Extramammary Paget disease (EMPD) is an uncommon condition that usually presents in apocrine sweat gland–rich areas, most commonly the vulva followed by the perianal region. Lesions clinically present as erythematous, well-demarcated plaques that may become ulcerated, erosive, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life.¹ Histologically, EMPD displays intraepidermal spread of large cells with plentiful amphophilic cytoplasm and large nuclei (Figure 1). These atypical cells may be seen “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (Figure 2). Frequently, the cytoplasm of these tumor cells is positive on mucicarmine staining, which indicates the presence of mucin, giving the cytoplasm a bluish gray color on hematoxylin and eosin–stained sections. Typically, EMPD cells can be found alone or in nests throughout the epithelium. The basal layer of the epithelium will appear crushed but not infiltrated by these atypical cells in some areas.² Extramammary Paget disease is epithelial membrane antigen and cytokeratin 7 positive, unlike other conditions in the differential diagnosis such as benign acral nevus, Bowen disease, mycosis fungoides, and superficial spreading melanoma in situ, with the rare exception of cytokeratin 7 positivity in Bowen disease.³

Figure 1. Intraepidermal spread of large cells with plentiful amphophilic cytoplasm in extramammary Paget disease (H&E, original magnification ×10).

Figure 2. Atypical cells of extramammary Paget disease “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (H&E, original magnification ×20).

Benign acral nevi, similar to melanoma in situ, can have melanocytes scattered above the basal layer, but they usually appear in the lower half of the epidermis without cytologic atypia.⁴ When present, these pagetoid cells are most often limited to the center of a well-delineated lesion. The compact thick stratum corneum characteristic of acral skin also is helpful in distinguishing a benign acral nevus from EMPD, which does not involve acral sites (Figure 3).²

Figure 3. Cytologically normal melanocytes in the lower half of the epidermis in a benign acral nevus with a thick stratum corneum that is indicative of acral skin (H&E, original magnification ×20).

Bowen disease (squamous cell carcinoma in situ) may have pagetoid spread (or buckshot scatter) through the epidermis similar to EMPD and melanoma in situ. However, in Bowen disease the malignant cells are keratinocytes that keratinize and become incorporated into the stratum corneum as parakeratotic nuclei rather than intact “spit out” cells, as seen in melanoma in situ and EMPD. Usually the pagetoid spread is only focal in Bowen disease with other areas of more characteristic full-thickness keratinocyte atypia (Figure 4).²

Figure 4. Parakeratosis and pagetoid spread of cells adjacent to areas of full-thickness epidermal keratinocyte atypia in Bowen disease (H&E, original magnification ×10).

Mycosis fungoides displays atypical lymphocytes with large dark nuclei and minimal to no cytoplasm scattered throughout the epidermis. The atypical cells have irregular nuclear contours and often a clear perinuclear space (Figure 5). These cells tend to line up along the dermoepidermal junction and form intraepidermal clusters known as Pautrier microabscesses. Papillary dermal fibroplasia also is usually present in mycosis fungoides.²

Figure 5. Atypical lymphocytes in the epidermis of mycosis fungoides display nuclei that are large, dark, and have irregular nuclear contours with perinuclear clearing (H&E, original magnification ×20).

Similar to EMPD, superficial spreading melanoma in situ shows single or nested atypical cells scattered throughout all levels of the epithelium and may be “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells. However, in melanoma, nests of atypical melanocytes predominate and involve the basal layer (Figure 6), whereas clusters of cells in EMPD typically are located superficial to the basal layer. The cells of melanoma also lack the amphophilic mucinous cytoplasm of EMPD.¹

Figure 6. Nests of atypical melanocytes predominately involving the basal layer in superficial spreading melanoma in situ (H&E, original magnification ×20).

Extramammary Paget disease (EMPD) is an uncommon condition that usually presents in apocrine sweat gland–rich areas, most commonly the vulva followed by the perianal region. Lesions clinically present as erythematous, well-demarcated plaques that may become ulcerated, erosive, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life.¹ Histologically, EMPD displays intraepidermal spread of large cells with plentiful amphophilic cytoplasm and large nuclei (Figure 1). These atypical cells may be seen “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (Figure 2). Frequently, the cytoplasm of these tumor cells is positive on mucicarmine staining, which indicates the presence of mucin, giving the cytoplasm a bluish gray color on hematoxylin and eosin–stained sections. Typically, EMPD cells can be found alone or in nests throughout the epithelium. The basal layer of the epithelium will appear crushed but not infiltrated by these atypical cells in some areas.² Extramammary Paget disease is epithelial membrane antigen and cytokeratin 7 positive, unlike other conditions in the differential diagnosis such as benign acral nevus, Bowen disease, mycosis fungoides, and superficial spreading melanoma in situ, with the rare exception of cytokeratin 7 positivity in Bowen disease.³

Figure 1. Intraepidermal spread of large cells with plentiful amphophilic cytoplasm in extramammary Paget disease (H&E, original magnification ×10).

