1. The patient’s original lesion is dark brown, macular, and ovoid. An additional 15 to 20 oval, papulosquamous lesions are seen elsewhere on her trunk. These are widely scattered, hyperpigmented, and have scaly centers. The long axes of her oval back lesions are parallel with natural lines of cleavage in the skin.

Diagnosis: Pityriasis rosea, which is commonly seen in patients ages 10 to 35 and is about twice as likely to occur in women as in men.

The so-called herald patch appears initially, in a majority of cases, as a salmon-pink patch that can become as large as 5 to 10 cm, on the trunk or arms. The smaller oval lesions begin to appear within a week or two, averaging 1 to 2 cm in diameter; most display the characteristic “centripetal” scaling, clearly sparing the lesions’ periphery and serving as an essentially pathognomic finding.

On darker-skinned patients, the lesions (including the herald patch) will tend to be brown to black. The examiner must then look for the other characteristic aspects of PR, including the oval (as opposed to round) shape, the long axes of which will often parallel the skin tension lines on the back to produce what is termed the “Christmas tree pattern.”

For more information on this case, see “All of Her Friends Say She Has Ringworm.” Clin Rev. 2013;23(2).

For the next photograph, proceed to the next page >>

2. A man has had an asymptomatic rash for several weeks. Prior to its appearance, he was diagnosed with strep throat and treated with amoxicillin. The rash is quite striking: brightly erythematous, with annular margins on which the skin is red. But just behind the advancing margin is a parallel band of scaling.

Diagnosis: Erythema annulare centrifugum (EAC), one of the so-called “reactive erythemas,” which have several potential causes including streptococcal infections. The clinical picture and classic histologic pattern seen on biopsy effectively ruled out the other items in the differential diagnosis. EAC lesions can be large, appear in multiples, and spare only palms and soles. EAC is most often idiopathic. However, there are many reported triggers, including drugs (eg, gold, antimalarials, penicillin, and aspirin), infections (such as strep and dermatophytosis), and malignancies.

For more information on this case, see “Is A Common Illness The Cause of This Man's Rash?” Clin Rev. 2011;21(12).

For the next photograph, proceed to the next page >>

3. For two months, an 8-year-old girl has had a mildly tender and markedly pruritic rash on her right lower leg. Physical exam reveals concentric annular lesions on the affected leg. The central areas demonstrate a bruised appearance that does not resolve with diascopy.

Image courtesy of Robert Brodell, MD; reprinted from The Journal of Family Practice (2014;63:395-396).

Diagnosis: Tinea corporis was confirmed by the results of a potassium hydroxide (KOH) preparation showing septate hyphae. A periodic acid-Schiff (PAS) stain performed on the previous biopsy specimen revealed septate hyphae in the stratum corneum that were not apparent on the original hematoxylin and eosin (H&E) stained sections.

Dermatophyte infections of the skin are known as tinea corporis or “ringworm.” Ringworm fungi belong to 3 genera, Microsporum, Trichophyton, and Epidermophyton. These infections occur at any age and are more common in warmer climates.¹ The classic lesion is an annular scaly patch, sometimes with the concentric rings, as seen in our patient. The bruising was almost certainly caused by rubbing and scratching.

1. Shrum JP, Millikan LE, Bataineh O. Superficial fungal infections in the tropics. Dermatol Clin. 1994;12:687-693.

For more information on this case, see “Young girl with lower leg rash.” J Fam Pract. 2014;63(7):395-396.

For the next photograph, proceed to the next page >>

4. For three months (since the long, cold winter), this man has had very itchy lesions on his legs that he often scratches vigorously. He is not atopic and has no new pets, but he does admit to being “addicted” to sitting in his new hot tub. Examination of the patient’s legs, particularly his calves, shows discrete and confluent round, scaly plaques of a striking reddish orange hue.

Diagnosis: Nummular eczema (NE), an extremely common condition, especially in older men with dry skin made drier by bathing habits, swimming, or use of hot tubs. But many cases appear without these conditions, causing much conjecture about potential triggers, such as contact versus irritant dermatitis. Indeed, the multiplicity of topical medications applied by this patient was probably making things worse, as is often the case. NE typically manifests acutely, but can persist for months. If need be, a 4-mm punch biopsy will rule out the other suspects in the differential diagnosis.

For more information on this case, see “Family Thinks Man has Worms.” Clin Rev. 2010;20(8):6.

1. The patient’s original lesion is dark brown, macular, and ovoid. An additional 15 to 20 oval, papulosquamous lesions are seen elsewhere on her trunk. These are widely scattered, hyperpigmented, and have scaly centers. The long axes of her oval back lesions are parallel with natural lines of cleavage in the skin.

Diagnosis: Pityriasis rosea, which is commonly seen in patients ages 10 to 35 and is about twice as likely to occur in women as in men.

The so-called herald patch appears initially, in a majority of cases, as a salmon-pink patch that can become as large as 5 to 10 cm, on the trunk or arms. The smaller oval lesions begin to appear within a week or two, averaging 1 to 2 cm in diameter; most display the characteristic “centripetal” scaling, clearly sparing the lesions’ periphery and serving as an essentially pathognomic finding.

On darker-skinned patients, the lesions (including the herald patch) will tend to be brown to black. The examiner must then look for the other characteristic aspects of PR, including the oval (as opposed to round) shape, the long axes of which will often parallel the skin tension lines on the back to produce what is termed the “Christmas tree pattern.”

For more information on this case, see “All of Her Friends Say She Has Ringworm.” Clin Rev. 2013;23(2).

For the next photograph, proceed to the next page >>

2. A man has had an asymptomatic rash for several weeks. Prior to its appearance, he was diagnosed with strep throat and treated with amoxicillin. The rash is quite striking: brightly erythematous, with annular margins on which the skin is red. But just behind the advancing margin is a parallel band of scaling.

Diagnosis: Erythema annulare centrifugum (EAC), one of the so-called “reactive erythemas,” which have several potential causes including streptococcal infections. The clinical picture and classic histologic pattern seen on biopsy effectively ruled out the other items in the differential diagnosis. EAC lesions can be large, appear in multiples, and spare only palms and soles. EAC is most often idiopathic. However, there are many reported triggers, including drugs (eg, gold, antimalarials, penicillin, and aspirin), infections (such as strep and dermatophytosis), and malignancies.

For more information on this case, see “Is A Common Illness The Cause of This Man's Rash?” Clin Rev. 2011;21(12).

For the next photograph, proceed to the next page >>

3. For two months, an 8-year-old girl has had a mildly tender and markedly pruritic rash on her right lower leg. Physical exam reveals concentric annular lesions on the affected leg. The central areas demonstrate a bruised appearance that does not resolve with diascopy.

Image courtesy of Robert Brodell, MD; reprinted from The Journal of Family Practice (2014;63:395-396).

Diagnosis: Tinea corporis was confirmed by the results of a potassium hydroxide (KOH) preparation showing septate hyphae. A periodic acid-Schiff (PAS) stain performed on the previous biopsy specimen revealed septate hyphae in the stratum corneum that were not apparent on the original hematoxylin and eosin (H&E) stained sections.

Dermatophyte infections of the skin are known as tinea corporis or “ringworm.” Ringworm fungi belong to 3 genera, Microsporum, Trichophyton, and Epidermophyton. These infections occur at any age and are more common in warmer climates.¹ The classic lesion is an annular scaly patch, sometimes with the concentric rings, as seen in our patient. The bruising was almost certainly caused by rubbing and scratching.

1. Shrum JP, Millikan LE, Bataineh O. Superficial fungal infections in the tropics. Dermatol Clin. 1994;12:687-693.

For more information on this case, see “Young girl with lower leg rash.” J Fam Pract. 2014;63(7):395-396.

For the next photograph, proceed to the next page >>

4. For three months (since the long, cold winter), this man has had very itchy lesions on his legs that he often scratches vigorously. He is not atopic and has no new pets, but he does admit to being “addicted” to sitting in his new hot tub. Examination of the patient’s legs, particularly his calves, shows discrete and confluent round, scaly plaques of a striking reddish orange hue.

Diagnosis: Nummular eczema (NE), an extremely common condition, especially in older men with dry skin made drier by bathing habits, swimming, or use of hot tubs. But many cases appear without these conditions, causing much conjecture about potential triggers, such as contact versus irritant dermatitis. Indeed, the multiplicity of topical medications applied by this patient was probably making things worse, as is often the case. NE typically manifests acutely, but can persist for months. If need be, a 4-mm punch biopsy will rule out the other suspects in the differential diagnosis.

For more information on this case, see “Family Thinks Man has Worms.” Clin Rev. 2010;20(8):6.

1. The patient’s original lesion is dark brown, macular, and ovoid. An additional 15 to 20 oval, papulosquamous lesions are seen elsewhere on her trunk. These are widely scattered, hyperpigmented, and have scaly centers. The long axes of her oval back lesions are parallel with natural lines of cleavage in the skin.

Diagnosis: Pityriasis rosea, which is commonly seen in patients ages 10 to 35 and is about twice as likely to occur in women as in men.

The so-called herald patch appears initially, in a majority of cases, as a salmon-pink patch that can become as large as 5 to 10 cm, on the trunk or arms. The smaller oval lesions begin to appear within a week or two, averaging 1 to 2 cm in diameter; most display the characteristic “centripetal” scaling, clearly sparing the lesions’ periphery and serving as an essentially pathognomic finding.

On darker-skinned patients, the lesions (including the herald patch) will tend to be brown to black. The examiner must then look for the other characteristic aspects of PR, including the oval (as opposed to round) shape, the long axes of which will often parallel the skin tension lines on the back to produce what is termed the “Christmas tree pattern.”

For more information on this case, see “All of Her Friends Say She Has Ringworm.” Clin Rev. 2013;23(2).

For the next photograph, proceed to the next page >>

2. A man has had an asymptomatic rash for several weeks. Prior to its appearance, he was diagnosed with strep throat and treated with amoxicillin. The rash is quite striking: brightly erythematous, with annular margins on which the skin is red. But just behind the advancing margin is a parallel band of scaling.

Diagnosis: Erythema annulare centrifugum (EAC), one of the so-called “reactive erythemas,” which have several potential causes including streptococcal infections. The clinical picture and classic histologic pattern seen on biopsy effectively ruled out the other items in the differential diagnosis. EAC lesions can be large, appear in multiples, and spare only palms and soles. EAC is most often idiopathic. However, there are many reported triggers, including drugs (eg, gold, antimalarials, penicillin, and aspirin), infections (such as strep and dermatophytosis), and malignancies.

For more information on this case, see “Is A Common Illness The Cause of This Man's Rash?” Clin Rev. 2011;21(12).

For the next photograph, proceed to the next page >>

3. For two months, an 8-year-old girl has had a mildly tender and markedly pruritic rash on her right lower leg. Physical exam reveals concentric annular lesions on the affected leg. The central areas demonstrate a bruised appearance that does not resolve with diascopy.

Image courtesy of Robert Brodell, MD; reprinted from The Journal of Family Practice (2014;63:395-396).

