these VSDs were located behind the septal leaflet of the tricuspid valve, under the posteroinferior limb of the septal band, and NOT between the two limbs of the septal band as was the case with the outlet VSDs.

This led them to state that there was a “blatant anatomical difference between the these two types of VSDs,” and pointed out the risk of confusion. “The presence of a fibrous continuity at the posteroinferior rim of the VSD is important for the surgeon, because it makes the conduction axis vulnerable during surgery and therefore must be described specifically in the preoperative assessment of the defect,” they warned.

“This anatomic approach places the outlet VSD as a cornerstone of the outflow tract defects, anatomically different from the isolated central perimembranous VSD. This may help us to better understand the anatomy of the VSDs and to clarify their classification and terminology,” Dr. Mostefa-Kara and her colleagues concluded.

The study was sponsored by the French Society of Cardiology. The authors reported having no relevant disclosures.

[email protected]

A 45-year-old woman brings her daughter for evaluation of the daughter’s acne. However, during the appointment, an odd lesion is noted on the mother’s shoulder.

Once the daughter’s evaluation is completed, attention turns to the mother’s lesion, which she reports “has been there for years.” Until last year, it hadn’t changed—but since then, it has grown considerably and also darkened.

The patient has an extensive history of poorly tolerated sun exposure in her childhood and young adulthood. She says she is able to tan but “it only holds for a short time.”

EXAMINATION
The lesion, a 2.8-cm black plaque with irregular margins, is located on the crown of the right shoulder. The patient has somewhat sun-damaged, freckled type II skin.

Dermatoscopic examination reveals regularly spaced white pinpoint areas scattered over the lesion’s surface. Focally, there is definite black streaking and pigment clumping on the borders of the lesion.

The white spots are consistent with pseudocysts seen in seborrheic keratosis. But the clumping and streaming of pigment are features we might expect to see with melanoma.

What is the diagnosis?

DISCUSSION
This case illustrates at least two useful principles:

1. The “patient” is not always the one listed on the charge sheet. I’ve found at least four melanomas and innumerable basal cell carcinomas on friends and relations who happen to be in the room with “the patient.” I can’t pretend I didn’t see the lesion, whoever it’s on. Of course, we must prioritize the patient of record—but then turn our attention to the “new” lesion/patient.

2. There is no law that says a seborrheic keratosis (SK) cannot occur in the same location as a melanoma. It may be rare, but it’s not unheard of. In this case, there were signs of both; the only way to sort it out, safely, was to excise the entire lesion and submit it to pathology. This provides the pathologist with adequate tissue to judge the whole lesion.

As it happens, this case entailed both diagnoses: the SK on the surface and a melanoma in situ on the underside. The latter was confined to the upper epidermis (ie, did not penetrate into the dermis). Re-excision with 5-mm margins was done, just to be on the safe side. Had the melanoma been left in place, it could have become invasive with time (though it might have taken years).

SKs are the most common benign lesions seen in dermatology practices—this patient had several others on her trunk—but can coincide with other lesions/diagnoses (eg, cancer). The oddity of the shoulder lesion’s appearance (a shape known as the black sheep sign), along with the patient’s fair, sun-damaged skin, prompted dermatoscopic examination.

With the power to visualize lesions under polarized light at 10x magnification, we have developed an entire body of knowledge about the features of benign vs malignant lesions—making the dermatoscope a common and valuable tool in dermatology practices across the world.

TAKE-HOME LEARNING POINTS
• Although a rare occurrence, seborrheic keratosis and melanoma (or another lesion) can co-exist in the same location.

• The odd appearance of the lesion, combined with the patient’s fair, sun-damaged skin, was enough to trigger a closer look.

• Dermatoscopic examination (10x magnification with polarized light) can identify features of benign and malignant lesions. In this case, both were found.

• Complete excision is the gold standard for biopsy of lesions suspicious for melanoma.

A 45-year-old woman brings her daughter for evaluation of the daughter’s acne. However, during the appointment, an odd lesion is noted on the mother’s shoulder.

Once the daughter’s evaluation is completed, attention turns to the mother’s lesion, which she reports “has been there for years.” Until last year, it hadn’t changed—but since then, it has grown considerably and also darkened.

The patient has an extensive history of poorly tolerated sun exposure in her childhood and young adulthood. She says she is able to tan but “it only holds for a short time.”

EXAMINATION
The lesion, a 2.8-cm black plaque with irregular margins, is located on the crown of the right shoulder. The patient has somewhat sun-damaged, freckled type II skin.

Dermatoscopic examination reveals regularly spaced white pinpoint areas scattered over the lesion’s surface. Focally, there is definite black streaking and pigment clumping on the borders of the lesion.

The white spots are consistent with pseudocysts seen in seborrheic keratosis. But the clumping and streaming of pigment are features we might expect to see with melanoma.

What is the diagnosis?

DISCUSSION
This case illustrates at least two useful principles:

1. The “patient” is not always the one listed on the charge sheet. I’ve found at least four melanomas and innumerable basal cell carcinomas on friends and relations who happen to be in the room with “the patient.” I can’t pretend I didn’t see the lesion, whoever it’s on. Of course, we must prioritize the patient of record—but then turn our attention to the “new” lesion/patient.

2. There is no law that says a seborrheic keratosis (SK) cannot occur in the same location as a melanoma. It may be rare, but it’s not unheard of. In this case, there were signs of both; the only way to sort it out, safely, was to excise the entire lesion and submit it to pathology. This provides the pathologist with adequate tissue to judge the whole lesion.

As it happens, this case entailed both diagnoses: the SK on the surface and a melanoma in situ on the underside. The latter was confined to the upper epidermis (ie, did not penetrate into the dermis). Re-excision with 5-mm margins was done, just to be on the safe side. Had the melanoma been left in place, it could have become invasive with time (though it might have taken years).

SKs are the most common benign lesions seen in dermatology practices—this patient had several others on her trunk—but can coincide with other lesions/diagnoses (eg, cancer). The oddity of the shoulder lesion’s appearance (a shape known as the black sheep sign), along with the patient’s fair, sun-damaged skin, prompted dermatoscopic examination.