Figure 2. Atypical cells of extramammary Paget disease “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (H&E, original magnification ×20).

Benign acral nevi, similar to melanoma in situ, can have melanocytes scattered above the basal layer, but they usually appear in the lower half of the epidermis without cytologic atypia.⁴ When present, these pagetoid cells are most often limited to the center of a well-delineated lesion. The compact thick stratum corneum characteristic of acral skin also is helpful in distinguishing a benign acral nevus from EMPD, which does not involve acral sites (Figure 3).²

Figure 3. Cytologically normal melanocytes in the lower half of the epidermis in a benign acral nevus with a thick stratum corneum that is indicative of acral skin (H&E, original magnification ×20).

Bowen disease (squamous cell carcinoma in situ) may have pagetoid spread (or buckshot scatter) through the epidermis similar to EMPD and melanoma in situ. However, in Bowen disease the malignant cells are keratinocytes that keratinize and become incorporated into the stratum corneum as parakeratotic nuclei rather than intact “spit out” cells, as seen in melanoma in situ and EMPD. Usually the pagetoid spread is only focal in Bowen disease with other areas of more characteristic full-thickness keratinocyte atypia (Figure 4).²

Figure 4. Parakeratosis and pagetoid spread of cells adjacent to areas of full-thickness epidermal keratinocyte atypia in Bowen disease (H&E, original magnification ×10).

Mycosis fungoides displays atypical lymphocytes with large dark nuclei and minimal to no cytoplasm scattered throughout the epidermis. The atypical cells have irregular nuclear contours and often a clear perinuclear space (Figure 5). These cells tend to line up along the dermoepidermal junction and form intraepidermal clusters known as Pautrier microabscesses. Papillary dermal fibroplasia also is usually present in mycosis fungoides.²

Figure 5. Atypical lymphocytes in the epidermis of mycosis fungoides display nuclei that are large, dark, and have irregular nuclear contours with perinuclear clearing (H&E, original magnification ×20).

Similar to EMPD, superficial spreading melanoma in situ shows single or nested atypical cells scattered throughout all levels of the epithelium and may be “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells. However, in melanoma, nests of atypical melanocytes predominate and involve the basal layer (Figure 6), whereas clusters of cells in EMPD typically are located superficial to the basal layer. The cells of melanoma also lack the amphophilic mucinous cytoplasm of EMPD.¹

Figure 6. Nests of atypical melanocytes predominately involving the basal layer in superficial spreading melanoma in situ (H&E, original magnification ×20).

Extramammary Paget disease (EMPD) is an uncommon condition that usually presents in apocrine sweat gland–rich areas, most commonly the vulva followed by the perianal region. Lesions clinically present as erythematous, well-demarcated plaques that may become ulcerated, erosive, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life.¹ Histologically, EMPD displays intraepidermal spread of large cells with plentiful amphophilic cytoplasm and large nuclei (Figure 1). These atypical cells may be seen “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (Figure 2). Frequently, the cytoplasm of these tumor cells is positive on mucicarmine staining, which indicates the presence of mucin, giving the cytoplasm a bluish gray color on hematoxylin and eosin–stained sections. Typically, EMPD cells can be found alone or in nests throughout the epithelium. The basal layer of the epithelium will appear crushed but not infiltrated by these atypical cells in some areas.² Extramammary Paget disease is epithelial membrane antigen and cytokeratin 7 positive, unlike other conditions in the differential diagnosis such as benign acral nevus, Bowen disease, mycosis fungoides, and superficial spreading melanoma in situ, with the rare exception of cytokeratin 7 positivity in Bowen disease.³

Figure 1. Intraepidermal spread of large cells with plentiful amphophilic cytoplasm in extramammary Paget disease (H&E, original magnification ×10).

Figure 2. Atypical cells of extramammary Paget disease “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (H&E, original magnification ×20).

Benign acral nevi, similar to melanoma in situ, can have melanocytes scattered above the basal layer, but they usually appear in the lower half of the epidermis without cytologic atypia.⁴ When present, these pagetoid cells are most often limited to the center of a well-delineated lesion. The compact thick stratum corneum characteristic of acral skin also is helpful in distinguishing a benign acral nevus from EMPD, which does not involve acral sites (Figure 3).²

Figure 3. Cytologically normal melanocytes in the lower half of the epidermis in a benign acral nevus with a thick stratum corneum that is indicative of acral skin (H&E, original magnification ×20).

Bowen disease (squamous cell carcinoma in situ) may have pagetoid spread (or buckshot scatter) through the epidermis similar to EMPD and melanoma in situ. However, in Bowen disease the malignant cells are keratinocytes that keratinize and become incorporated into the stratum corneum as parakeratotic nuclei rather than intact “spit out” cells, as seen in melanoma in situ and EMPD. Usually the pagetoid spread is only focal in Bowen disease with other areas of more characteristic full-thickness keratinocyte atypia (Figure 4).²

Figure 4. Parakeratosis and pagetoid spread of cells adjacent to areas of full-thickness epidermal keratinocyte atypia in Bowen disease (H&E, original magnification ×10).