Diagnosis: Tinea corporis was confirmed by the results of a potassium hydroxide (KOH) preparation showing septate hyphae. A periodic acid-Schiff (PAS) stain performed on the previous biopsy specimen revealed septate hyphae in the stratum corneum that were not apparent on the original hematoxylin and eosin (H&E) stained sections.

Dermatophyte infections of the skin are known as tinea corporis or “ringworm.” Ringworm fungi belong to 3 genera, Microsporum, Trichophyton, and Epidermophyton. These infections occur at any age and are more common in warmer climates.¹ The classic lesion is an annular scaly patch, sometimes with the concentric rings, as seen in our patient. The bruising was almost certainly caused by rubbing and scratching.

1. Shrum JP, Millikan LE, Bataineh O. Superficial fungal infections in the tropics. Dermatol Clin. 1994;12:687-693.

For more information on this case, see “Young girl with lower leg rash.” J Fam Pract. 2014;63(7):395-396.

For the next photograph, proceed to the next page >>

4. For three months (since the long, cold winter), this man has had very itchy lesions on his legs that he often scratches vigorously. He is not atopic and has no new pets, but he does admit to being “addicted” to sitting in his new hot tub. Examination of the patient’s legs, particularly his calves, shows discrete and confluent round, scaly plaques of a striking reddish orange hue.

Diagnosis: Nummular eczema (NE), an extremely common condition, especially in older men with dry skin made drier by bathing habits, swimming, or use of hot tubs. But many cases appear without these conditions, causing much conjecture about potential triggers, such as contact versus irritant dermatitis. Indeed, the multiplicity of topical medications applied by this patient was probably making things worse, as is often the case. NE typically manifests acutely, but can persist for months. If need be, a 4-mm punch biopsy will rule out the other suspects in the differential diagnosis.

For more information on this case, see “Family Thinks Man has Worms.” Clin Rev. 2010;20(8):6.

In October 2010, a 33-year-old woman with type 1 diabetes presented to a medical center in Cook County, Illinois, with shortness of breath. She was diagnosed with excessive fluid around her lungs, for which she received treatment. When her pain persisted, she was placed on hydromorphone. A long-­acting form of insulin was also  prescribed.

Two days later, the woman experienced respiratory arrest­—presumed to be a reaction to the medication. She was resuscitated and remained in the ICU. Although she was not eating food by mouth, no order for a diet change was received or documented. She continued to be administered insulin and went into a diabetic coma, dying about a week after admission.

The plaintiff claimed that the internal medicine physician employed by the hospital failed to review the decedent’s medical chart and discuss the decedent’s risk for low blood sugar levels with the attending physician. The defendants argued that the decedent was receiving regular dialysis due to end-stage renal failure and had a short life expectancy.

What was the outcome? >>

OUTCOME 
A $2 million settlement was reached.

COMMENT 
This patient’s admission to the ICU and continued monitoring were obviously stressful and ensured that her serum glucose would be high. Systems should have been in place to prevent a fatal outcome—yet the system failed in this case.

The clinicians failed to recognize the need for closer monitoring and management in a sick, acutely stressed patient. The internist did not revisit the prescribed diet and did not appreciate the impact an acute illness can have on glycemic control—and thus did not order closer serum glucose monitoring.

Because diabetes is common, jurors expect competent management; as a result, this case was likely difficult to defend. The case report tells us that the defense did not challenge a breach of the standard of care (liability) but instead focused on the ultimate impact of the mistake, given the patient’s end-stage renal failure and short life expectancy (damages).

The $2 million settlement is relatively restrained, given the patient’s young age and the location of the case. This suggests the defense had some success arguing that the patient, at baseline, was gravely ill with a diminished lifespan.

As clinicians, we would all agree that an acutely stressed, hospitalized diabetic patient should be managed closely. But how often do we see diabetic patients in an ambulatory setting who are moderately stressed, ill, vomiting, and not eating? How often do we consider the possibility that these patients could slip out of control if not monitored more closely?

While we can’t revamp our diabetic patients’ regimens for every cold, we can encourage them to develop a “sick day” plan and remind them to be vigilant about managing their diabetes during illness. Consider the “sick day” advice given to patients by the Joslin Diabetes Center:
• Always take your diabetes medication. If you have difficulty keeping the medicine down due to vomiting, call your clinician.
• Check your blood glucose level at least 4 times a day. If you are too sick to test it yourself, have someone else do it. Record your levels in case you need to contact your clinician.
• Check for ketones if your blood glucose is 250 or higher. Again, write down your levels for reference.
• Stick to your normal meal plan, if possible.
• Drink lots of sugar-free liquids to prevent dehydration.¹

Patients are also advised to contact their health care provider if they have any of the following symptoms: a fever of more than 100.5°F; vomiting or diarrhea of more than two hours’ duration; blood glucose levels higher than 250 mg after two checks, or levels that do not decrease after extra insulin is taken; and moderate or large ketones.¹

The instruction to call the office for any fever higher than 100.5°F may seem abundantly cautious. But the discussion that ensues would serve as an opportunity to reinforce the need for closer monitoring—perhaps preventing a patient with a modest illness from spiraling out of glycemic control. —DML

REFERENCE 
1. Joslin Diabetes Center. Sick Days. www.joslin.org/info/Sick_Days.html. Accessed June 10, 2015.

In October 2010, a 33-year-old woman with type 1 diabetes presented to a medical center in Cook County, Illinois, with shortness of breath. She was diagnosed with excessive fluid around her lungs, for which she received treatment. When her pain persisted, she was placed on hydromorphone. A long-­acting form of insulin was also  prescribed.

Two days later, the woman experienced respiratory arrest­—presumed to be a reaction to the medication. She was resuscitated and remained in the ICU. Although she was not eating food by mouth, no order for a diet change was received or documented. She continued to be administered insulin and went into a diabetic coma, dying about a week after admission.

The plaintiff claimed that the internal medicine physician employed by the hospital failed to review the decedent’s medical chart and discuss the decedent’s risk for low blood sugar levels with the attending physician. The defendants argued that the decedent was receiving regular dialysis due to end-stage renal failure and had a short life expectancy.

What was the outcome? >>

OUTCOME 
A $2 million settlement was reached.

COMMENT 
This patient’s admission to the ICU and continued monitoring were obviously stressful and ensured that her serum glucose would be high. Systems should have been in place to prevent a fatal outcome—yet the system failed in this case.

The clinicians failed to recognize the need for closer monitoring and management in a sick, acutely stressed patient. The internist did not revisit the prescribed diet and did not appreciate the impact an acute illness can have on glycemic control—and thus did not order closer serum glucose monitoring.

Because diabetes is common, jurors expect competent management; as a result, this case was likely difficult to defend. The case report tells us that the defense did not challenge a breach of the standard of care (liability) but instead focused on the ultimate impact of the mistake, given the patient’s end-stage renal failure and short life expectancy (damages).

The $2 million settlement is relatively restrained, given the patient’s young age and the location of the case. This suggests the defense had some success arguing that the patient, at baseline, was gravely ill with a diminished lifespan.

As clinicians, we would all agree that an acutely stressed, hospitalized diabetic patient should be managed closely. But how often do we see diabetic patients in an ambulatory setting who are moderately stressed, ill, vomiting, and not eating? How often do we consider the possibility that these patients could slip out of control if not monitored more closely?

While we can’t revamp our diabetic patients’ regimens for every cold, we can encourage them to develop a “sick day” plan and remind them to be vigilant about managing their diabetes during illness. Consider the “sick day” advice given to patients by the Joslin Diabetes Center:
• Always take your diabetes medication. If you have difficulty keeping the medicine down due to vomiting, call your clinician.
• Check your blood glucose level at least 4 times a day. If you are too sick to test it yourself, have someone else do it. Record your levels in case you need to contact your clinician.
• Check for ketones if your blood glucose is 250 or higher. Again, write down your levels for reference.
• Stick to your normal meal plan, if possible.
• Drink lots of sugar-free liquids to prevent dehydration.¹

Patients are also advised to contact their health care provider if they have any of the following symptoms: a fever of more than 100.5°F; vomiting or diarrhea of more than two hours’ duration; blood glucose levels higher than 250 mg after two checks, or levels that do not decrease after extra insulin is taken; and moderate or large ketones.¹

The instruction to call the office for any fever higher than 100.5°F may seem abundantly cautious. But the discussion that ensues would serve as an opportunity to reinforce the need for closer monitoring—perhaps preventing a patient with a modest illness from spiraling out of glycemic control. —DML

REFERENCE 
1. Joslin Diabetes Center. Sick Days. www.joslin.org/info/Sick_Days.html. Accessed June 10, 2015.

In October 2010, a 33-year-old woman with type 1 diabetes presented to a medical center in Cook County, Illinois, with shortness of breath. She was diagnosed with excessive fluid around her lungs, for which she received treatment. When her pain persisted, she was placed on hydromorphone. A long-­acting form of insulin was also  prescribed.

Two days later, the woman experienced respiratory arrest­—presumed to be a reaction to the medication. She was resuscitated and remained in the ICU. Although she was not eating food by mouth, no order for a diet change was received or documented. She continued to be administered insulin and went into a diabetic coma, dying about a week after admission.

The plaintiff claimed that the internal medicine physician employed by the hospital failed to review the decedent’s medical chart and discuss the decedent’s risk for low blood sugar levels with the attending physician. The defendants argued that the decedent was receiving regular dialysis due to end-stage renal failure and had a short life expectancy.

What was the outcome? >>

OUTCOME 
A $2 million settlement was reached.

COMMENT 
This patient’s admission to the ICU and continued monitoring were obviously stressful and ensured that her serum glucose would be high. Systems should have been in place to prevent a fatal outcome—yet the system failed in this case.

The clinicians failed to recognize the need for closer monitoring and management in a sick, acutely stressed patient. The internist did not revisit the prescribed diet and did not appreciate the impact an acute illness can have on glycemic control—and thus did not order closer serum glucose monitoring.

Because diabetes is common, jurors expect competent management; as a result, this case was likely difficult to defend. The case report tells us that the defense did not challenge a breach of the standard of care (liability) but instead focused on the ultimate impact of the mistake, given the patient’s end-stage renal failure and short life expectancy (damages).

The $2 million settlement is relatively restrained, given the patient’s young age and the location of the case. This suggests the defense had some success arguing that the patient, at baseline, was gravely ill with a diminished lifespan.

As clinicians, we would all agree that an acutely stressed, hospitalized diabetic patient should be managed closely. But how often do we see diabetic patients in an ambulatory setting who are moderately stressed, ill, vomiting, and not eating? How often do we consider the possibility that these patients could slip out of control if not monitored more closely?