With the power to visualize lesions under polarized light at 10x magnification, we have developed an entire body of knowledge about the features of benign vs malignant lesions—making the dermatoscope a common and valuable tool in dermatology practices across the world.

TAKE-HOME LEARNING POINTS
• Although a rare occurrence, seborrheic keratosis and melanoma (or another lesion) can co-exist in the same location.

• The odd appearance of the lesion, combined with the patient’s fair, sun-damaged skin, was enough to trigger a closer look.

• Dermatoscopic examination (10x magnification with polarized light) can identify features of benign and malignant lesions. In this case, both were found.

• Complete excision is the gold standard for biopsy of lesions suspicious for melanoma.

A 45-year-old woman brings her daughter for evaluation of the daughter’s acne. However, during the appointment, an odd lesion is noted on the mother’s shoulder.

Once the daughter’s evaluation is completed, attention turns to the mother’s lesion, which she reports “has been there for years.” Until last year, it hadn’t changed—but since then, it has grown considerably and also darkened.

The patient has an extensive history of poorly tolerated sun exposure in her childhood and young adulthood. She says she is able to tan but “it only holds for a short time.”

EXAMINATION
The lesion, a 2.8-cm black plaque with irregular margins, is located on the crown of the right shoulder. The patient has somewhat sun-damaged, freckled type II skin.

Dermatoscopic examination reveals regularly spaced white pinpoint areas scattered over the lesion’s surface. Focally, there is definite black streaking and pigment clumping on the borders of the lesion.

The white spots are consistent with pseudocysts seen in seborrheic keratosis. But the clumping and streaming of pigment are features we might expect to see with melanoma.

What is the diagnosis?

DISCUSSION
This case illustrates at least two useful principles:

1. The “patient” is not always the one listed on the charge sheet. I’ve found at least four melanomas and innumerable basal cell carcinomas on friends and relations who happen to be in the room with “the patient.” I can’t pretend I didn’t see the lesion, whoever it’s on. Of course, we must prioritize the patient of record—but then turn our attention to the “new” lesion/patient.

2. There is no law that says a seborrheic keratosis (SK) cannot occur in the same location as a melanoma. It may be rare, but it’s not unheard of. In this case, there were signs of both; the only way to sort it out, safely, was to excise the entire lesion and submit it to pathology. This provides the pathologist with adequate tissue to judge the whole lesion.

As it happens, this case entailed both diagnoses: the SK on the surface and a melanoma in situ on the underside. The latter was confined to the upper epidermis (ie, did not penetrate into the dermis). Re-excision with 5-mm margins was done, just to be on the safe side. Had the melanoma been left in place, it could have become invasive with time (though it might have taken years).

SKs are the most common benign lesions seen in dermatology practices—this patient had several others on her trunk—but can coincide with other lesions/diagnoses (eg, cancer). The oddity of the shoulder lesion’s appearance (a shape known as the black sheep sign), along with the patient’s fair, sun-damaged skin, prompted dermatoscopic examination.

With the power to visualize lesions under polarized light at 10x magnification, we have developed an entire body of knowledge about the features of benign vs malignant lesions—making the dermatoscope a common and valuable tool in dermatology practices across the world.

TAKE-HOME LEARNING POINTS
• Although a rare occurrence, seborrheic keratosis and melanoma (or another lesion) can co-exist in the same location.

• The odd appearance of the lesion, combined with the patient’s fair, sun-damaged skin, was enough to trigger a closer look.

• Dermatoscopic examination (10x magnification with polarized light) can identify features of benign and malignant lesions. In this case, both were found.

• Complete excision is the gold standard for biopsy of lesions suspicious for melanoma.

As the director of the Visceral Inflammation and Pain Center at the University of Pittsburgh Medical Center, psychiatrist Eva Szigethy has been instrumental in the creation of a unique specialty medical home dedicated to the integrated treatment of inflammatory bowel disease.

Listen to Dr. Szigethy discuss how the inclusion of psychiatric care for patients with chronic illness can help drive down health care delivery costs while improving patient outcomes.

Dr. Szigethy had no relevant disclosures.

[email protected]

On Twitter @whitneymcknight

As the director of the Visceral Inflammation and Pain Center at the University of Pittsburgh Medical Center, psychiatrist Eva Szigethy has been instrumental in the creation of a unique specialty medical home dedicated to the integrated treatment of inflammatory bowel disease.

Listen to Dr. Szigethy discuss how the inclusion of psychiatric care for patients with chronic illness can help drive down health care delivery costs while improving patient outcomes.

Dr. Szigethy had no relevant disclosures.

[email protected]

On Twitter @whitneymcknight

As the director of the Visceral Inflammation and Pain Center at the University of Pittsburgh Medical Center, psychiatrist Eva Szigethy has been instrumental in the creation of a unique specialty medical home dedicated to the integrated treatment of inflammatory bowel disease.

Listen to Dr. Szigethy discuss how the inclusion of psychiatric care for patients with chronic illness can help drive down health care delivery costs while improving patient outcomes.

Dr. Szigethy had no relevant disclosures.

[email protected]

On Twitter @whitneymcknight

When doctors become patients, the experience forces us to better our ability to practice the art of medicine because we gain more empathy and are able to relate to our patients’ feelings on a different level.

It’s one thing to read about the conditions we treat, and quite another when we are the ones lying flat on our backs looking up at the faces of complete strangers whom we are expected to trust for compassionate, competent, and sometimes life-altering care.

One of my first brushes with walking in my patients’ shoes was undergoing an MRI. Patients’ concerns that I had considered irrational and unfounded became understandable as I lay in the machine, unable to see anything but the inside of a tube or to move more than a few inches in any direction. All I could hear was the incessant, loud clicking of the machine as it took image after image. Alone with my thoughts, and the uncertainty of the test results, I could truly empathize with my patients’ anxieties about the procedure.