Mycosis fungoides displays atypical lymphocytes with large dark nuclei and minimal to no cytoplasm scattered throughout the epidermis. The atypical cells have irregular nuclear contours and often a clear perinuclear space (Figure 5). These cells tend to line up along the dermoepidermal junction and form intraepidermal clusters known as Pautrier microabscesses. Papillary dermal fibroplasia also is usually present in mycosis fungoides.²

Figure 5. Atypical lymphocytes in the epidermis of mycosis fungoides display nuclei that are large, dark, and have irregular nuclear contours with perinuclear clearing (H&E, original magnification ×20).

Similar to EMPD, superficial spreading melanoma in situ shows single or nested atypical cells scattered throughout all levels of the epithelium and may be “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells. However, in melanoma, nests of atypical melanocytes predominate and involve the basal layer (Figure 6), whereas clusters of cells in EMPD typically are located superficial to the basal layer. The cells of melanoma also lack the amphophilic mucinous cytoplasm of EMPD.¹

Figure 6. Nests of atypical melanocytes predominately involving the basal layer in superficial spreading melanoma in situ (H&E, original magnification ×20).

Nepal – a peaceful, small country lying amidst the Himalayas – was struck by an enormous 7.8-magnitude earthquake on April 25, 2015. Over 8,000 people lost their lives; tens of thousands were injured. The earthquake launched an avalanche on Mt. Everest, killing at least 19, with many more reported missing. The villages were wiped away. The capital, Kathmandu, famous for its brick-and-timber attached houses, was in rubble.

I was born and raised in Nepal, and I earned my medical degree there before I moved to the United States for further studies. I was in Nepal weeks before the earthquake, and it was heart wrenching to later see all those familiar places turned into debris. The first few hours of this news were terrifying, as I struggled to track down my family members from afar. When I learned everyone was safe, I didn’t know if I should be thankful or feel unfortunate that I wasn’t there with them. Within hours, Nepal was all over the news, and the world responded. The next few days were worse, with continuous aftershocks. My family members, along with the rest of Nepal, spent days and nights in open tents, cold and soaked in heavy rains.

Weeks before the earthquake I was there – visiting hospitals, teaching medical students, and analyzing the health care scenario. In Nepal, the family treatment budget is limited, and the physician decides which test/procedure will provide maximum information for management. Health care facilities, sanitation, and hygiene are very poor and are beyond the means of most Nepalese people. Mortality for those under 5 years of age is 51 per 1,000, and the chances of dying while giving birth are 1 in 80.

I revisited “clinical decision making” as obtaining labs and imaging was out of reach, and I realized how many unnecessary medical tests and procedures are done in the United States. I learned how to make a continuous positive airway pressure (CPAP) machine with a bottle of water, a piece of tubing, oxygen, and medical tape. In my 14-day trip, I witnessed purulent fluid being drained from spinal taps, constant seizures that refused to go away in spite of antiseizure medications, and children left to die as the family could not afford to pay for medical treatment.

In the days after the earthquake, I kept in constant touch with my family and friends from the medical community. Nepalese doctors worked endlessly, operating in paddy fields under the open sky with minimal medical supplies. People dug with bare hands to get trapped neighbors out. Time has elapsed since then, but life will not be the same again for these people. The strength and perseverance that the medical community showed was commendable. They showed the world, with so little, so much can be done. If only we here in the United States could embrace this.

Dr. Rajbhandari is a fellow in hospital medicine at Cleveland Clinic Children’s Hospital. Email her at [email protected].

Nepal – a peaceful, small country lying amidst the Himalayas – was struck by an enormous 7.8-magnitude earthquake on April 25, 2015. Over 8,000 people lost their lives; tens of thousands were injured. The earthquake launched an avalanche on Mt. Everest, killing at least 19, with many more reported missing. The villages were wiped away. The capital, Kathmandu, famous for its brick-and-timber attached houses, was in rubble.

I was born and raised in Nepal, and I earned my medical degree there before I moved to the United States for further studies. I was in Nepal weeks before the earthquake, and it was heart wrenching to later see all those familiar places turned into debris. The first few hours of this news were terrifying, as I struggled to track down my family members from afar. When I learned everyone was safe, I didn’t know if I should be thankful or feel unfortunate that I wasn’t there with them. Within hours, Nepal was all over the news, and the world responded. The next few days were worse, with continuous aftershocks. My family members, along with the rest of Nepal, spent days and nights in open tents, cold and soaked in heavy rains.