While we can’t revamp our diabetic patients’ regimens for every cold, we can encourage them to develop a “sick day” plan and remind them to be vigilant about managing their diabetes during illness. Consider the “sick day” advice given to patients by the Joslin Diabetes Center:
• Always take your diabetes medication. If you have difficulty keeping the medicine down due to vomiting, call your clinician.
• Check your blood glucose level at least 4 times a day. If you are too sick to test it yourself, have someone else do it. Record your levels in case you need to contact your clinician.
• Check for ketones if your blood glucose is 250 or higher. Again, write down your levels for reference.
• Stick to your normal meal plan, if possible.
• Drink lots of sugar-free liquids to prevent dehydration.¹

Patients are also advised to contact their health care provider if they have any of the following symptoms: a fever of more than 100.5°F; vomiting or diarrhea of more than two hours’ duration; blood glucose levels higher than 250 mg after two checks, or levels that do not decrease after extra insulin is taken; and moderate or large ketones.¹

The instruction to call the office for any fever higher than 100.5°F may seem abundantly cautious. But the discussion that ensues would serve as an opportunity to reinforce the need for closer monitoring—perhaps preventing a patient with a modest illness from spiraling out of glycemic control. —DML

REFERENCE 
1. Joslin Diabetes Center. Sick Days. www.joslin.org/info/Sick_Days.html. Accessed June 10, 2015.

ANSWER

The ECG shows marked sinus bradycardia with a four-second pause consistent with sinus arrest. This may be due to conduction disease within the sinus node and may be exacerbated by use of β-blockers or calcium-channel blockers, or by hypothyroidism.

The patient’s episodes of near-syncope coincided with sinus arrest on telemetry monitoring. She underwent implantation of a dual-chamber permanent pacemaker and resumed all previous activities without issue.

ANSWER

The ECG shows marked sinus bradycardia with a four-second pause consistent with sinus arrest. This may be due to conduction disease within the sinus node and may be exacerbated by use of β-blockers or calcium-channel blockers, or by hypothyroidism.

The patient’s episodes of near-syncope coincided with sinus arrest on telemetry monitoring. She underwent implantation of a dual-chamber permanent pacemaker and resumed all previous activities without issue.

ANSWER

The ECG shows marked sinus bradycardia with a four-second pause consistent with sinus arrest. This may be due to conduction disease within the sinus node and may be exacerbated by use of β-blockers or calcium-channel blockers, or by hypothyroidism.

The patient’s episodes of near-syncope coincided with sinus arrest on telemetry monitoring. She underwent implantation of a dual-chamber permanent pacemaker and resumed all previous activities without issue.

The first connection between cancer and a patient’s genome was documented by Peter Nowell and David Hungerford when they identified a unique chromosome in the metaphase spread of 7 patients diagnosed with chronic myeloid leukemia (CML). In 1973, renowned cytopathologist Janet Rowley determined that this chromosome is part of a chromosomal translocation between chromosome 9 and chromosome 22. Further delineation of this translocation showed that the gene ABL1, normally located on chromosome 9, is translocated to the Philadelphia (Ph+) chromosome in patients with CML. ABL1 was found to be located downstream of a specific genetic region in each patient, and this region became known as the BCR, or “breakpoint cluster region.” The BCR-ABL1 translocation found in patients with CML creates a constitutively active tyrosine kinase necessary for cellular transformation.

To read the full article in PDF:

Click here

The first connection between cancer and a patient’s genome was documented by Peter Nowell and David Hungerford when they identified a unique chromosome in the metaphase spread of 7 patients diagnosed with chronic myeloid leukemia (CML). In 1973, renowned cytopathologist Janet Rowley determined that this chromosome is part of a chromosomal translocation between chromosome 9 and chromosome 22. Further delineation of this translocation showed that the gene ABL1, normally located on chromosome 9, is translocated to the Philadelphia (Ph+) chromosome in patients with CML. ABL1 was found to be located downstream of a specific genetic region in each patient, and this region became known as the BCR, or “breakpoint cluster region.” The BCR-ABL1 translocation found in patients with CML creates a constitutively active tyrosine kinase necessary for cellular transformation.

To read the full article in PDF:

Click here

The first connection between cancer and a patient’s genome was documented by Peter Nowell and David Hungerford when they identified a unique chromosome in the metaphase spread of 7 patients diagnosed with chronic myeloid leukemia (CML). In 1973, renowned cytopathologist Janet Rowley determined that this chromosome is part of a chromosomal translocation between chromosome 9 and chromosome 22. Further delineation of this translocation showed that the gene ABL1, normally located on chromosome 9, is translocated to the Philadelphia (Ph+) chromosome in patients with CML. ABL1 was found to be located downstream of a specific genetic region in each patient, and this region became known as the BCR, or “breakpoint cluster region.” The BCR-ABL1 translocation found in patients with CML creates a constitutively active tyrosine kinase necessary for cellular transformation.

To read the full article in PDF:

Click here

ROME – Clinicians who care for patients with chronic inflammatory rheumatic diseases should consider regularly assessing six potential comorbidities these patients might develop, according to a set of “points to consider” developed by a task force of the European League Against Rheumatism.

The six comorbidities the working group’s report cites are ischemic cardiovascular disease, malignancies, infections, peptic ulcer, osteoporosis, and depression, Dr. Maxime Dougados said at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

This is the “minimum list of comorbidities to systematically check” for patients with inflammatory rheumatic diseases, said Dr. Dougados, professor and chief of rheumatology at Cochin Hospital in Paris.

The task force he heads plans to soon make available on the EULAR Website screening questionnaires for assessing the status of each of these six comorbidities. “We hope you will consider this initiative and implement these points to consider in your practice,” he said.

A seventh comorbidity to potentially add to the list for regular assessment is hypertension, said Dr. Deborah P.M. Symmons, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester (England), in a separate talk at the meeting. Roughly 80% of patients with rheumatoid arthritis (RA) have at least one comorbidity, she noted.

Recent study results have documented the prevalence of comorbidities in patients with RA, Dr. Symmons said. For example, an analysis of data collected during 2011 and 2012 from 3,920 RA patients in 17 countries, including 400 U.S. patients, showed that depression was the most common comorbidity, affecting 15% of patients; other comorbidities included ischemic cardiovascular disease in 6%, malignancy in 5%, and hypertension in 11% (Ann. Rheum. Dis. 2014;73:62-8). A separate survey of 9,874 RA patients from 34 countries also published last year found patients had a median of two comorbidities each. The most common were hypertension in 32% of patients, osteoporosis in 18%, and osteoarthritis in 16% (Clin. Exp. Rheum. 2014;32:869-77).

Mitchel L. Zoler/Frontline Medical News

“Chronic diseases cluster together, more than you would expect by chance, perhaps because of shared risk factors such as genetic or environmental, the direct impact of inflammation, and because of treatment” patients receive for their rheumatic disease, Dr. Symmons said.

The consequence is that clinicians who manage patients with RA or other rheumatic disease must be on the lookout for comorbidities and take them into consideration when planning management strategies. A rheumatologist might be most concerned about how comobidities will affect the rheumatic disease, but for patients the overriding concern is how all their chronic diseases, not just their rheumatic disease, will affect their quality of life and physical function, she noted. “We must constantly ask ourselves whether treatment of the RA will worsen the comorbidities, or will treatment of the comorbidities worsen the RA?”

Knowledge of how RA treatments will affect comorbidities is often lacking because patients with comorbidities are usually not enrolled in clinical trials, Dr. Symmons said.

She recommended that rheumatologists systematically screen patients annually for comorbidities and discuss with each patient and with clinicians from other relevant specialties appropriate treatment based on the patient’s global status. Steroid treatment should be minimized because of the risk it poses for causing or exacerbating hypertension, hyperlipidemia, diabetes, osteoporosis, and infection.

The rheumatologist does not necessarily need to be the clinician who manages all of a patient’s comorbidities, which might be better done by a primary care physician, but the rheumatologist should know that a patient’s comorbidities are being managed by someone, and this fact should be documented in the rheumatologist’s records for each patient, she said.

Dr. Dougados and Dr. Symmons said they had no relevant financial disclosures.

[email protected]

On Twitter@mitchelzoler

ROME – Clinicians who care for patients with chronic inflammatory rheumatic diseases should consider regularly assessing six potential comorbidities these patients might develop, according to a set of “points to consider” developed by a task force of the European League Against Rheumatism.

The six comorbidities the working group’s report cites are ischemic cardiovascular disease, malignancies, infections, peptic ulcer, osteoporosis, and depression, Dr. Maxime Dougados said at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

This is the “minimum list of comorbidities to systematically check” for patients with inflammatory rheumatic diseases, said Dr. Dougados, professor and chief of rheumatology at Cochin Hospital in Paris.

The task force he heads plans to soon make available on the EULAR Website screening questionnaires for assessing the status of each of these six comorbidities. “We hope you will consider this initiative and implement these points to consider in your practice,” he said.

A seventh comorbidity to potentially add to the list for regular assessment is hypertension, said Dr. Deborah P.M. Symmons, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester (England), in a separate talk at the meeting. Roughly 80% of patients with rheumatoid arthritis (RA) have at least one comorbidity, she noted.

Recent study results have documented the prevalence of comorbidities in patients with RA, Dr. Symmons said. For example, an analysis of data collected during 2011 and 2012 from 3,920 RA patients in 17 countries, including 400 U.S. patients, showed that depression was the most common comorbidity, affecting 15% of patients; other comorbidities included ischemic cardiovascular disease in 6%, malignancy in 5%, and hypertension in 11% (Ann. Rheum. Dis. 2014;73:62-8). A separate survey of 9,874 RA patients from 34 countries also published last year found patients had a median of two comorbidities each. The most common were hypertension in 32% of patients, osteoporosis in 18%, and osteoarthritis in 16% (Clin. Exp. Rheum. 2014;32:869-77).

Mitchel L. Zoler/Frontline Medical News

“Chronic diseases cluster together, more than you would expect by chance, perhaps because of shared risk factors such as genetic or environmental, the direct impact of inflammation, and because of treatment” patients receive for their rheumatic disease, Dr. Symmons said.

The consequence is that clinicians who manage patients with RA or other rheumatic disease must be on the lookout for comorbidities and take them into consideration when planning management strategies. A rheumatologist might be most concerned about how comobidities will affect the rheumatic disease, but for patients the overriding concern is how all their chronic diseases, not just their rheumatic disease, will affect their quality of life and physical function, she noted. “We must constantly ask ourselves whether treatment of the RA will worsen the comorbidities, or will treatment of the comorbidities worsen the RA?”

Knowledge of how RA treatments will affect comorbidities is often lacking because patients with comorbidities are usually not enrolled in clinical trials, Dr. Symmons said.

She recommended that rheumatologists systematically screen patients annually for comorbidities and discuss with each patient and with clinicians from other relevant specialties appropriate treatment based on the patient’s global status. Steroid treatment should be minimized because of the risk it poses for causing or exacerbating hypertension, hyperlipidemia, diabetes, osteoporosis, and infection.

The rheumatologist does not necessarily need to be the clinician who manages all of a patient’s comorbidities, which might be better done by a primary care physician, but the rheumatologist should know that a patient’s comorbidities are being managed by someone, and this fact should be documented in the rheumatologist’s records for each patient, she said.

Dr. Dougados and Dr. Symmons said they had no relevant financial disclosures.

[email protected]

On Twitter@mitchelzoler

ROME – Clinicians who care for patients with chronic inflammatory rheumatic diseases should consider regularly assessing six potential comorbidities these patients might develop, according to a set of “points to consider” developed by a task force of the European League Against Rheumatism.