If you have never personally experienced a significant illness, I strongly recommend watching a movie called “The Doctor.” Early in my career, I remember watching this movie and it had a profound impact, the next best thing to getting sick myself, so to speak. The main character, played by William Hurt, is a brilliant, albeit insensitive doctor who is diagnosed with cancer and forced to deal in his most vulnerable state with the frustration of an inefficient medical system. Perhaps most intriguing, he is confronted head on with his own mortality and must seemingly place his trust in the hands of another brilliant and cold clinician. The result is a moving storyline; if you have never been seriously ill, this movie might just forever change your practice style.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

When doctors become patients, the experience forces us to better our ability to practice the art of medicine because we gain more empathy and are able to relate to our patients’ feelings on a different level.

It’s one thing to read about the conditions we treat, and quite another when we are the ones lying flat on our backs looking up at the faces of complete strangers whom we are expected to trust for compassionate, competent, and sometimes life-altering care.

One of my first brushes with walking in my patients’ shoes was undergoing an MRI. Patients’ concerns that I had considered irrational and unfounded became understandable as I lay in the machine, unable to see anything but the inside of a tube or to move more than a few inches in any direction. All I could hear was the incessant, loud clicking of the machine as it took image after image. Alone with my thoughts, and the uncertainty of the test results, I could truly empathize with my patients’ anxieties about the procedure.

If you have never personally experienced a significant illness, I strongly recommend watching a movie called “The Doctor.” Early in my career, I remember watching this movie and it had a profound impact, the next best thing to getting sick myself, so to speak. The main character, played by William Hurt, is a brilliant, albeit insensitive doctor who is diagnosed with cancer and forced to deal in his most vulnerable state with the frustration of an inefficient medical system. Perhaps most intriguing, he is confronted head on with his own mortality and must seemingly place his trust in the hands of another brilliant and cold clinician. The result is a moving storyline; if you have never been seriously ill, this movie might just forever change your practice style.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

When doctors become patients, the experience forces us to better our ability to practice the art of medicine because we gain more empathy and are able to relate to our patients’ feelings on a different level.

It’s one thing to read about the conditions we treat, and quite another when we are the ones lying flat on our backs looking up at the faces of complete strangers whom we are expected to trust for compassionate, competent, and sometimes life-altering care.

One of my first brushes with walking in my patients’ shoes was undergoing an MRI. Patients’ concerns that I had considered irrational and unfounded became understandable as I lay in the machine, unable to see anything but the inside of a tube or to move more than a few inches in any direction. All I could hear was the incessant, loud clicking of the machine as it took image after image. Alone with my thoughts, and the uncertainty of the test results, I could truly empathize with my patients’ anxieties about the procedure.

If you have never personally experienced a significant illness, I strongly recommend watching a movie called “The Doctor.” Early in my career, I remember watching this movie and it had a profound impact, the next best thing to getting sick myself, so to speak. The main character, played by William Hurt, is a brilliant, albeit insensitive doctor who is diagnosed with cancer and forced to deal in his most vulnerable state with the frustration of an inefficient medical system. Perhaps most intriguing, he is confronted head on with his own mortality and must seemingly place his trust in the hands of another brilliant and cold clinician. The result is a moving storyline; if you have never been seriously ill, this movie might just forever change your practice style.

Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].

Alcohol is a drug, the abuse of which is the third leading cause of preventable death and disability in the United States. Most clinicians intuitively appreciate that 80% of drinkers consume only 20% of all the alcohol consumed in the United States. In other words, most problem drinkers consume most of the alcohol and most drinkers are not problem drinkers. Perhaps as a result, clinicians may recommend the consumption of alcohol in moderation for its putative health promoting effects (e.g., reduction in cardiovascular events and increases in HDL), hoping that patients can benefit without being put at risk.

I am personally guilty of such allowances among patients who already consume modestly. With all the potential negative consequences of alcohol use, it might not have taken much for me to change my clinical advice-giving.

Knott and colleagues conducted a population based study from the Health Survey for England encompassing the years 1998-2008 linked to national mortality data. The investigators observed that compared with never drinkers, protective effects of alcohol were limited to younger men (aged 50-64 years) and older women (≥ 65 years).

What this study adds to the literature is a cleaner comparison between alcohol consumers and never drinkers and adjustments for additional confounders. Many of the previous studies showing alcohol’s beneficial effects have included former drinkers in the nondrinker comparison group; however, former drinkers have a higher mortality risk than do never drinkers because they tend to be unhealthier than never drinkers. Compared to a healthier population of never drinkers, alcohol’s effects attenuate. The use of additional adjustment variables not used in previous studies also attenuated the effect of alcohol.

As patients age, their ability to metabolize and eliminate alcohol changes. Such alterations can lead to increased adverse health consequences and accidents. If the benefit of alcohol is not as great as we previously thought, maybe the time has come to change our advice on alcohol.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

Alcohol is a drug, the abuse of which is the third leading cause of preventable death and disability in the United States. Most clinicians intuitively appreciate that 80% of drinkers consume only 20% of all the alcohol consumed in the United States. In other words, most problem drinkers consume most of the alcohol and most drinkers are not problem drinkers. Perhaps as a result, clinicians may recommend the consumption of alcohol in moderation for its putative health promoting effects (e.g., reduction in cardiovascular events and increases in HDL), hoping that patients can benefit without being put at risk.

I am personally guilty of such allowances among patients who already consume modestly. With all the potential negative consequences of alcohol use, it might not have taken much for me to change my clinical advice-giving.

Knott and colleagues conducted a population based study from the Health Survey for England encompassing the years 1998-2008 linked to national mortality data. The investigators observed that compared with never drinkers, protective effects of alcohol were limited to younger men (aged 50-64 years) and older women (≥ 65 years).

What this study adds to the literature is a cleaner comparison between alcohol consumers and never drinkers and adjustments for additional confounders. Many of the previous studies showing alcohol’s beneficial effects have included former drinkers in the nondrinker comparison group; however, former drinkers have a higher mortality risk than do never drinkers because they tend to be unhealthier than never drinkers. Compared to a healthier population of never drinkers, alcohol’s effects attenuate. The use of additional adjustment variables not used in previous studies also attenuated the effect of alcohol.