Weeks before the earthquake I was there – visiting hospitals, teaching medical students, and analyzing the health care scenario. In Nepal, the family treatment budget is limited, and the physician decides which test/procedure will provide maximum information for management. Health care facilities, sanitation, and hygiene are very poor and are beyond the means of most Nepalese people. Mortality for those under 5 years of age is 51 per 1,000, and the chances of dying while giving birth are 1 in 80.

I revisited “clinical decision making” as obtaining labs and imaging was out of reach, and I realized how many unnecessary medical tests and procedures are done in the United States. I learned how to make a continuous positive airway pressure (CPAP) machine with a bottle of water, a piece of tubing, oxygen, and medical tape. In my 14-day trip, I witnessed purulent fluid being drained from spinal taps, constant seizures that refused to go away in spite of antiseizure medications, and children left to die as the family could not afford to pay for medical treatment.

In the days after the earthquake, I kept in constant touch with my family and friends from the medical community. Nepalese doctors worked endlessly, operating in paddy fields under the open sky with minimal medical supplies. People dug with bare hands to get trapped neighbors out. Time has elapsed since then, but life will not be the same again for these people. The strength and perseverance that the medical community showed was commendable. They showed the world, with so little, so much can be done. If only we here in the United States could embrace this.

Dr. Rajbhandari is a fellow in hospital medicine at Cleveland Clinic Children’s Hospital. Email her at [email protected].

Nepal – a peaceful, small country lying amidst the Himalayas – was struck by an enormous 7.8-magnitude earthquake on April 25, 2015. Over 8,000 people lost their lives; tens of thousands were injured. The earthquake launched an avalanche on Mt. Everest, killing at least 19, with many more reported missing. The villages were wiped away. The capital, Kathmandu, famous for its brick-and-timber attached houses, was in rubble.

I was born and raised in Nepal, and I earned my medical degree there before I moved to the United States for further studies. I was in Nepal weeks before the earthquake, and it was heart wrenching to later see all those familiar places turned into debris. The first few hours of this news were terrifying, as I struggled to track down my family members from afar. When I learned everyone was safe, I didn’t know if I should be thankful or feel unfortunate that I wasn’t there with them. Within hours, Nepal was all over the news, and the world responded. The next few days were worse, with continuous aftershocks. My family members, along with the rest of Nepal, spent days and nights in open tents, cold and soaked in heavy rains.

Weeks before the earthquake I was there – visiting hospitals, teaching medical students, and analyzing the health care scenario. In Nepal, the family treatment budget is limited, and the physician decides which test/procedure will provide maximum information for management. Health care facilities, sanitation, and hygiene are very poor and are beyond the means of most Nepalese people. Mortality for those under 5 years of age is 51 per 1,000, and the chances of dying while giving birth are 1 in 80.

I revisited “clinical decision making” as obtaining labs and imaging was out of reach, and I realized how many unnecessary medical tests and procedures are done in the United States. I learned how to make a continuous positive airway pressure (CPAP) machine with a bottle of water, a piece of tubing, oxygen, and medical tape. In my 14-day trip, I witnessed purulent fluid being drained from spinal taps, constant seizures that refused to go away in spite of antiseizure medications, and children left to die as the family could not afford to pay for medical treatment.

In the days after the earthquake, I kept in constant touch with my family and friends from the medical community. Nepalese doctors worked endlessly, operating in paddy fields under the open sky with minimal medical supplies. People dug with bare hands to get trapped neighbors out. Time has elapsed since then, but life will not be the same again for these people. The strength and perseverance that the medical community showed was commendable. They showed the world, with so little, so much can be done. If only we here in the United States could embrace this.

Dr. Rajbhandari is a fellow in hospital medicine at Cleveland Clinic Children’s Hospital. Email her at [email protected].

From the Wake Forest School of Medicine, Winston-Salem, NC.

 

Abstract

• Objective: To assess outcomes and pharmacotherapy in a cohort of patients with type 2 diabetes in a university-based family medicine teaching practice.
• Methods: We used ICD-9-CM codes to identify a cohort of patients with diabetes seen in 2006 and 2012. A total of 891 patients were identified who made follow-up visits in both years. We collected data on patient characteristics, pharmacotherapy, and outcomes for glycemia, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol. We determined type and number of medications taken to achieve target outcomes.
• Results: A1C remained constant between 2006 and 2012 (7.6% to 7.7%) along with BMI (34.7 kg/m² to 34.1 kg/m²), while mean LDL cholesterol significantly decreased from 109 mg/dL in 2006 to 98.8 mg/dL in 2012. The number of patients achieving a goal LDL < 100 mg/dL increased from 43.5 % in 2006 to 58.6% in 2012. The largest group with controlled A1C (< 7 %) were taking metformin with a sulfonylurea, DPP-4 inhibitor, glitazone or an injectable GLP-agonist. The majority achieved an LDL goal of < 100 mg/dl. The majority of hypertensive regimens included use of an ACE inhibitor or ARB with overall BP control achieved in at least 45% of patients.
• Conclusion: Multiple medications are necessary to achieve control among patients with type 2 diabetes over time and this cannot be attributed to an increase in BMI. Overall control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications, with the primary agent for LDL reduction being a statin.