The six comorbidities the working group’s report cites are ischemic cardiovascular disease, malignancies, infections, peptic ulcer, osteoporosis, and depression, Dr. Maxime Dougados said at the European Congress of Rheumatology.

Mitchel L. Zoler/Frontline Medical News

This is the “minimum list of comorbidities to systematically check” for patients with inflammatory rheumatic diseases, said Dr. Dougados, professor and chief of rheumatology at Cochin Hospital in Paris.

The task force he heads plans to soon make available on the EULAR Website screening questionnaires for assessing the status of each of these six comorbidities. “We hope you will consider this initiative and implement these points to consider in your practice,” he said.

A seventh comorbidity to potentially add to the list for regular assessment is hypertension, said Dr. Deborah P.M. Symmons, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester (England), in a separate talk at the meeting. Roughly 80% of patients with rheumatoid arthritis (RA) have at least one comorbidity, she noted.

Recent study results have documented the prevalence of comorbidities in patients with RA, Dr. Symmons said. For example, an analysis of data collected during 2011 and 2012 from 3,920 RA patients in 17 countries, including 400 U.S. patients, showed that depression was the most common comorbidity, affecting 15% of patients; other comorbidities included ischemic cardiovascular disease in 6%, malignancy in 5%, and hypertension in 11% (Ann. Rheum. Dis. 2014;73:62-8). A separate survey of 9,874 RA patients from 34 countries also published last year found patients had a median of two comorbidities each. The most common were hypertension in 32% of patients, osteoporosis in 18%, and osteoarthritis in 16% (Clin. Exp. Rheum. 2014;32:869-77).

Mitchel L. Zoler/Frontline Medical News

“Chronic diseases cluster together, more than you would expect by chance, perhaps because of shared risk factors such as genetic or environmental, the direct impact of inflammation, and because of treatment” patients receive for their rheumatic disease, Dr. Symmons said.

The consequence is that clinicians who manage patients with RA or other rheumatic disease must be on the lookout for comorbidities and take them into consideration when planning management strategies. A rheumatologist might be most concerned about how comobidities will affect the rheumatic disease, but for patients the overriding concern is how all their chronic diseases, not just their rheumatic disease, will affect their quality of life and physical function, she noted. “We must constantly ask ourselves whether treatment of the RA will worsen the comorbidities, or will treatment of the comorbidities worsen the RA?”

Knowledge of how RA treatments will affect comorbidities is often lacking because patients with comorbidities are usually not enrolled in clinical trials, Dr. Symmons said.

She recommended that rheumatologists systematically screen patients annually for comorbidities and discuss with each patient and with clinicians from other relevant specialties appropriate treatment based on the patient’s global status. Steroid treatment should be minimized because of the risk it poses for causing or exacerbating hypertension, hyperlipidemia, diabetes, osteoporosis, and infection.

The rheumatologist does not necessarily need to be the clinician who manages all of a patient’s comorbidities, which might be better done by a primary care physician, but the rheumatologist should know that a patient’s comorbidities are being managed by someone, and this fact should be documented in the rheumatologist’s records for each patient, she said.

Dr. Dougados and Dr. Symmons said they had no relevant financial disclosures.

[email protected]

On Twitter@mitchelzoler

ANSWER
The correct answer is to perform a KOH examination (choice “b”), which takes just five minutes and offers the chance to establish the fungal origin of the rash. Although the patient’s skin is quite dry, the use of a moisturizer (choice “a”) is unlikely to address the overall problem. A punch biopsy (choice “c”) would be a logical choice if the KOH failed to solve the mystery. The use of combination creams (choice “d”) that contain a steroid (triamcinolone) and an antifungal (nystatin) is essentially an admission of the lack of a definitive diagnosis. For reasons discussed below, this strategy has almost no chance of helping.

DISCUSSION
In this case, the KOH prep showed numerous hyphal elements, confirming suspicions of a fungal origin. One potential source of these organisms was the patient’s feet, where fungal infection had been present for years (“more than 30,” questioning revealed).

A common scenario is one in which the patient applies a steroid cream to a bit of dry skin just above the feet, which allows the fungi to gain a “foothold” from which to spread upward onto the leg; this progress is assisted through scratching and additional steroid application. If no firm diagnosis is ever established, definitive treatment cannot be undertaken and the problem never resolves.

In my opinion, there is never a reason to prescribe a product containing nystatin. In 1950, when it was discovered by researchers working in New York State laboratories (after which it was named), its efficacy against Candida species represented a notable advance, given the limited drug choices available for that purpose. But it has little, if any, activity against the dermatophytes causing our patient’s problems. And the steroid (triamcinolone) in this combination product, far from adding any therapeutic benefit, effectively diminishes any natural immune response.

The other reason to refrain from prescribing nystatin is that, since its discovery, at least three generations of products that treat both fungi and yeast (the azoles, such as clotrimazole, econazole, and fluconazole) have become available and have been found to be very effective.

The more important issue in this case, however, is finally having an accurate diagnosis: tinea corporis, probably caused by the most common dermatophyte, Trichophyton rubrum. The patient’s body is obviously a very happy home for this ubiquitous organism, to the extent that our chances of eliminating it are quite small. But we can at least make the patient more comfortable.

Treatment entailed ketoconazole foam (applied bid to his legs) and a two-month course of oral terbinafine (250 mg/d), which cleared up most of the skin problem. For his overgrown toenails, the patient was advised to establish care with a podiatrist for regular trimming.

In terms of a differential, this patient might have had psoriasis or eczema—and may still have one or both, since there’s no law against having more than one condition in the same location. In time, we may have to reconsider our solitary diagnosis.

ANSWER
The correct answer is to perform a KOH examination (choice “b”), which takes just five minutes and offers the chance to establish the fungal origin of the rash. Although the patient’s skin is quite dry, the use of a moisturizer (choice “a”) is unlikely to address the overall problem. A punch biopsy (choice “c”) would be a logical choice if the KOH failed to solve the mystery. The use of combination creams (choice “d”) that contain a steroid (triamcinolone) and an antifungal (nystatin) is essentially an admission of the lack of a definitive diagnosis. For reasons discussed below, this strategy has almost no chance of helping.

DISCUSSION
In this case, the KOH prep showed numerous hyphal elements, confirming suspicions of a fungal origin. One potential source of these organisms was the patient’s feet, where fungal infection had been present for years (“more than 30,” questioning revealed).

A common scenario is one in which the patient applies a steroid cream to a bit of dry skin just above the feet, which allows the fungi to gain a “foothold” from which to spread upward onto the leg; this progress is assisted through scratching and additional steroid application. If no firm diagnosis is ever established, definitive treatment cannot be undertaken and the problem never resolves.

In my opinion, there is never a reason to prescribe a product containing nystatin. In 1950, when it was discovered by researchers working in New York State laboratories (after which it was named), its efficacy against Candida species represented a notable advance, given the limited drug choices available for that purpose. But it has little, if any, activity against the dermatophytes causing our patient’s problems. And the steroid (triamcinolone) in this combination product, far from adding any therapeutic benefit, effectively diminishes any natural immune response.

The other reason to refrain from prescribing nystatin is that, since its discovery, at least three generations of products that treat both fungi and yeast (the azoles, such as clotrimazole, econazole, and fluconazole) have become available and have been found to be very effective.

The more important issue in this case, however, is finally having an accurate diagnosis: tinea corporis, probably caused by the most common dermatophyte, Trichophyton rubrum. The patient’s body is obviously a very happy home for this ubiquitous organism, to the extent that our chances of eliminating it are quite small. But we can at least make the patient more comfortable.

Treatment entailed ketoconazole foam (applied bid to his legs) and a two-month course of oral terbinafine (250 mg/d), which cleared up most of the skin problem. For his overgrown toenails, the patient was advised to establish care with a podiatrist for regular trimming.

In terms of a differential, this patient might have had psoriasis or eczema—and may still have one or both, since there’s no law against having more than one condition in the same location. In time, we may have to reconsider our solitary diagnosis.

ANSWER
The correct answer is to perform a KOH examination (choice “b”), which takes just five minutes and offers the chance to establish the fungal origin of the rash. Although the patient’s skin is quite dry, the use of a moisturizer (choice “a”) is unlikely to address the overall problem. A punch biopsy (choice “c”) would be a logical choice if the KOH failed to solve the mystery. The use of combination creams (choice “d”) that contain a steroid (triamcinolone) and an antifungal (nystatin) is essentially an admission of the lack of a definitive diagnosis. For reasons discussed below, this strategy has almost no chance of helping.

DISCUSSION
In this case, the KOH prep showed numerous hyphal elements, confirming suspicions of a fungal origin. One potential source of these organisms was the patient’s feet, where fungal infection had been present for years (“more than 30,” questioning revealed).

A common scenario is one in which the patient applies a steroid cream to a bit of dry skin just above the feet, which allows the fungi to gain a “foothold” from which to spread upward onto the leg; this progress is assisted through scratching and additional steroid application. If no firm diagnosis is ever established, definitive treatment cannot be undertaken and the problem never resolves.

In my opinion, there is never a reason to prescribe a product containing nystatin. In 1950, when it was discovered by researchers working in New York State laboratories (after which it was named), its efficacy against Candida species represented a notable advance, given the limited drug choices available for that purpose. But it has little, if any, activity against the dermatophytes causing our patient’s problems. And the steroid (triamcinolone) in this combination product, far from adding any therapeutic benefit, effectively diminishes any natural immune response.

The other reason to refrain from prescribing nystatin is that, since its discovery, at least three generations of products that treat both fungi and yeast (the azoles, such as clotrimazole, econazole, and fluconazole) have become available and have been found to be very effective.

The more important issue in this case, however, is finally having an accurate diagnosis: tinea corporis, probably caused by the most common dermatophyte, Trichophyton rubrum. The patient’s body is obviously a very happy home for this ubiquitous organism, to the extent that our chances of eliminating it are quite small. But we can at least make the patient more comfortable.

Treatment entailed ketoconazole foam (applied bid to his legs) and a two-month course of oral terbinafine (250 mg/d), which cleared up most of the skin problem. For his overgrown toenails, the patient was advised to establish care with a podiatrist for regular trimming.

In terms of a differential, this patient might have had psoriasis or eczema—and may still have one or both, since there’s no law against having more than one condition in the same location. In time, we may have to reconsider our solitary diagnosis.

Q) My hematuria patient had more significant proteinuria recently, so the nephrologist sent him for kidney biopsy. It was read as IgA nephropathy: “classic mesangial staining on IF with moderate-advanced chronic injury (15/32 gloms globally sclerosed, 40% IFTA, mild arteriosclerosis).” What exactly does this mean, and what is IgA nephropathy?

Immunoglobulin A (IgA) nephropathy is the most common type of glomerulonephritis; up to 40% of patients with IgA nephropathy develop end-stage renal disease within 20 years of diagnosis. More common in men, IgA nephropathy is usually diagnosed in people in their second or third decades of life.^2,3

Considered an autoimmune disease, IgA nephropathy typically presents with macroscopic or gross hematuria that occurs within 24 hours of the onset of an upper respiratory infection (URI). The hematuria typically resolves quickly, in one to three days. An individual bacterial or viral element has not yet been identified.