As patients age, their ability to metabolize and eliminate alcohol changes. Such alterations can lead to increased adverse health consequences and accidents. If the benefit of alcohol is not as great as we previously thought, maybe the time has come to change our advice on alcohol.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

Alcohol is a drug, the abuse of which is the third leading cause of preventable death and disability in the United States. Most clinicians intuitively appreciate that 80% of drinkers consume only 20% of all the alcohol consumed in the United States. In other words, most problem drinkers consume most of the alcohol and most drinkers are not problem drinkers. Perhaps as a result, clinicians may recommend the consumption of alcohol in moderation for its putative health promoting effects (e.g., reduction in cardiovascular events and increases in HDL), hoping that patients can benefit without being put at risk.

I am personally guilty of such allowances among patients who already consume modestly. With all the potential negative consequences of alcohol use, it might not have taken much for me to change my clinical advice-giving.

Knott and colleagues conducted a population based study from the Health Survey for England encompassing the years 1998-2008 linked to national mortality data. The investigators observed that compared with never drinkers, protective effects of alcohol were limited to younger men (aged 50-64 years) and older women (≥ 65 years).

What this study adds to the literature is a cleaner comparison between alcohol consumers and never drinkers and adjustments for additional confounders. Many of the previous studies showing alcohol’s beneficial effects have included former drinkers in the nondrinker comparison group; however, former drinkers have a higher mortality risk than do never drinkers because they tend to be unhealthier than never drinkers. Compared to a healthier population of never drinkers, alcohol’s effects attenuate. The use of additional adjustment variables not used in previous studies also attenuated the effect of alcohol.

As patients age, their ability to metabolize and eliminate alcohol changes. Such alterations can lead to increased adverse health consequences and accidents. If the benefit of alcohol is not as great as we previously thought, maybe the time has come to change our advice on alcohol.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Megakaryocytes (blue) release

proplatelets (green) that will

become mature platelets

Image from Tufts University

Researchers say they’ve developed a 3-dimensional system that reproduces the structure and physiology of human bone marrow.

Using this silk-based bone marrow niche tissue system, the team was able to manufacture functional human platelets.

The system might also prove useful for studying platelet-related diseases and predicting the efficacy of new drugs, according to the researchers, who said the new system could be a more precise and cheaper alternative to animal models.

“There are many diseases where platelet production or function is impaired,” said Alessandra Balduini, MD, of Tufts University in Medford, Massachusetts.

“New insight into the formation of platelets would have a major impact on patients and healthcare. In this tissue system, we can culture patient-derived megakaryocytes—the bone marrow cells that make platelets—and also endothelial cells, which are found in bone marrow and promote platelet production, to design patient-specific drug administration regimens.”

Dr Balduini and her colleagues described the system in Blood.

The system combined microtubes spun of silk, collagen, and fibronectin surrounded by a porous silk sponge. Megakaryocytes—some derived from patients—were seeded into the engineered microvasculature.

The researchers were able to increase platelet production in the bioreactor by embedding the silk with active endothelial cells and endothelial-related molecular proteins that support platelet formation.

The special properties of silk protein were essential to successfully mimicking the bone marrow microenvironment, said study author David Kaplan, PhD, of Tufts University.

“Silk protein possesses a unique molecular structure that enables it to be modeled in a wide variety of forms and stiffnesses, characteristics that have been shown to affect platelet formation and release,” Dr Kaplan said.

“Furthermore, silk is biocompatible and has the ability to stabilize bioactive agents at normal temperatures. Therefore, we can ‘functionalize’ it by adding such agents.”

In addition, the silk is nonactivating to platelets, which allowed the researchers to collect functional platelets from the bioreactor. Tests showed the platelets were able to aggregate and clot.

Although the number of platelets produced per megakaryocyte was lower than normally made in the body, the researchers said the system represents a significant advance over previous models. The scalable nature of the bioreactor system provides engineering options to increase the yield of platelets in ongoing studies.

In addition to providing a platform for studying the processes that regulate platelet production and related diseases, the researchers hope the platelets produced can be used as a source of growth factors for wound healing in regenerative medicine.

“The need for platelet production systems to treat patients with related diseases is significant,” Dr Kaplan said. “This patient-specific system could provide new insight and options for clinical treatments.”

“Further, the platelets can be generated on demand, avoiding the complications of storage problems, and in greater quantities and with better quality and control in terms of morphology and function.”

Megakaryocytes (blue) release

proplatelets (green) that will

become mature platelets

Image from Tufts University

Researchers say they’ve developed a 3-dimensional system that reproduces the structure and physiology of human bone marrow.

Using this silk-based bone marrow niche tissue system, the team was able to manufacture functional human platelets.

The system might also prove useful for studying platelet-related diseases and predicting the efficacy of new drugs, according to the researchers, who said the new system could be a more precise and cheaper alternative to animal models.

“There are many diseases where platelet production or function is impaired,” said Alessandra Balduini, MD, of Tufts University in Medford, Massachusetts.

“New insight into the formation of platelets would have a major impact on patients and healthcare. In this tissue system, we can culture patient-derived megakaryocytes—the bone marrow cells that make platelets—and also endothelial cells, which are found in bone marrow and promote platelet production, to design patient-specific drug administration regimens.”

Dr Balduini and her colleagues described the system in Blood.

The system combined microtubes spun of silk, collagen, and fibronectin surrounded by a porous silk sponge. Megakaryocytes—some derived from patients—were seeded into the engineered microvasculature.

The researchers were able to increase platelet production in the bioreactor by embedding the silk with active endothelial cells and endothelial-related molecular proteins that support platelet formation.

The special properties of silk protein were essential to successfully mimicking the bone marrow microenvironment, said study author David Kaplan, PhD, of Tufts University.

“Silk protein possesses a unique molecular structure that enables it to be modeled in a wide variety of forms and stiffnesses, characteristics that have been shown to affect platelet formation and release,” Dr Kaplan said.

“Furthermore, silk is biocompatible and has the ability to stabilize bioactive agents at normal temperatures. Therefore, we can ‘functionalize’ it by adding such agents.”

In addition, the silk is nonactivating to platelets, which allowed the researchers to collect functional platelets from the bioreactor. Tests showed the platelets were able to aggregate and clot.