Diabetes is an illness that affects an estimated 25.8 million Americans and is quickly becoming a worldwide epidemic [1,2]. Diabetes is a significant cause of both microvascular and macrovascular sequelae, but its frequent association with the comorbid conditions of hypertension and dyslipidemia further increases the risk of heart disease, stroke, peripheral vascular complications, and renal impairment [3–5]. The American Diabetes Association (ADA) publishes consensus guidelines annually to guide management for patients with diabetes. From 2006 to 2012, the accepted standard of medical care included achieving a hemoglobin A1C (A1C) measurement of < 7%, a low-density lipoprotein (LDL) level of < 100 mg/dL, and a blood pressure (BP) of < 130/80 mm Hg [6,7]. The National Health and Nutrition Examination Survey (NHANES) recently reported that the goal of simultaneous control of A1C, LDL and BP is met in only about 19% of diabetes patients [8]. Target glycemic control is relaxed to an A1C < 8% in some patients with multiple comorbidities, limited life span, or risk for hypoglycemia; and in 2013 the BP goal was modified to < 140/80 based on clinical trial evidence [9].

In combination with lifestyle modification, pharmacotherapy is a critical component of chronic disease management. Initial pharmacotherapy treatment recommendations include metformin for diabetes, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertension, and a statin for dyslipidemia [6,7,9]. In patients who already have a diagnosis of diabetes, achieving control becomes more difficult to accomplish with lifestyle alone, and the benefit of lifestyle intervention on all-cause mortality as well as cardiovascular and microvascular events remains a debated issue [10]. The need for pharmacologic agents in most patients with diabetes is inevitable. Metformin is the agent of choice for initial treatment with drug therapy, with the option of adding a variety of other oral or injectable medications based on clinician decision-making [7]. In this study, we reviewed data from a longitudinal cohort of type 2 diabetes patients and compared medication use and outcomes at 2 different time-points (2006 and 2012) to see how medical management and outcome measures changed over time.

 

Methods

Setting

Data were obtained from an academic family medicine clinic in the southeastern United States. Approximately 56,000 patient visits to this clinic are conducted annually. Family medicine residents in training, fellows, faculty physicians, physician assistants, a nutritionist, and diabetes educators care for patients seen in this practice.

Data Collection

A cohort of patients was identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes for type 2 diabetes. The cohort comprised patients with diabetes in 2006 and 2012 who made follow-up visits in both years.

The data from both time-points were obtained from electronic medical record (EMR) data capture and structured chart review. Two reviewers reviewed 10% of the charts for accuracy after the data was pre-populated from the EMR. The following data were obtained: demographic variables (patient age, gender, and race), height, weight, insurance, smoking status, A1C, LDL, and BP measurements, pharmacotherapy for glycemia, hypertension, and hyperlipidemia, and number of medications needed for control. For variables that had multiple measures, we calculated an average for the year.

The study protocol was approved by the Institutional Review Board at Wake Forest School of Medicine.

Statistical Analysis

Descriptive statistics were performed to compute means, standard deviations, frequencies, and percentages for demographic variables and for glycemia, BP, LDL includ-ing patient characteristics, diabetes outcomes, and pharmacotherapy medication variables. Paired t tests were used to assess for a difference at the level of the patient in the means of the A1C, BP, and LDL between the 2 study time-points (2-sided alpha = 0.05). The non-parametric McNemar test was used to assess for differences in the proportions of patients at the identified goal for A1C, LDL, and BP for 2006 and 2012.

Results

The longitudinal cohort population consisted of 891 patients, 49.5% white and 48.1% African American, with a mean age of 57.9 years (Table 1). The cohort represented 63.7% (891/1398) of the baseline population of patients with diabetes in 2006. Over half of the patients were female and the majority of the sample was overweight or obese. At baseline, almost the entire cohort had some type of insurance including private, Medicare, Medicaid, or a combination.

The number of visits per patient was 5.9 in 2006 and 5.3 in 2012. A1C remained constant between 2006 and 2012 (mean 7.6% vs. 7.7%, ± 1.8) along with body mass index (BMI), while mean LDL cholesterol significantly decreased from 109 ± 36.4 mg/dL in 2006 to 98.8 ± 40.4 mg/dL in 2012 (Table 2). Mean systolic BP marginally increased over the 6-year period from 131.5 ± 14.2 to 134.8 ± 16.1 mm Hg with diastolic BP remaining constant.