IgA nephropathy is an immune response to the URI. IgA is secreted from mucosal surfaces at the back of the mouth and then deposited in the glomerular mesangium, a “stalk of cells” associated with the capillaries of the renal glomerulus.¹ It is speculated that genetics, environment, and/or hypersensitivity to food antigens may play a part in IgA nephropathy. Results from biopsies of blood relatives of patients with confirmed IgA nephropathy suggest a familial role.¹

IgA nephropathy is prevalent in persons who live in the Pacific Rim and Southern Europe. However, this association may be the result of a sampling error due to investigation of all microscopic hematuria in these areas. In all, 90% of IgA is sporadic.⁴ It is often asymptomatic, aside from occasional back and flank pain secondary to inflammation of the renal capsule. Unfortunately, many patients develop renal impairment and hypertension by the time they are diagnosed.

Renal biopsy is used to confirm/diagnose IgA nephropathy. IgA, deposited in the mesangium of the glomerulus, lights up under immunofluorescence (IF; see Figure 1). In some patients, this mesangial deposition results in sclerosis, scarring, and/or inflammation of the glomerulus (see Figure 2).

An international panel of experts created guidelines (the Oxford classification system) for reporting IgA kidney biopsies. Six adverse pathologic features have been identified:
• Mesangial cellularity score
• Percentage of segmental sclerosis
• Endocapillary ­hypercellularity
• Cellular and/or fibrocellular crescents
• Percentage of interstitial fibrosis/tubular atrophy (IFTA)
• Arteriosclerosis score^5,6

Interstitial fibrosis, crescents, and as little as 25% glomerular sclerosis found on biopsy increases the likelihood of disease progression.5 Clinically, hypertension, a reduced glomerular filtration rate, increasing age, and proteinuria of > 1g/24h have been identified as risk factors for progression of IgA nephropathy. Up to 30% of patients diagnosed will require renal replacement therapy within 20 years.¹

The case patient’s findings include the typical IF staining of IgA in the glomerulus. The biopsy report also indicates that 40% of the glomeruli (less than half) have interstitial fibrosis and that the structural integrity of the tubules has been affected secondary to IgA accumulation in the mesangium. These findings are suggestive of progressive disease.

There is no known way to stop IgA deposition in the mesangium. Tonsillectomy to reduce mucosal IgA release has been suggested but is controversial.

Treatment of IgA nephropathy focuses on preserving renal function by reducing proteinuria through the use of ACE inhibitors and/or angiotensin receptor blockers. Aggressive blood pressure management is achieved by blocking the renin-angiotensin-aldosterone system (RAAS).

Other methods for decreasing progression of renal disease are directed at reducing the immune and inflammatory response via immunosuppressant medications.³ The use of immunosuppressive agents, though controversial, is recommended for those who have progressive disease and/or proteinuria despite achieving target blood pressure with full RAAS blockade.¹

Amy L. Hazel, RN, MSN, CNP
Kidney & Hypertension Consultants, Canton, Ohio

REFERENCES
1. Greenberg A. Primer on Kidney Diseases. 5th ed. Philadelphia, PA: Elsevier Saunders; 2005.
2. Barratt J, Feehally J. IgA nephropathy [disease of the month]. J Am Soc Nephrol. 2005;16(7): 2088-2097.
3. Barratt J, Feehally J. Treatment of IgA nephropathy. Kidney Int. 2006;69(11):1934-1938.
4. Johnson R, Feehally J. Comprehensive Clinical Nephrology. 2nd ed. London: Mosby; 2000.
5. Walsh M, Sar A, Lee D, et al. Histopathologic features aid in predicting risk for progression of IgA nephropathy. Clin J Am Soc Nephrol. 2010; 5(3):425-430.
6. Roberts I. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int. 2009; 76(5):546-556.    

Q) My hematuria patient had more significant proteinuria recently, so the nephrologist sent him for kidney biopsy. It was read as IgA nephropathy: “classic mesangial staining on IF with moderate-advanced chronic injury (15/32 gloms globally sclerosed, 40% IFTA, mild arteriosclerosis).” What exactly does this mean, and what is IgA nephropathy?

Immunoglobulin A (IgA) nephropathy is the most common type of glomerulonephritis; up to 40% of patients with IgA nephropathy develop end-stage renal disease within 20 years of diagnosis. More common in men, IgA nephropathy is usually diagnosed in people in their second or third decades of life.^2,3

Considered an autoimmune disease, IgA nephropathy typically presents with macroscopic or gross hematuria that occurs within 24 hours of the onset of an upper respiratory infection (URI). The hematuria typically resolves quickly, in one to three days. An individual bacterial or viral element has not yet been identified.

IgA nephropathy is an immune response to the URI. IgA is secreted from mucosal surfaces at the back of the mouth and then deposited in the glomerular mesangium, a “stalk of cells” associated with the capillaries of the renal glomerulus.¹ It is speculated that genetics, environment, and/or hypersensitivity to food antigens may play a part in IgA nephropathy. Results from biopsies of blood relatives of patients with confirmed IgA nephropathy suggest a familial role.¹

IgA nephropathy is prevalent in persons who live in the Pacific Rim and Southern Europe. However, this association may be the result of a sampling error due to investigation of all microscopic hematuria in these areas. In all, 90% of IgA is sporadic.⁴ It is often asymptomatic, aside from occasional back and flank pain secondary to inflammation of the renal capsule. Unfortunately, many patients develop renal impairment and hypertension by the time they are diagnosed.

Renal biopsy is used to confirm/diagnose IgA nephropathy. IgA, deposited in the mesangium of the glomerulus, lights up under immunofluorescence (IF; see Figure 1). In some patients, this mesangial deposition results in sclerosis, scarring, and/or inflammation of the glomerulus (see Figure 2).

An international panel of experts created guidelines (the Oxford classification system) for reporting IgA kidney biopsies. Six adverse pathologic features have been identified:
• Mesangial cellularity score
• Percentage of segmental sclerosis
• Endocapillary ­hypercellularity
• Cellular and/or fibrocellular crescents
• Percentage of interstitial fibrosis/tubular atrophy (IFTA)
• Arteriosclerosis score^5,6

Interstitial fibrosis, crescents, and as little as 25% glomerular sclerosis found on biopsy increases the likelihood of disease progression.5 Clinically, hypertension, a reduced glomerular filtration rate, increasing age, and proteinuria of > 1g/24h have been identified as risk factors for progression of IgA nephropathy. Up to 30% of patients diagnosed will require renal replacement therapy within 20 years.¹

The case patient’s findings include the typical IF staining of IgA in the glomerulus. The biopsy report also indicates that 40% of the glomeruli (less than half) have interstitial fibrosis and that the structural integrity of the tubules has been affected secondary to IgA accumulation in the mesangium. These findings are suggestive of progressive disease.

There is no known way to stop IgA deposition in the mesangium. Tonsillectomy to reduce mucosal IgA release has been suggested but is controversial.

Treatment of IgA nephropathy focuses on preserving renal function by reducing proteinuria through the use of ACE inhibitors and/or angiotensin receptor blockers. Aggressive blood pressure management is achieved by blocking the renin-angiotensin-aldosterone system (RAAS).

Other methods for decreasing progression of renal disease are directed at reducing the immune and inflammatory response via immunosuppressant medications.³ The use of immunosuppressive agents, though controversial, is recommended for those who have progressive disease and/or proteinuria despite achieving target blood pressure with full RAAS blockade.¹

Amy L. Hazel, RN, MSN, CNP
Kidney & Hypertension Consultants, Canton, Ohio

REFERENCES
1. Greenberg A. Primer on Kidney Diseases. 5th ed. Philadelphia, PA: Elsevier Saunders; 2005.
2. Barratt J, Feehally J. IgA nephropathy [disease of the month]. J Am Soc Nephrol. 2005;16(7): 2088-2097.
3. Barratt J, Feehally J. Treatment of IgA nephropathy. Kidney Int. 2006;69(11):1934-1938.
4. Johnson R, Feehally J. Comprehensive Clinical Nephrology. 2nd ed. London: Mosby; 2000.
5. Walsh M, Sar A, Lee D, et al. Histopathologic features aid in predicting risk for progression of IgA nephropathy. Clin J Am Soc Nephrol. 2010; 5(3):425-430.
6. Roberts I. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int. 2009; 76(5):546-556.    

Q) My hematuria patient had more significant proteinuria recently, so the nephrologist sent him for kidney biopsy. It was read as IgA nephropathy: “classic mesangial staining on IF with moderate-advanced chronic injury (15/32 gloms globally sclerosed, 40% IFTA, mild arteriosclerosis).” What exactly does this mean, and what is IgA nephropathy?

Immunoglobulin A (IgA) nephropathy is the most common type of glomerulonephritis; up to 40% of patients with IgA nephropathy develop end-stage renal disease within 20 years of diagnosis. More common in men, IgA nephropathy is usually diagnosed in people in their second or third decades of life.^2,3

Considered an autoimmune disease, IgA nephropathy typically presents with macroscopic or gross hematuria that occurs within 24 hours of the onset of an upper respiratory infection (URI). The hematuria typically resolves quickly, in one to three days. An individual bacterial or viral element has not yet been identified.

IgA nephropathy is an immune response to the URI. IgA is secreted from mucosal surfaces at the back of the mouth and then deposited in the glomerular mesangium, a “stalk of cells” associated with the capillaries of the renal glomerulus.¹ It is speculated that genetics, environment, and/or hypersensitivity to food antigens may play a part in IgA nephropathy. Results from biopsies of blood relatives of patients with confirmed IgA nephropathy suggest a familial role.¹

IgA nephropathy is prevalent in persons who live in the Pacific Rim and Southern Europe. However, this association may be the result of a sampling error due to investigation of all microscopic hematuria in these areas. In all, 90% of IgA is sporadic.⁴ It is often asymptomatic, aside from occasional back and flank pain secondary to inflammation of the renal capsule. Unfortunately, many patients develop renal impairment and hypertension by the time they are diagnosed.

Renal biopsy is used to confirm/diagnose IgA nephropathy. IgA, deposited in the mesangium of the glomerulus, lights up under immunofluorescence (IF; see Figure 1). In some patients, this mesangial deposition results in sclerosis, scarring, and/or inflammation of the glomerulus (see Figure 2).

An international panel of experts created guidelines (the Oxford classification system) for reporting IgA kidney biopsies. Six adverse pathologic features have been identified:
• Mesangial cellularity score
• Percentage of segmental sclerosis
• Endocapillary ­hypercellularity
• Cellular and/or fibrocellular crescents
• Percentage of interstitial fibrosis/tubular atrophy (IFTA)
• Arteriosclerosis score^5,6

Interstitial fibrosis, crescents, and as little as 25% glomerular sclerosis found on biopsy increases the likelihood of disease progression.5 Clinically, hypertension, a reduced glomerular filtration rate, increasing age, and proteinuria of > 1g/24h have been identified as risk factors for progression of IgA nephropathy. Up to 30% of patients diagnosed will require renal replacement therapy within 20 years.¹

The case patient’s findings include the typical IF staining of IgA in the glomerulus. The biopsy report also indicates that 40% of the glomeruli (less than half) have interstitial fibrosis and that the structural integrity of the tubules has been affected secondary to IgA accumulation in the mesangium. These findings are suggestive of progressive disease.