Although the number of platelets produced per megakaryocyte was lower than normally made in the body, the researchers said the system represents a significant advance over previous models. The scalable nature of the bioreactor system provides engineering options to increase the yield of platelets in ongoing studies.

In addition to providing a platform for studying the processes that regulate platelet production and related diseases, the researchers hope the platelets produced can be used as a source of growth factors for wound healing in regenerative medicine.

“The need for platelet production systems to treat patients with related diseases is significant,” Dr Kaplan said. “This patient-specific system could provide new insight and options for clinical treatments.”

“Further, the platelets can be generated on demand, avoiding the complications of storage problems, and in greater quantities and with better quality and control in terms of morphology and function.”

Megakaryocytes (blue) release

proplatelets (green) that will

become mature platelets

Image from Tufts University

Researchers say they’ve developed a 3-dimensional system that reproduces the structure and physiology of human bone marrow.

Using this silk-based bone marrow niche tissue system, the team was able to manufacture functional human platelets.

The system might also prove useful for studying platelet-related diseases and predicting the efficacy of new drugs, according to the researchers, who said the new system could be a more precise and cheaper alternative to animal models.

“There are many diseases where platelet production or function is impaired,” said Alessandra Balduini, MD, of Tufts University in Medford, Massachusetts.

“New insight into the formation of platelets would have a major impact on patients and healthcare. In this tissue system, we can culture patient-derived megakaryocytes—the bone marrow cells that make platelets—and also endothelial cells, which are found in bone marrow and promote platelet production, to design patient-specific drug administration regimens.”

Dr Balduini and her colleagues described the system in Blood.

The system combined microtubes spun of silk, collagen, and fibronectin surrounded by a porous silk sponge. Megakaryocytes—some derived from patients—were seeded into the engineered microvasculature.

The researchers were able to increase platelet production in the bioreactor by embedding the silk with active endothelial cells and endothelial-related molecular proteins that support platelet formation.

The special properties of silk protein were essential to successfully mimicking the bone marrow microenvironment, said study author David Kaplan, PhD, of Tufts University.

“Silk protein possesses a unique molecular structure that enables it to be modeled in a wide variety of forms and stiffnesses, characteristics that have been shown to affect platelet formation and release,” Dr Kaplan said.

“Furthermore, silk is biocompatible and has the ability to stabilize bioactive agents at normal temperatures. Therefore, we can ‘functionalize’ it by adding such agents.”

In addition, the silk is nonactivating to platelets, which allowed the researchers to collect functional platelets from the bioreactor. Tests showed the platelets were able to aggregate and clot.

Although the number of platelets produced per megakaryocyte was lower than normally made in the body, the researchers said the system represents a significant advance over previous models. The scalable nature of the bioreactor system provides engineering options to increase the yield of platelets in ongoing studies.

In addition to providing a platform for studying the processes that regulate platelet production and related diseases, the researchers hope the platelets produced can be used as a source of growth factors for wound healing in regenerative medicine.

“The need for platelet production systems to treat patients with related diseases is significant,” Dr Kaplan said. “This patient-specific system could provide new insight and options for clinical treatments.”

“Further, the platelets can be generated on demand, avoiding the complications of storage problems, and in greater quantities and with better quality and control in terms of morphology and function.”

Capsules

The US Food and Drug Administration (FDA) has expanded the existing indication for lenalidomide (Revlimid)—in combination with dexamethasone—to include patients with newly diagnosed multiple myeloma (MM).

The FDA previously approved lenalidomide in combination with dexamethasone to treat MM patients who had received at least 1 prior therapy.

Lenalidomide is also FDA-approved to treat mantle cell lymphoma patients who have failed 2 prior therapies, including bortezomib.

And the drug is approved to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion, with or without additional cytogenetic abnormalities.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, of Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts.

“We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The FDA’s latest approval of lenalidomide was based on safety and efficacy results from phase 3 studies, particularly the FIRST trial.

The FIRST trial

In this phase 3 trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%) and abdominal pain (20.5%, 14.4%, 11.1%).

The most frequently reported grade 3/4 events in the continuous Rd arm (until disease progression) were neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep vein thrombosis (5.6%), and hyperglycemia (5.3%).

The incidence of invasive second primary malignancies was 3% in the continuous Rd arm, 6% in the Rd18 arm, and 5% in the MPT arm. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

Capsules

The US Food and Drug Administration (FDA) has expanded the existing indication for lenalidomide (Revlimid)—in combination with dexamethasone—to include patients with newly diagnosed multiple myeloma (MM).

The FDA previously approved lenalidomide in combination with dexamethasone to treat MM patients who had received at least 1 prior therapy.

Lenalidomide is also FDA-approved to treat mantle cell lymphoma patients who have failed 2 prior therapies, including bortezomib.

And the drug is approved to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion, with or without additional cytogenetic abnormalities.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, of Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts.

“We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The FDA’s latest approval of lenalidomide was based on safety and efficacy results from phase 3 studies, particularly the FIRST trial.

The FIRST trial

In this phase 3 trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%) and abdominal pain (20.5%, 14.4%, 11.1%).

The most frequently reported grade 3/4 events in the continuous Rd arm (until disease progression) were neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep vein thrombosis (5.6%), and hyperglycemia (5.3%).

The incidence of invasive second primary malignancies was 3% in the continuous Rd arm, 6% in the Rd18 arm, and 5% in the MPT arm. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

Capsules

The US Food and Drug Administration (FDA) has expanded the existing indication for lenalidomide (Revlimid)—in combination with dexamethasone—to include patients with newly diagnosed multiple myeloma (MM).

The FDA previously approved lenalidomide in combination with dexamethasone to treat MM patients who had received at least 1 prior therapy.

Lenalidomide is also FDA-approved to treat mantle cell lymphoma patients who have failed 2 prior therapies, including bortezomib.

And the drug is approved to treat patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion, with or without additional cytogenetic abnormalities.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, of Dana-Farber/Brigham and Women’s Cancer Center in Boston, Massachusetts.