The percentage of patients achieving the less stringent A1C goal of < 8% comprised over 50% of the population at both time points; however, compared with 2006, in 2012 there was a lower percentage of patients at the more stringent A1C target of < 7% (43.2% vs. 39.6%). The percentage of patients achieving goal for systolic BP was significantly decreased to 38.6% in 2012 versus 46.5% in 2006 (Table 2). However, the proportion of patients with controlled diastolic BP rose significantly from 70% to 77.6%. The number of patients achieving goal LDL (< 100 mg/dL) increased from 43.5% in 2006 to 58.6% in 2012.

The most common therapeutic regimen was combination therapy with insulin and oral medications, taken by 37% (n = 277) of the cohort (Table 3). Approximately one-third of the study population was taking oral combination therapy using metformin. There were 149 (16.7%) patients who did not have A1C measurements available in both years. The largest group by medication regimen with controlled A1C (< 7 %) were those taking metformin with a combination drug (ie, sulfonylurea, DPP-4 inhibitor, glitazone, or an injectable GLP-agonist). There were 71 patients on no medication, and 86% were at A1C goal.

Table 3 shows number of patients at LDL goal of < 100 mg/dL by lipid-lowering agent. There was a large portion (n = 303 or 34%) of the 891 patients that did not have LDL values available in both 2006 and 2012. A total of 89 patients were taking no medications for LDL, with 64% achieving controlled levels. The large majority of patients were controlled on a single statin drug (n = 195, 59%) while those requiring more than a statin drug for control comprised 53% of patients (n = 92).

 

Table 3 shows achievement of BP < 130/80 by anti-hypertensive regimen. The majority of the hypertensive regimens included the use of an ACEI or an ARB, with overall BP control achieved in at least 45% of patients. The highest BP control (49%) was achieved in the diuretic and CCB–containing regimens without an ACEI or ARB, represented by a smaller group of patients (n = 65). There were 32 patients whose hypertension was controlled without antihypertensive therapy. Ninety-three percent of the cohort had data for evaluation in both years.

The numbers of medications needed to achieve control for glycemia, hypertension, and LDL are shown in Table 4. The mean number of glucose medications increased from 1.2 to 2.2 between 2006 and 2012. For BP and LDL management, the mean number of medications nearly doubled over the 6-year period. The highest number of medications was needed to reach BP goals, with 2.7 medications needed for systolic BP and 3.3 medications necessary for diastolic control. Results were similar for number of required medications for patients achieving a goal A1C of < 7% or a relaxed goal of < 8% in this cohort.

Discussion

Despite the availability of evidence-based guidelines and vast knowledge about microvascular and macrovascular complications due to diabetes, clinical goals for diabetes outcomes are not being routinely achieved in practice. More work is needed to achieve national standards of care. NHANES data from 2007 to 2010 revealed that 52.5% of patients with diabetes achieved an A1C of < 7% while 51.1% had a BP < 130/80 and 56.2% had an LDL < 100 mg/dL [8].

Improvement in LDL cholesterol was seen in the current study, and A1C remained constant during the 6-year time period. While mean A1C, BP, and LDL measurements were close to ADA target goals, a smaller proportion of patients were controlled in 2012 compared with 2006. Hoerger and colleagues [11] found using NHANES data 1999 to 2004 that mean A1C levels significantly declined over time, with 55.7% (up from 36.9%) achieving an A1C of < 7% by 2004  [11]. In our sample of patient with diabetes, only 39.6% were at A1C goal in 2012; 8.2% (61/742) achieved control with no medications.

Metformin is first-line therapy according to ADA recommendations. Most regimens in our study included this drug, with a large percentage of patients with controlled A1C taking this very affordable agent [12]. The combination regimens with metformin plus another oral therapy or 2 oral drugs with insulin resulted in a higher percentage of patients controlled  compared to metformin or insulin monotherapy. From our previous chart review [13] of the entire practice of patients with diabetes (n = 1398) from 2006, A1C control was similarly achieved in patients taking insulin (31% vs. 33%) or insulin combinations (19% vs. 20%) from 2006 to 2012, respectively.

For LDL cholesterol control, 9.7% (57/588) of the cohort used no medications to reach goal. Statin use predominated, with 60% of the cohort reaching goal with a single statin agent. Approximately one-third (175/588) of evaluable patients were on  more than 1 cholesterol medication, and about half of these (53%) reached goal. Over the 6-year period, atorvastatin become available generically, which may have impacted the number of patients able to use this statin. Compared with a recent literature review over a 12-year period of LDL attainment in primary care [14], the results of our study show equivalent or better LDL goal achievement among patient with diabetes.