There is no known way to stop IgA deposition in the mesangium. Tonsillectomy to reduce mucosal IgA release has been suggested but is controversial.

Treatment of IgA nephropathy focuses on preserving renal function by reducing proteinuria through the use of ACE inhibitors and/or angiotensin receptor blockers. Aggressive blood pressure management is achieved by blocking the renin-angiotensin-aldosterone system (RAAS).

Other methods for decreasing progression of renal disease are directed at reducing the immune and inflammatory response via immunosuppressant medications.³ The use of immunosuppressive agents, though controversial, is recommended for those who have progressive disease and/or proteinuria despite achieving target blood pressure with full RAAS blockade.¹

Amy L. Hazel, RN, MSN, CNP
Kidney & Hypertension Consultants, Canton, Ohio

REFERENCES
1. Greenberg A. Primer on Kidney Diseases. 5th ed. Philadelphia, PA: Elsevier Saunders; 2005.
2. Barratt J, Feehally J. IgA nephropathy [disease of the month]. J Am Soc Nephrol. 2005;16(7): 2088-2097.
3. Barratt J, Feehally J. Treatment of IgA nephropathy. Kidney Int. 2006;69(11):1934-1938.
4. Johnson R, Feehally J. Comprehensive Clinical Nephrology. 2nd ed. London: Mosby; 2000.
5. Walsh M, Sar A, Lee D, et al. Histopathologic features aid in predicting risk for progression of IgA nephropathy. Clin J Am Soc Nephrol. 2010; 5(3):425-430.
6. Roberts I. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int. 2009; 76(5):546-556.    

Grafenrheinfeld nuclear

power plant in Germany

Protracted exposure to ionizing radiation, even at low doses, can increase a person’s risk of dying from certain leukemias, according to research published in The Lancet Haematology.

The study showed that protracted radiation exposure was associated with an excess risk of leukemia mortality, particularly for chronic myeloid leukemia (CML).

However, there was no excess mortality risk for chronic lymphocytic leukemia (CLL).

Investigators also observed an association between ionizing radiation exposure and death from multiple myeloma or lymphoma, but they said the evidence for these associations was not strong.

“To date, this study provides the most precise evaluation of the risk of developing leukemia linked to the protracted low doses of radiation received by nuclear workers throughout their careers,” said study author Ausrele Kesminiene, MD, of the International Agency for Research on Cancer, the specialized cancer agency of the World Health Organization.

“It shows that the nuclear workers we studied have a small increase in the risk of dying from leukemia as their exposure to radiation increases.”

This study, known as INWORKS, included 308,297 workers who were monitored for exposure to radiation.

Subjects were employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France or the Departments of Energy and Defense in the US. The study also included nuclear industry employers in the National Registry for Radiation Workers in the UK.

Investigators assessed the risk of death from hematologic malignancies among these subjects. The team used Poisson regression to quantify associations between the estimated radiation dose in the red bone marrow and mortality from malignancy.

The mean follow-up was 27 years, and nearly 22% of workers died during that time. The mean cumulative radiation dose was 16 mGy, the median was 2.1 mGy, and the mean yearly dose was 1.1 mGy.

Quantifying the risk

The investigators found “strong evidence” for a positive association between exposure to ionizing radiation and the risk of death from leukemias, excluding CLL. Specifically, the excess relative risk of mortality per Gy of radiation was 2.96 (90% CI 1.17-5.21).

Even low doses of radiation posed a risk. Fifty-three percent of deaths from leukemia (excluding CLL) occurred in workers who had accrued less than 5 mGy of radiation.

However, the relative risk of death from leukemia (excluding CLL) increased with the radiation dose. The relative risk was 1.00 for 0-5 mGy, 1.01 for 5-50 mGy, 1.30 for 50-100 mGy, 1.19 for 100-200 mGy, 2.30 for 200-300 mGy, and 1.70 for more than 300 mGy.

The data also showed the risk of cancer mortality associated with radiation exposure varied according to the type of leukemia.

The excess relative risk of mortality was 10.45 for CML, 1.29 for acute myeloid leukemia, and 5.80 for acute lymphoblastic leukemia. For CLL, the excess relative risk was -1.06.

The investigators also found positive associations between radiation exposure and mortality from Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma. However, the findings were “highly imprecise,” with confidence intervals that spanned 0.

Grafenrheinfeld nuclear

power plant in Germany

Protracted exposure to ionizing radiation, even at low doses, can increase a person’s risk of dying from certain leukemias, according to research published in The Lancet Haematology.

The study showed that protracted radiation exposure was associated with an excess risk of leukemia mortality, particularly for chronic myeloid leukemia (CML).

However, there was no excess mortality risk for chronic lymphocytic leukemia (CLL).

Investigators also observed an association between ionizing radiation exposure and death from multiple myeloma or lymphoma, but they said the evidence for these associations was not strong.

“To date, this study provides the most precise evaluation of the risk of developing leukemia linked to the protracted low doses of radiation received by nuclear workers throughout their careers,” said study author Ausrele Kesminiene, MD, of the International Agency for Research on Cancer, the specialized cancer agency of the World Health Organization.

“It shows that the nuclear workers we studied have a small increase in the risk of dying from leukemia as their exposure to radiation increases.”

This study, known as INWORKS, included 308,297 workers who were monitored for exposure to radiation.

Subjects were employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France or the Departments of Energy and Defense in the US. The study also included nuclear industry employers in the National Registry for Radiation Workers in the UK.

Investigators assessed the risk of death from hematologic malignancies among these subjects. The team used Poisson regression to quantify associations between the estimated radiation dose in the red bone marrow and mortality from malignancy.

The mean follow-up was 27 years, and nearly 22% of workers died during that time. The mean cumulative radiation dose was 16 mGy, the median was 2.1 mGy, and the mean yearly dose was 1.1 mGy.

Quantifying the risk

The investigators found “strong evidence” for a positive association between exposure to ionizing radiation and the risk of death from leukemias, excluding CLL. Specifically, the excess relative risk of mortality per Gy of radiation was 2.96 (90% CI 1.17-5.21).

Even low doses of radiation posed a risk. Fifty-three percent of deaths from leukemia (excluding CLL) occurred in workers who had accrued less than 5 mGy of radiation.

However, the relative risk of death from leukemia (excluding CLL) increased with the radiation dose. The relative risk was 1.00 for 0-5 mGy, 1.01 for 5-50 mGy, 1.30 for 50-100 mGy, 1.19 for 100-200 mGy, 2.30 for 200-300 mGy, and 1.70 for more than 300 mGy.

The data also showed the risk of cancer mortality associated with radiation exposure varied according to the type of leukemia.

The excess relative risk of mortality was 10.45 for CML, 1.29 for acute myeloid leukemia, and 5.80 for acute lymphoblastic leukemia. For CLL, the excess relative risk was -1.06.

The investigators also found positive associations between radiation exposure and mortality from Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma. However, the findings were “highly imprecise,” with confidence intervals that spanned 0.

Grafenrheinfeld nuclear

power plant in Germany

Protracted exposure to ionizing radiation, even at low doses, can increase a person’s risk of dying from certain leukemias, according to research published in The Lancet Haematology.

The study showed that protracted radiation exposure was associated with an excess risk of leukemia mortality, particularly for chronic myeloid leukemia (CML).

However, there was no excess mortality risk for chronic lymphocytic leukemia (CLL).

Investigators also observed an association between ionizing radiation exposure and death from multiple myeloma or lymphoma, but they said the evidence for these associations was not strong.

“To date, this study provides the most precise evaluation of the risk of developing leukemia linked to the protracted low doses of radiation received by nuclear workers throughout their careers,” said study author Ausrele Kesminiene, MD, of the International Agency for Research on Cancer, the specialized cancer agency of the World Health Organization.

“It shows that the nuclear workers we studied have a small increase in the risk of dying from leukemia as their exposure to radiation increases.”

This study, known as INWORKS, included 308,297 workers who were monitored for exposure to radiation.

Subjects were employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France or the Departments of Energy and Defense in the US. The study also included nuclear industry employers in the National Registry for Radiation Workers in the UK.

Investigators assessed the risk of death from hematologic malignancies among these subjects. The team used Poisson regression to quantify associations between the estimated radiation dose in the red bone marrow and mortality from malignancy.

The mean follow-up was 27 years, and nearly 22% of workers died during that time. The mean cumulative radiation dose was 16 mGy, the median was 2.1 mGy, and the mean yearly dose was 1.1 mGy.

Quantifying the risk

The investigators found “strong evidence” for a positive association between exposure to ionizing radiation and the risk of death from leukemias, excluding CLL. Specifically, the excess relative risk of mortality per Gy of radiation was 2.96 (90% CI 1.17-5.21).

Even low doses of radiation posed a risk. Fifty-three percent of deaths from leukemia (excluding CLL) occurred in workers who had accrued less than 5 mGy of radiation.

However, the relative risk of death from leukemia (excluding CLL) increased with the radiation dose. The relative risk was 1.00 for 0-5 mGy, 1.01 for 5-50 mGy, 1.30 for 50-100 mGy, 1.19 for 100-200 mGy, 2.30 for 200-300 mGy, and 1.70 for more than 300 mGy.

The data also showed the risk of cancer mortality associated with radiation exposure varied according to the type of leukemia.

The excess relative risk of mortality was 10.45 for CML, 1.29 for acute myeloid leukemia, and 5.80 for acute lymphoblastic leukemia. For CLL, the excess relative risk was -1.06.

The investigators also found positive associations between radiation exposure and mortality from Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma. However, the findings were “highly imprecise,” with confidence intervals that spanned 0.

rFIXFc components

Photo courtesy of Biogen

TORONTO—Full results of a phase 3 study support extended-interval dosing with a recombinant factor IX Fc fusion protein (rFIXFc) over FIX products with a standard half-life, according to a speaker at the 2015 ISTH Congress.

Kathelijn Fischer, MD, PhD, of the University Medical Center Utrecht in The Netherlands, reported results with rFIXFc (also known as eftrenonacog alfa and Alprolix), in children with severe hemophilia B who were enrolled on the KIDS B-LONG study.

rFIXFc was successful in preventing and treating bleeding episodes in these patients. Furthermore, the patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Dr Fischer presented these results as abstract LB009. Interim results of this study helped support the US approval of rFIXFc for use in children. The trial was sponsored by Sobi and Biogen, the companies developing rFIXFc.

KIDS B-LONG included 30 boys younger than 12 who had severe hemophilia B. The patients had at least 50 prior exposure days to FIX therapies and no history of inhibitors.