“We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The FDA’s latest approval of lenalidomide was based on safety and efficacy results from phase 3 studies, particularly the FIRST trial.

The FIRST trial

In this phase 3 trial, researchers enrolled 1623 patients who were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive lenalidomide and dexamethasone (Rd) in 28-day cycles until disease progression (n=535), 18 cycles of lenalidomide and dexamethasone (Rd18) for 72 weeks (n=541), or melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

Response rates were significantly better with continuous Rd (75%) and Rd18 (73%) than with MPT (62%, P<0.001 for both comparisons). Complete response rates were 15%, 14%, and 9%, respectively.

The median progression-free survival was 25.5 months with continuous Rd, 20.7 months with Rd18, and 21.2 months with MPT.

This resulted in a 28% reduction in the risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (hazard ratio[HR]=0.72, P<0.001) and a 30% reduction compared with Rd18 (HR=0.70, P<0.001).

The pre-planned interim analysis of overall survival showed a 22% reduction in the risk of death for continuous Rd vs MPT (HR=0.78, P=0.02), but the difference did not cross the pre-specified superiority boundary (P<0.0096).

Adverse events reported in 20% or more of patients in the continuous Rd, Rd18, or MPT arms included diarrhea (45.5%, 38.5%, 16.5%), anemia (43.8%, 35.7%, 42.3%), neutropenia (35.0%, 33.0%, 60.6%), fatigue (32.5%, 32.8%, 28.5%), back pain (32.0%, 26.9%, 21.4%), insomnia (27.6%, 23.5%, 9.8%), asthenia (28.2%, 22.8%, 22.9%), rash (26.1%, 28.0%, 19.4%), decreased appetite (23.1%, 21.3%, 13.3%), cough (22.7%, 17.4%, 12.6%), pyrexia (21.4%, 18.9%, 14.0%), muscle spasms (20.5%, 18.9%, 11.3%) and abdominal pain (20.5%, 14.4%, 11.1%).

The most frequently reported grade 3/4 events in the continuous Rd arm (until disease progression) were neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep vein thrombosis (5.6%), and hyperglycemia (5.3%).

The incidence of invasive second primary malignancies was 3% in the continuous Rd arm, 6% in the Rd18 arm, and 5% in the MPT arm. The overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.

Nature cover image relating

to the Epigenome Roadmap

Image by Nik Spencer/Nature

Scientists have created new maps of the human epigenome that may help unravel the complex links between DNA and disease.

Researchers supported by the Common Fund’s Epigenomics Program have mapped the epigenomes of more than 100 types of cells and tissues, providing new insight into which parts of the genome are used to make a particular type of cell.

The group published an article describing the epigenome maps in the journal Nature.

Twenty-three additional papers in Nature Publishing Group journals show how these maps can be used to study human biology.

The papers are available on Nature’s Epigenome Roadmap site.

For the Roadmap Epigenomics Project, scientists compared epigenomic signatures and established their differences across a variety of cell types. The resulting information may help us understand how changes to the genome and epigenome can lead to cancers and other conditions.

“These 111 reference epigenome maps are essentially a vocabulary book that helps us decipher each DNA segment in distinct cell and tissue types,” said Bing Ren, PhD, of the University of California, San Diego.

For cancer research, the new data will hasten a merging of genomic and epigenomic perspectives that was already underway, according to Joseph F. Costello, PhD, of the University of California, San Francisco.

“You’ve had cancer researchers studying the genome—the role of mutations, deletions, and so on—and others studying epigenomes,” Dr Costello said. “They’ve almost been working on parallel tracks, and they didn’t talk to each other all that much.”

“Over the past 5 or 6 years, there’s been a reframing of the discussion, because the most recurrent mutations in cancer affect epigenomic regulators. So the way mutations in the genome play out is through epigenomic mechanisms, and major pharmaceutical companies now view epigenomes as an important target.”

Nature cover image relating

to the Epigenome Roadmap

Image by Nik Spencer/Nature

Scientists have created new maps of the human epigenome that may help unravel the complex links between DNA and disease.

Researchers supported by the Common Fund’s Epigenomics Program have mapped the epigenomes of more than 100 types of cells and tissues, providing new insight into which parts of the genome are used to make a particular type of cell.

The group published an article describing the epigenome maps in the journal Nature.

Twenty-three additional papers in Nature Publishing Group journals show how these maps can be used to study human biology.

The papers are available on Nature’s Epigenome Roadmap site.

For the Roadmap Epigenomics Project, scientists compared epigenomic signatures and established their differences across a variety of cell types. The resulting information may help us understand how changes to the genome and epigenome can lead to cancers and other conditions.

“These 111 reference epigenome maps are essentially a vocabulary book that helps us decipher each DNA segment in distinct cell and tissue types,” said Bing Ren, PhD, of the University of California, San Diego.

For cancer research, the new data will hasten a merging of genomic and epigenomic perspectives that was already underway, according to Joseph F. Costello, PhD, of the University of California, San Francisco.

“You’ve had cancer researchers studying the genome—the role of mutations, deletions, and so on—and others studying epigenomes,” Dr Costello said. “They’ve almost been working on parallel tracks, and they didn’t talk to each other all that much.”

“Over the past 5 or 6 years, there’s been a reframing of the discussion, because the most recurrent mutations in cancer affect epigenomic regulators. So the way mutations in the genome play out is through epigenomic mechanisms, and major pharmaceutical companies now view epigenomes as an important target.”

Nature cover image relating

to the Epigenome Roadmap

Image by Nik Spencer/Nature

Scientists have created new maps of the human epigenome that may help unravel the complex links between DNA and disease.

Researchers supported by the Common Fund’s Epigenomics Program have mapped the epigenomes of more than 100 types of cells and tissues, providing new insight into which parts of the genome are used to make a particular type of cell.

The group published an article describing the epigenome maps in the journal Nature.

Twenty-three additional papers in Nature Publishing Group journals show how these maps can be used to study human biology.

The papers are available on Nature’s Epigenome Roadmap site.

For the Roadmap Epigenomics Project, scientists compared epigenomic signatures and established their differences across a variety of cell types. The resulting information may help us understand how changes to the genome and epigenome can lead to cancers and other conditions.