The majority of the patients received an ACEI or ARB. There were a comparable number of patients controlled with ACEI or ARB with a diuretic, versus an ACEI or ARB with a diuretic and CCB. Large-scale clinical trials have shown that using an ACEI or ARB in combination with a CCB is superior to a hydrochlorathiazide-based combination for reducing risk of major cardiovascular events [15]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that serious adverse events attributed to antihypertensive treatment occurred more frequently in the intensive therapy group (< 120/80) than in the standard therapy (< 140/80) group [16]. The stringent systolic BP goal in accord was accomplished using 3.4 medications. Aggressive lowering of BP may be dangerous in patients with diabetes and there is no benefit found in many large-scale studies [17]. The 2013 ADA goal for BP is now < 140/80 mm Hg, and while our data show that a significant increase in BP was seen over a 6-year period, the number of medications needed to control BP will likely be lower with the new ADA target and potentially safer.

In our cohort, over the 6-year period there was an increase in the number of medications needed to achieve glycemic, BP, and LDL goals. During this time, there were no major changes in the way the patients received care in the clinic environment. We cannot comment on whether lifestyle changes or diabetes education may have impacted the need for increased medication use. Limitations to this study include the unavailability of  A1C (17%) and LDL (34%) data at both time points for every patient, inability to verify insurance data for the 2012 time period, and that the data are from a single practice. We also were unable to determine the duration of diabetes diagnosis due to a change in electronic medical record systems and lack of full documentation by providers.

These findings suggest that as patients live longer with type 2 diabetes, they will need increasing numbers of medications to achieve standard of care goals. Research has shown that there are challenges in implementing diabetes guidelines in primary care, including potential inaccuracies contained in electronic patient health information, inadequate coordination among health care providers, physician lack of awareness of guidelines, and clinical inertia [18]. As shown in the current study and other research, intensification of traditional therapies for glycemic control can sustain target outcomes without the risk of significant weight gain [19].

The chronic condition of diabetes is associated with medical complications as well as challenges for providing optimal care, despite advances in pharmacotherapy. As more medications are added to a patient’s regimen, adherence can become challenging. The cost of medications also warrants consideration. Research is needed to understand the impact on quality of life, cost of care, and outcomes of these regimens as well as whether lifestyle modifications can impact the number of medications needed by individual patients. The current study indicates that overall outcome control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications with the primary agent being a statin drug.

 

Acknowledgements: We would like to thank Drs. Elizabeth Strachan and Madhavi Peechara for their past contributions and diligence in the original chart review.

Corresponding author: Julienne K. Kirk, PharmD, CDE, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1084, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JKK, KL, RWL; analysis and interpretation of data, JKK, SWD, KL, CAH, RWL; drafting of article, JKK, KL, RWL; critical revision of the article, JKK, KL, CAH; provision of study materials or patients, JKK, SWD; statistical expertise, SWD; administrative or technical support, CAH; collection and assembly of data, JKK, KL, CAH.

From the Wake Forest School of Medicine, Winston-Salem, NC.

 

Abstract

• Objective: To assess outcomes and pharmacotherapy in a cohort of patients with type 2 diabetes in a university-based family medicine teaching practice.
• Methods: We used ICD-9-CM codes to identify a cohort of patients with diabetes seen in 2006 and 2012. A total of 891 patients were identified who made follow-up visits in both years. We collected data on patient characteristics, pharmacotherapy, and outcomes for glycemia, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol. We determined type and number of medications taken to achieve target outcomes.
• Results: A1C remained constant between 2006 and 2012 (7.6% to 7.7%) along with BMI (34.7 kg/m² to 34.1 kg/m²), while mean LDL cholesterol significantly decreased from 109 mg/dL in 2006 to 98.8 mg/dL in 2012. The number of patients achieving a goal LDL < 100 mg/dL increased from 43.5 % in 2006 to 58.6% in 2012. The largest group with controlled A1C (< 7 %) were taking metformin with a sulfonylurea, DPP-4 inhibitor, glitazone or an injectable GLP-agonist. The majority achieved an LDL goal of < 100 mg/dl. The majority of hypertensive regimens included use of an ACE inhibitor or ARB with overall BP control achieved in at least 45% of patients.
• Conclusion: Multiple medications are necessary to achieve control among patients with type 2 diabetes over time and this cannot be attributed to an increase in BMI. Overall control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications, with the primary agent for LDL reduction being a statin.

Diabetes is an illness that affects an estimated 25.8 million Americans and is quickly becoming a worldwide epidemic [1,2]. Diabetes is a significant cause of both microvascular and macrovascular sequelae, but its frequent association with the comorbid conditions of hypertension and dyslipidemia further increases the risk of heart disease, stroke, peripheral vascular complications, and renal impairment [3–5]. The American Diabetes Association (ADA) publishes consensus guidelines annually to guide management for patients with diabetes. From 2006 to 2012, the accepted standard of medical care included achieving a hemoglobin A1C (A1C) measurement of < 7%, a low-density lipoprotein (LDL) level of < 100 mg/dL, and a blood pressure (BP) of < 130/80 mm Hg [6,7]. The National Health and Nutrition Examination Survey (NHANES) recently reported that the goal of simultaneous control of A1C, LDL and BP is met in only about 19% of diabetes patients [8]. Target glycemic control is relaxed to an A1C < 8% in some patients with multiple comorbidities, limited life span, or risk for hypoglycemia; and in 2013 the BP goal was modified to < 140/80 based on clinical trial evidence [9].