At baseline, all patients were receiving FIX prophylaxis. Seventy-seven percent of patients were receiving 2 or more doses a week.

On day 1 of the study, patients received rFIXFc at 50 IU/kg. They then received weekly prophylaxis at an initial dose of 50 IU/kg to 60 IU/kg. Doses were adjusted throughout the study, but the maximum was 100 IU/kg. The minimum dosing frequency was once a week, and the maximum was twice a week.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 patients (80%) received rFIXFc injections on at least 50 separate days.

Safety

None of the patients developed inhibitors or non-neutralizing anti-rFIXFc antibodies. There were no anaphylactic reactions, hypersensitivity reactions, thrombotic events, or deaths.

Adverse events occurred in 86.7% of patients. The most frequent were nanopharyngitis (23.3%) and falls (20%). Eleven serious adverse events occurred in 4 patients. None were considered related to treatment, and none led to study discontinuation.

One adverse event was considered related to rFIXFc. A 3-year-old child experienced decreased appetite.

Efficacy

The median annualized bleeding rate (ABR) was 2.0 overall, 1.1 in children under 6, and 2.1 in children ages 6 to 11.

For spontaneous bleeds, the median ABR was 0, both overall and in the 2 age groups. For joint bleeds, the median ABR was 0 overall and in the younger age group, but it was 1.1 for the older children.

Thirty-three percent of patients had no bleeding episodes while on study, and 63% had no joint bleeds.

Ninety-seven percent of patients receiving rFIXFc prophylaxis had no change in their dosing interval.

For patients under 6, the median prophylactic dose was 59.4 IU/kg/week (range, 53.0-64.8). For patients ages 6 to 11, the median dose was 57.8 IU/kg/week (range, 51.7-65.0)

When patients received rFIXFc to treat bleeding, 75% of bleeds were controlled with 1 infusion, and 91.7% were controlled with 1 or 2 infusions. The median dose per infusion was 63.5 IU/kg (range, 48.9-99.4).

Pharmacokinetics

The terminal half-life of rFIXFc was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11. The clearance was 4.4 mL/hour/kg and 3.5 mL/hour/kg, respectively. The incremental recovery (IR) was 0.59 IU/dL per IU/kg and 0.72 IU/dL per IU/kg, respectively.

Compared to pre-study treatment with BeneFIX (recombinant FIX) at 50 IU/kg, rFIXFc at 50 IU/kg had a significantly longer half-life. In children younger than 6, the half-life was 66.5 hours for rFIXFc and 18.2 hours for BeneFIX (P<0.001). In children ages 6 to 11, the half-lives were 71.1 and 19.2 hours, respectively (P<0.001).

There was no significant difference between the treatments with regard to IR for children under 6. IR was 0.59 with rFIXFc and 0.52 with BeneFIX (P=0.109). However, there was a significant difference in IR for children ages 6 to 11—0.70 for rFIXFc and 0.54 for BeneFIX (P=0.003).

rFIXFc components

Photo courtesy of Biogen

TORONTO—Full results of a phase 3 study support extended-interval dosing with a recombinant factor IX Fc fusion protein (rFIXFc) over FIX products with a standard half-life, according to a speaker at the 2015 ISTH Congress.

Kathelijn Fischer, MD, PhD, of the University Medical Center Utrecht in The Netherlands, reported results with rFIXFc (also known as eftrenonacog alfa and Alprolix), in children with severe hemophilia B who were enrolled on the KIDS B-LONG study.

rFIXFc was successful in preventing and treating bleeding episodes in these patients. Furthermore, the patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Dr Fischer presented these results as abstract LB009. Interim results of this study helped support the US approval of rFIXFc for use in children. The trial was sponsored by Sobi and Biogen, the companies developing rFIXFc.

KIDS B-LONG included 30 boys younger than 12 who had severe hemophilia B. The patients had at least 50 prior exposure days to FIX therapies and no history of inhibitors.

At baseline, all patients were receiving FIX prophylaxis. Seventy-seven percent of patients were receiving 2 or more doses a week.

On day 1 of the study, patients received rFIXFc at 50 IU/kg. They then received weekly prophylaxis at an initial dose of 50 IU/kg to 60 IU/kg. Doses were adjusted throughout the study, but the maximum was 100 IU/kg. The minimum dosing frequency was once a week, and the maximum was twice a week.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 patients (80%) received rFIXFc injections on at least 50 separate days.

Safety

None of the patients developed inhibitors or non-neutralizing anti-rFIXFc antibodies. There were no anaphylactic reactions, hypersensitivity reactions, thrombotic events, or deaths.

Adverse events occurred in 86.7% of patients. The most frequent were nanopharyngitis (23.3%) and falls (20%). Eleven serious adverse events occurred in 4 patients. None were considered related to treatment, and none led to study discontinuation.

One adverse event was considered related to rFIXFc. A 3-year-old child experienced decreased appetite.

Efficacy

The median annualized bleeding rate (ABR) was 2.0 overall, 1.1 in children under 6, and 2.1 in children ages 6 to 11.

For spontaneous bleeds, the median ABR was 0, both overall and in the 2 age groups. For joint bleeds, the median ABR was 0 overall and in the younger age group, but it was 1.1 for the older children.

Thirty-three percent of patients had no bleeding episodes while on study, and 63% had no joint bleeds.

Ninety-seven percent of patients receiving rFIXFc prophylaxis had no change in their dosing interval.

For patients under 6, the median prophylactic dose was 59.4 IU/kg/week (range, 53.0-64.8). For patients ages 6 to 11, the median dose was 57.8 IU/kg/week (range, 51.7-65.0)

When patients received rFIXFc to treat bleeding, 75% of bleeds were controlled with 1 infusion, and 91.7% were controlled with 1 or 2 infusions. The median dose per infusion was 63.5 IU/kg (range, 48.9-99.4).

Pharmacokinetics

The terminal half-life of rFIXFc was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11. The clearance was 4.4 mL/hour/kg and 3.5 mL/hour/kg, respectively. The incremental recovery (IR) was 0.59 IU/dL per IU/kg and 0.72 IU/dL per IU/kg, respectively.

Compared to pre-study treatment with BeneFIX (recombinant FIX) at 50 IU/kg, rFIXFc at 50 IU/kg had a significantly longer half-life. In children younger than 6, the half-life was 66.5 hours for rFIXFc and 18.2 hours for BeneFIX (P<0.001). In children ages 6 to 11, the half-lives were 71.1 and 19.2 hours, respectively (P<0.001).

There was no significant difference between the treatments with regard to IR for children under 6. IR was 0.59 with rFIXFc and 0.52 with BeneFIX (P=0.109). However, there was a significant difference in IR for children ages 6 to 11—0.70 for rFIXFc and 0.54 for BeneFIX (P=0.003).

rFIXFc components

Photo courtesy of Biogen

TORONTO—Full results of a phase 3 study support extended-interval dosing with a recombinant factor IX Fc fusion protein (rFIXFc) over FIX products with a standard half-life, according to a speaker at the 2015 ISTH Congress.

Kathelijn Fischer, MD, PhD, of the University Medical Center Utrecht in The Netherlands, reported results with rFIXFc (also known as eftrenonacog alfa and Alprolix), in children with severe hemophilia B who were enrolled on the KIDS B-LONG study.

rFIXFc was successful in preventing and treating bleeding episodes in these patients. Furthermore, the patients did not develop inhibitors, and there were no serious adverse events related to treatment.

Dr Fischer presented these results as abstract LB009. Interim results of this study helped support the US approval of rFIXFc for use in children. The trial was sponsored by Sobi and Biogen, the companies developing rFIXFc.

KIDS B-LONG included 30 boys younger than 12 who had severe hemophilia B. The patients had at least 50 prior exposure days to FIX therapies and no history of inhibitors.

At baseline, all patients were receiving FIX prophylaxis. Seventy-seven percent of patients were receiving 2 or more doses a week.

On day 1 of the study, patients received rFIXFc at 50 IU/kg. They then received weekly prophylaxis at an initial dose of 50 IU/kg to 60 IU/kg. Doses were adjusted throughout the study, but the maximum was 100 IU/kg. The minimum dosing frequency was once a week, and the maximum was twice a week.

Twenty-seven patients (90%) completed the study. The median time spent on study was 49.4 weeks, and 24 patients (80%) received rFIXFc injections on at least 50 separate days.

Safety

None of the patients developed inhibitors or non-neutralizing anti-rFIXFc antibodies. There were no anaphylactic reactions, hypersensitivity reactions, thrombotic events, or deaths.

Adverse events occurred in 86.7% of patients. The most frequent were nanopharyngitis (23.3%) and falls (20%). Eleven serious adverse events occurred in 4 patients. None were considered related to treatment, and none led to study discontinuation.

One adverse event was considered related to rFIXFc. A 3-year-old child experienced decreased appetite.

Efficacy

The median annualized bleeding rate (ABR) was 2.0 overall, 1.1 in children under 6, and 2.1 in children ages 6 to 11.

For spontaneous bleeds, the median ABR was 0, both overall and in the 2 age groups. For joint bleeds, the median ABR was 0 overall and in the younger age group, but it was 1.1 for the older children.

Thirty-three percent of patients had no bleeding episodes while on study, and 63% had no joint bleeds.

Ninety-seven percent of patients receiving rFIXFc prophylaxis had no change in their dosing interval.

For patients under 6, the median prophylactic dose was 59.4 IU/kg/week (range, 53.0-64.8). For patients ages 6 to 11, the median dose was 57.8 IU/kg/week (range, 51.7-65.0)

When patients received rFIXFc to treat bleeding, 75% of bleeds were controlled with 1 infusion, and 91.7% were controlled with 1 or 2 infusions. The median dose per infusion was 63.5 IU/kg (range, 48.9-99.4).

Pharmacokinetics

The terminal half-life of rFIXFc was 66.5 hours for children under 6 and 70.3 hours for children ages 6 to 11. The clearance was 4.4 mL/hour/kg and 3.5 mL/hour/kg, respectively. The incremental recovery (IR) was 0.59 IU/dL per IU/kg and 0.72 IU/dL per IU/kg, respectively.

Compared to pre-study treatment with BeneFIX (recombinant FIX) at 50 IU/kg, rFIXFc at 50 IU/kg had a significantly longer half-life. In children younger than 6, the half-life was 66.5 hours for rFIXFc and 18.2 hours for BeneFIX (P<0.001). In children ages 6 to 11, the half-lives were 71.1 and 19.2 hours, respectively (P<0.001).

There was no significant difference between the treatments with regard to IR for children under 6. IR was 0.59 with rFIXFc and 0.52 with BeneFIX (P=0.109). However, there was a significant difference in IR for children ages 6 to 11—0.70 for rFIXFc and 0.54 for BeneFIX (P=0.003).

Micrograph showing

anaplastic large cell lymphoma

The histone deacetylase inhibitor belinostat can produce durable responses in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), results of the BELIEF study suggest.

The overall response rate (ORR) was low in this heavily pretreated population, at about 26%.

But responses occurred across PTCL subtypes and irrespective of a patient’s prior treatment, and the median duration of response was 13.6 months.