“These 111 reference epigenome maps are essentially a vocabulary book that helps us decipher each DNA segment in distinct cell and tissue types,” said Bing Ren, PhD, of the University of California, San Diego.

For cancer research, the new data will hasten a merging of genomic and epigenomic perspectives that was already underway, according to Joseph F. Costello, PhD, of the University of California, San Francisco.

“You’ve had cancer researchers studying the genome—the role of mutations, deletions, and so on—and others studying epigenomes,” Dr Costello said. “They’ve almost been working on parallel tracks, and they didn’t talk to each other all that much.”

“Over the past 5 or 6 years, there’s been a reframing of the discussion, because the most recurrent mutations in cancer affect epigenomic regulators. So the way mutations in the genome play out is through epigenomic mechanisms, and major pharmaceutical companies now view epigenomes as an important target.”

The challenges in primary care are many, and one of increasing importance is what to say to vaccine refusers. After much debate and thoughtful discussion, my medical partner, Dr. Janet Casey at Legacy Pediatrics, decided that the practice would refuse to care for the refusers.

Over the years, I have accepted such patients into my practice and worked with them to gain their confidence and debunk the many myths about the safety of vaccination that are so visible on the Internet. The approach worked well, and by the time the children were 1 year of age, I cannot remember but a handful of parents who did not come around to realize that it was best to vaccinate. However, with the recent measles outbreak at Disneyland in California, pertussis at epidemic proportions in pockets of the United States and elsewhere in the world, and the antivaccine voices gaining more and more attention, I agree, it is time to take a stand.

When a family brings their unvaccinated or undervaccinated child into the waiting room of a physician’s practice, that family is potentially exposing others in that waiting room to serious infectious diseases – that is not fair. In the waiting room may well be a patient who is on chemotherapy or immunotherapy or otherwise immunocompromised, and he relies on the “herd immunity” achieved by vaccinations of those who can safely be vaccinated for individual protection and public health. Those patients who have weakened immune systems did not choose to have their medical condition, whereas the vaccine refusers are choosing not to vaccinate their child (or typically themselves as well). And the reasons they are choosing not to vaccinate are based on misrepresentation of medical facts, fabrications of safety concerns, long ago disproven speculations by well-meaning and not so well-meaning physicians and scientists, pseudoscience published in pseudoscientific journals, and/or general distrust of the federal government that mandates vaccinations for the good of the public health.

My personal experience with vaccine scares dates back to a time when whole-cell pertussis vaccine was the only pertussis vaccine available. I was a medical student, resident, and then an infectious diseases fellow during the escalating debate about the significant side effects of vaccines. I joined in the chorus of voices questioning the need for clear data on the problem, and then the pursuit of a safer acellular pertussis vaccine. The physician community and the public were ready for change, and the National Institutes of Health took the lead in organizing multiple studies and clinical trials leading to eventual replacement of the whole cell pertussis vaccine with the current acellular vaccines.

Much more recently, at the request of National Institutes of Health, I led studies of the safety of thimerosal preservative in multidose vaccine vials that appeared in the Lancet (2002;360:1737-41); Pediatrics (2008;121:e208-14) and the Journal of Pediatrics (2009;155:495-9). Using the data from those three studies, the World Health Organization (WHO), the United Nations, the Institute of Medicine, and other organizations were able to see that the metabolism and elimination from the body of ethylmercury in thimerosal was dramatically faster, compared with methylmercury in fish. Therefore, the presumption of possible accumulation of mercury in the body of infants receiving vaccines from multidose vials when such vaccines were closely spaced was disproven by scientific data.

In plain language, there was never a known risk from thimerosal, but a premature, hurried decision was made to mandate removal of thimerosal from vaccines given to children in the United States and western Europe; thereby the myth lives on that thimerosal is not safe. Yet thimerosal is safe, and the WHO continues to advocate use of thimerosal in multidose vaccine vials. Nevertheless, I have been criticized personally on the Internet for this work. The accusation is that I, the rest of the scientists who participated in the study, and the NIH oversight were biased because our academic institutions had previously received funding from vaccine companies to perform clinical and translational research. I received many hate e-mails and even a death threat.

To close this column with a sense of humor, I suggest you Google the responses by U.S. presidential hopefuls on their stand with regard to vaccine refusers. The comments, then the reversal and “corrections” to their comments is amusing. The presidential hopefuls quickly recognized that the right to choose may not be the best policy for the public health of American citizens. Refusing to vaccinate a child potentially harms the child and may harm others!

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said he had no relevant financial disclosures. E-mail him at [email protected].

The challenges in primary care are many, and one of increasing importance is what to say to vaccine refusers. After much debate and thoughtful discussion, my medical partner, Dr. Janet Casey at Legacy Pediatrics, decided that the practice would refuse to care for the refusers.

Over the years, I have accepted such patients into my practice and worked with them to gain their confidence and debunk the many myths about the safety of vaccination that are so visible on the Internet. The approach worked well, and by the time the children were 1 year of age, I cannot remember but a handful of parents who did not come around to realize that it was best to vaccinate. However, with the recent measles outbreak at Disneyland in California, pertussis at epidemic proportions in pockets of the United States and elsewhere in the world, and the antivaccine voices gaining more and more attention, I agree, it is time to take a stand.

When a family brings their unvaccinated or undervaccinated child into the waiting room of a physician’s practice, that family is potentially exposing others in that waiting room to serious infectious diseases – that is not fair. In the waiting room may well be a patient who is on chemotherapy or immunotherapy or otherwise immunocompromised, and he relies on the “herd immunity” achieved by vaccinations of those who can safely be vaccinated for individual protection and public health. Those patients who have weakened immune systems did not choose to have their medical condition, whereas the vaccine refusers are choosing not to vaccinate their child (or typically themselves as well). And the reasons they are choosing not to vaccinate are based on misrepresentation of medical facts, fabrications of safety concerns, long ago disproven speculations by well-meaning and not so well-meaning physicians and scientists, pseudoscience published in pseudoscientific journals, and/or general distrust of the federal government that mandates vaccinations for the good of the public health.

My personal experience with vaccine scares dates back to a time when whole-cell pertussis vaccine was the only pertussis vaccine available. I was a medical student, resident, and then an infectious diseases fellow during the escalating debate about the significant side effects of vaccines. I joined in the chorus of voices questioning the need for clear data on the problem, and then the pursuit of a safer acellular pertussis vaccine. The physician community and the public were ready for change, and the National Institutes of Health took the lead in organizing multiple studies and clinical trials leading to eventual replacement of the whole cell pertussis vaccine with the current acellular vaccines.

Much more recently, at the request of National Institutes of Health, I led studies of the safety of thimerosal preservative in multidose vaccine vials that appeared in the Lancet (2002;360:1737-41); Pediatrics (2008;121:e208-14) and the Journal of Pediatrics (2009;155:495-9). Using the data from those three studies, the World Health Organization (WHO), the United Nations, the Institute of Medicine, and other organizations were able to see that the metabolism and elimination from the body of ethylmercury in thimerosal was dramatically faster, compared with methylmercury in fish. Therefore, the presumption of possible accumulation of mercury in the body of infants receiving vaccines from multidose vials when such vaccines were closely spaced was disproven by scientific data.

In plain language, there was never a known risk from thimerosal, but a premature, hurried decision was made to mandate removal of thimerosal from vaccines given to children in the United States and western Europe; thereby the myth lives on that thimerosal is not safe. Yet thimerosal is safe, and the WHO continues to advocate use of thimerosal in multidose vaccine vials. Nevertheless, I have been criticized personally on the Internet for this work. The accusation is that I, the rest of the scientists who participated in the study, and the NIH oversight were biased because our academic institutions had previously received funding from vaccine companies to perform clinical and translational research. I received many hate e-mails and even a death threat.

To close this column with a sense of humor, I suggest you Google the responses by U.S. presidential hopefuls on their stand with regard to vaccine refusers. The comments, then the reversal and “corrections” to their comments is amusing. The presidential hopefuls quickly recognized that the right to choose may not be the best policy for the public health of American citizens. Refusing to vaccinate a child potentially harms the child and may harm others!

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said he had no relevant financial disclosures. E-mail him at [email protected].

The challenges in primary care are many, and one of increasing importance is what to say to vaccine refusers. After much debate and thoughtful discussion, my medical partner, Dr. Janet Casey at Legacy Pediatrics, decided that the practice would refuse to care for the refusers.

Over the years, I have accepted such patients into my practice and worked with them to gain their confidence and debunk the many myths about the safety of vaccination that are so visible on the Internet. The approach worked well, and by the time the children were 1 year of age, I cannot remember but a handful of parents who did not come around to realize that it was best to vaccinate. However, with the recent measles outbreak at Disneyland in California, pertussis at epidemic proportions in pockets of the United States and elsewhere in the world, and the antivaccine voices gaining more and more attention, I agree, it is time to take a stand.

When a family brings their unvaccinated or undervaccinated child into the waiting room of a physician’s practice, that family is potentially exposing others in that waiting room to serious infectious diseases – that is not fair. In the waiting room may well be a patient who is on chemotherapy or immunotherapy or otherwise immunocompromised, and he relies on the “herd immunity” achieved by vaccinations of those who can safely be vaccinated for individual protection and public health. Those patients who have weakened immune systems did not choose to have their medical condition, whereas the vaccine refusers are choosing not to vaccinate their child (or typically themselves as well). And the reasons they are choosing not to vaccinate are based on misrepresentation of medical facts, fabrications of safety concerns, long ago disproven speculations by well-meaning and not so well-meaning physicians and scientists, pseudoscience published in pseudoscientific journals, and/or general distrust of the federal government that mandates vaccinations for the good of the public health.

My personal experience with vaccine scares dates back to a time when whole-cell pertussis vaccine was the only pertussis vaccine available. I was a medical student, resident, and then an infectious diseases fellow during the escalating debate about the significant side effects of vaccines. I joined in the chorus of voices questioning the need for clear data on the problem, and then the pursuit of a safer acellular pertussis vaccine. The physician community and the public were ready for change, and the National Institutes of Health took the lead in organizing multiple studies and clinical trials leading to eventual replacement of the whole cell pertussis vaccine with the current acellular vaccines.

Much more recently, at the request of National Institutes of Health, I led studies of the safety of thimerosal preservative in multidose vaccine vials that appeared in the Lancet (2002;360:1737-41); Pediatrics (2008;121:e208-14) and the Journal of Pediatrics (2009;155:495-9). Using the data from those three studies, the World Health Organization (WHO), the United Nations, the Institute of Medicine, and other organizations were able to see that the metabolism and elimination from the body of ethylmercury in thimerosal was dramatically faster, compared with methylmercury in fish. Therefore, the presumption of possible accumulation of mercury in the body of infants receiving vaccines from multidose vials when such vaccines were closely spaced was disproven by scientific data.

In plain language, there was never a known risk from thimerosal, but a premature, hurried decision was made to mandate removal of thimerosal from vaccines given to children in the United States and western Europe; thereby the myth lives on that thimerosal is not safe. Yet thimerosal is safe, and the WHO continues to advocate use of thimerosal in multidose vaccine vials. Nevertheless, I have been criticized personally on the Internet for this work. The accusation is that I, the rest of the scientists who participated in the study, and the NIH oversight were biased because our academic institutions had previously received funding from vaccine companies to perform clinical and translational research. I received many hate e-mails and even a death threat.

To close this column with a sense of humor, I suggest you Google the responses by U.S. presidential hopefuls on their stand with regard to vaccine refusers. The comments, then the reversal and “corrections” to their comments is amusing. The presidential hopefuls quickly recognized that the right to choose may not be the best policy for the public health of American citizens. Refusing to vaccinate a child potentially harms the child and may harm others!

Dr. Pichichero, a specialist in pediatric infectious diseases, is director of the Research Institute, Rochester (N.Y.) General Hospital. He is also a pediatrician at Legacy Pediatrics in Rochester. Dr. Pichichero said he had no relevant financial disclosures. E-mail him at [email protected].