The researchers said toxicity was manageable, and the rate of grade 3/4 thrombocytopenia was low.

“This is a very exciting time in the treatment of patients with PTCL,” said Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, New York.

“At long last, we finally have tools in the therapeutic armamentarium to help our patients. Belinostat represents the latest drug approved for patients with [relapsed/refractory] PTCL that has relatively few side effects and produces long durations of benefit, even in patients who have received multiple conventional treatments in the past.”

Dr O’Connor and his colleagues reported results with belinostat in the Journal of Clinical Oncology. The research was sponsored by Spectrum Pharmaceuticals, Inc., the company developing belinostat (as Beleodaq).

BELIEF was a single-arm, phase 2 trial that enrolled 129 patients with relapsed/refractory PTCL. One hundred and twenty patients were evaluable. They had a median age of 64 (range, 29-81), and roughly half of patients were female.

PTCL subtypes included PTCL-not otherwise specified (n=77), angioimmunoblastic T-cell lymphoma (n=22), ALK-negative anaplastic large cell lymphoma (n=13), ALK-positive anaplastic large cell lymphoma (n=2), enteropathy-associated T-cell lymphoma (n=2), nasal type extranodal natural killer T-cell lymphoma (n=2), and hepatosplenic T-cell lymphoma (n=2).

The patients had received a median of 2 prior therapies (range, 1-8), including multi-agent and single-agent regimens, as well as transplant.

For this study, the patients received belinostat (1000 mg/m²) as daily, 30-minute infusions on days 1-5 every 21 days until disease progression or unacceptable toxicity.

Response and survival

The study’s primary endpoint was ORR, as assessed by an independent review committee using the International Working Group criteria. The ORR was 25.8% (n=31), including 13 complete responses (10.8%) and 18 partial responses (15%).

The median time to response was 5.6 weeks, and the median duration of response was 13.6 months by International Working Group criteria. The median duration of response based on the date of first response to progressive disease or death was 8.4 months.

Among patients who achieved a complete response, the median duration of response was not reached and exceeded 29 months. The longest ongoing patient response is more than 36 months.

The median progression-free survival was 1.6 months, and the median overall survival was 7.9 months.

Forty-six patients were censored for overall survival because they were alive at the data cutoff point. Seven of these patients continued to receive belinostat. Five were in complete response, 1 had a partial response, and 1 had stable disease.

Twelve patients underwent stem cell transplant after belinostat, and 10 of these patients were still alive at the data cutoff. Their overall survival ranged from 9.4 months to 22.9 months.

Adverse events

Treatment-emergent adverse events (AEs) occurred in 96.9% of patients, and treatment-related AEs occurred in 83.7%. The most common treatment-related AEs were nausea (38.0%), fatigue (28.7%), and vomiting (24.0%). Serious AEs occurred in 47.3% of patients.

Grade 3/4 related AEs were reported in 61.2% of patients, and the most common were anemia (10.9%), thrombocytopenia (7.0%), dyspnea (6.2%), neutropenia (6.2%), fatigue (5.4%), and pneumonia (5.4%).

About 12% of patients underwent a dose reduction due to AEs, 19.4% discontinued treatment due to AEs, and 10.9% of these AEs were considered treatment-related.

Twenty-two patients (17.1%) died, 12 (9.3%) of progressive disease and 10 (7.8%) of AEs. One death was considered related to belinostat. This patient had tolerated 9 cycles of the drug without complications but had elevated liver function tests at the start of cycle 10 that subsequently led to death from toxic liver failure.

Micrograph showing

anaplastic large cell lymphoma

The histone deacetylase inhibitor belinostat can produce durable responses in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), results of the BELIEF study suggest.

The overall response rate (ORR) was low in this heavily pretreated population, at about 26%.

But responses occurred across PTCL subtypes and irrespective of a patient’s prior treatment, and the median duration of response was 13.6 months.

The researchers said toxicity was manageable, and the rate of grade 3/4 thrombocytopenia was low.

“This is a very exciting time in the treatment of patients with PTCL,” said Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, New York.

“At long last, we finally have tools in the therapeutic armamentarium to help our patients. Belinostat represents the latest drug approved for patients with [relapsed/refractory] PTCL that has relatively few side effects and produces long durations of benefit, even in patients who have received multiple conventional treatments in the past.”

Dr O’Connor and his colleagues reported results with belinostat in the Journal of Clinical Oncology. The research was sponsored by Spectrum Pharmaceuticals, Inc., the company developing belinostat (as Beleodaq).

BELIEF was a single-arm, phase 2 trial that enrolled 129 patients with relapsed/refractory PTCL. One hundred and twenty patients were evaluable. They had a median age of 64 (range, 29-81), and roughly half of patients were female.

PTCL subtypes included PTCL-not otherwise specified (n=77), angioimmunoblastic T-cell lymphoma (n=22), ALK-negative anaplastic large cell lymphoma (n=13), ALK-positive anaplastic large cell lymphoma (n=2), enteropathy-associated T-cell lymphoma (n=2), nasal type extranodal natural killer T-cell lymphoma (n=2), and hepatosplenic T-cell lymphoma (n=2).

The patients had received a median of 2 prior therapies (range, 1-8), including multi-agent and single-agent regimens, as well as transplant.

For this study, the patients received belinostat (1000 mg/m²) as daily, 30-minute infusions on days 1-5 every 21 days until disease progression or unacceptable toxicity.

Response and survival

The study’s primary endpoint was ORR, as assessed by an independent review committee using the International Working Group criteria. The ORR was 25.8% (n=31), including 13 complete responses (10.8%) and 18 partial responses (15%).

The median time to response was 5.6 weeks, and the median duration of response was 13.6 months by International Working Group criteria. The median duration of response based on the date of first response to progressive disease or death was 8.4 months.

Among patients who achieved a complete response, the median duration of response was not reached and exceeded 29 months. The longest ongoing patient response is more than 36 months.

The median progression-free survival was 1.6 months, and the median overall survival was 7.9 months.

Forty-six patients were censored for overall survival because they were alive at the data cutoff point. Seven of these patients continued to receive belinostat. Five were in complete response, 1 had a partial response, and 1 had stable disease.

Twelve patients underwent stem cell transplant after belinostat, and 10 of these patients were still alive at the data cutoff. Their overall survival ranged from 9.4 months to 22.9 months.

Adverse events

Treatment-emergent adverse events (AEs) occurred in 96.9% of patients, and treatment-related AEs occurred in 83.7%. The most common treatment-related AEs were nausea (38.0%), fatigue (28.7%), and vomiting (24.0%). Serious AEs occurred in 47.3% of patients.

Grade 3/4 related AEs were reported in 61.2% of patients, and the most common were anemia (10.9%), thrombocytopenia (7.0%), dyspnea (6.2%), neutropenia (6.2%), fatigue (5.4%), and pneumonia (5.4%).

About 12% of patients underwent a dose reduction due to AEs, 19.4% discontinued treatment due to AEs, and 10.9% of these AEs were considered treatment-related.

Twenty-two patients (17.1%) died, 12 (9.3%) of progressive disease and 10 (7.8%) of AEs. One death was considered related to belinostat. This patient had tolerated 9 cycles of the drug without complications but had elevated liver function tests at the start of cycle 10 that subsequently led to death from toxic liver failure.

Micrograph showing

anaplastic large cell lymphoma

The histone deacetylase inhibitor belinostat can produce durable responses in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), results of the BELIEF study suggest.

The overall response rate (ORR) was low in this heavily pretreated population, at about 26%.

But responses occurred across PTCL subtypes and irrespective of a patient’s prior treatment, and the median duration of response was 13.6 months.

The researchers said toxicity was manageable, and the rate of grade 3/4 thrombocytopenia was low.

“This is a very exciting time in the treatment of patients with PTCL,” said Owen O’Connor, MD, PhD, of Columbia University Medical Center in New York, New York.

“At long last, we finally have tools in the therapeutic armamentarium to help our patients. Belinostat represents the latest drug approved for patients with [relapsed/refractory] PTCL that has relatively few side effects and produces long durations of benefit, even in patients who have received multiple conventional treatments in the past.”

Dr O’Connor and his colleagues reported results with belinostat in the Journal of Clinical Oncology. The research was sponsored by Spectrum Pharmaceuticals, Inc., the company developing belinostat (as Beleodaq).

BELIEF was a single-arm, phase 2 trial that enrolled 129 patients with relapsed/refractory PTCL. One hundred and twenty patients were evaluable. They had a median age of 64 (range, 29-81), and roughly half of patients were female.

PTCL subtypes included PTCL-not otherwise specified (n=77), angioimmunoblastic T-cell lymphoma (n=22), ALK-negative anaplastic large cell lymphoma (n=13), ALK-positive anaplastic large cell lymphoma (n=2), enteropathy-associated T-cell lymphoma (n=2), nasal type extranodal natural killer T-cell lymphoma (n=2), and hepatosplenic T-cell lymphoma (n=2).

The patients had received a median of 2 prior therapies (range, 1-8), including multi-agent and single-agent regimens, as well as transplant.

For this study, the patients received belinostat (1000 mg/m²) as daily, 30-minute infusions on days 1-5 every 21 days until disease progression or unacceptable toxicity.

Response and survival

The study’s primary endpoint was ORR, as assessed by an independent review committee using the International Working Group criteria. The ORR was 25.8% (n=31), including 13 complete responses (10.8%) and 18 partial responses (15%).

The median time to response was 5.6 weeks, and the median duration of response was 13.6 months by International Working Group criteria. The median duration of response based on the date of first response to progressive disease or death was 8.4 months.

Among patients who achieved a complete response, the median duration of response was not reached and exceeded 29 months. The longest ongoing patient response is more than 36 months.

The median progression-free survival was 1.6 months, and the median overall survival was 7.9 months.

Forty-six patients were censored for overall survival because they were alive at the data cutoff point. Seven of these patients continued to receive belinostat. Five were in complete response, 1 had a partial response, and 1 had stable disease.

Twelve patients underwent stem cell transplant after belinostat, and 10 of these patients were still alive at the data cutoff. Their overall survival ranged from 9.4 months to 22.9 months.

Adverse events

Treatment-emergent adverse events (AEs) occurred in 96.9% of patients, and treatment-related AEs occurred in 83.7%. The most common treatment-related AEs were nausea (38.0%), fatigue (28.7%), and vomiting (24.0%). Serious AEs occurred in 47.3% of patients.

Grade 3/4 related AEs were reported in 61.2% of patients, and the most common were anemia (10.9%), thrombocytopenia (7.0%), dyspnea (6.2%), neutropenia (6.2%), fatigue (5.4%), and pneumonia (5.4%).

About 12% of patients underwent a dose reduction due to AEs, 19.4% discontinued treatment due to AEs, and 10.9% of these AEs were considered treatment-related.

Twenty-two patients (17.1%) died, 12 (9.3%) of progressive disease and 10 (7.8%) of AEs. One death was considered related to belinostat. This patient had tolerated 9 cycles of the drug without complications but had elevated liver function tests at the start of cycle 10 that subsequently led to death from toxic liver failure.