In combination with lifestyle modification, pharmacotherapy is a critical component of chronic disease management. Initial pharmacotherapy treatment recommendations include metformin for diabetes, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertension, and a statin for dyslipidemia [6,7,9]. In patients who already have a diagnosis of diabetes, achieving control becomes more difficult to accomplish with lifestyle alone, and the benefit of lifestyle intervention on all-cause mortality as well as cardiovascular and microvascular events remains a debated issue [10]. The need for pharmacologic agents in most patients with diabetes is inevitable. Metformin is the agent of choice for initial treatment with drug therapy, with the option of adding a variety of other oral or injectable medications based on clinician decision-making [7]. In this study, we reviewed data from a longitudinal cohort of type 2 diabetes patients and compared medication use and outcomes at 2 different time-points (2006 and 2012) to see how medical management and outcome measures changed over time.

 

Methods

Setting

Data were obtained from an academic family medicine clinic in the southeastern United States. Approximately 56,000 patient visits to this clinic are conducted annually. Family medicine residents in training, fellows, faculty physicians, physician assistants, a nutritionist, and diabetes educators care for patients seen in this practice.

Data Collection

A cohort of patients was identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes for type 2 diabetes. The cohort comprised patients with diabetes in 2006 and 2012 who made follow-up visits in both years.

The data from both time-points were obtained from electronic medical record (EMR) data capture and structured chart review. Two reviewers reviewed 10% of the charts for accuracy after the data was pre-populated from the EMR. The following data were obtained: demographic variables (patient age, gender, and race), height, weight, insurance, smoking status, A1C, LDL, and BP measurements, pharmacotherapy for glycemia, hypertension, and hyperlipidemia, and number of medications needed for control. For variables that had multiple measures, we calculated an average for the year.

The study protocol was approved by the Institutional Review Board at Wake Forest School of Medicine.

Statistical Analysis

Descriptive statistics were performed to compute means, standard deviations, frequencies, and percentages for demographic variables and for glycemia, BP, LDL includ-ing patient characteristics, diabetes outcomes, and pharmacotherapy medication variables. Paired t tests were used to assess for a difference at the level of the patient in the means of the A1C, BP, and LDL between the 2 study time-points (2-sided alpha = 0.05). The non-parametric McNemar test was used to assess for differences in the proportions of patients at the identified goal for A1C, LDL, and BP for 2006 and 2012.

Results

The longitudinal cohort population consisted of 891 patients, 49.5% white and 48.1% African American, with a mean age of 57.9 years (Table 1). The cohort represented 63.7% (891/1398) of the baseline population of patients with diabetes in 2006. Over half of the patients were female and the majority of the sample was overweight or obese. At baseline, almost the entire cohort had some type of insurance including private, Medicare, Medicaid, or a combination.

The number of visits per patient was 5.9 in 2006 and 5.3 in 2012. A1C remained constant between 2006 and 2012 (mean 7.6% vs. 7.7%, ± 1.8) along with body mass index (BMI), while mean LDL cholesterol significantly decreased from 109 ± 36.4 mg/dL in 2006 to 98.8 ± 40.4 mg/dL in 2012 (Table 2). Mean systolic BP marginally increased over the 6-year period from 131.5 ± 14.2 to 134.8 ± 16.1 mm Hg with diastolic BP remaining constant.

The percentage of patients achieving the less stringent A1C goal of < 8% comprised over 50% of the population at both time points; however, compared with 2006, in 2012 there was a lower percentage of patients at the more stringent A1C target of < 7% (43.2% vs. 39.6%). The percentage of patients achieving goal for systolic BP was significantly decreased to 38.6% in 2012 versus 46.5% in 2006 (Table 2). However, the proportion of patients with controlled diastolic BP rose significantly from 70% to 77.6%. The number of patients achieving goal LDL (< 100 mg/dL) increased from 43.5% in 2006 to 58.6% in 2012.

The most common therapeutic regimen was combination therapy with insulin and oral medications, taken by 37% (n = 277) of the cohort (Table 3). Approximately one-third of the study population was taking oral combination therapy using metformin. There were 149 (16.7%) patients who did not have A1C measurements available in both years. The largest group by medication regimen with controlled A1C (< 7 %) were those taking metformin with a combination drug (ie, sulfonylurea, DPP-4 inhibitor, glitazone, or an injectable GLP-agonist). There were 71 patients on no medication, and 86% were at A1C goal.

Table 3 shows number of patients at LDL goal of < 100 mg/dL by lipid-lowering agent. There was a large portion (n = 303 or 34%) of the 891 patients that did not have LDL values available in both 2006 and 2012. A total of 89 patients were taking no medications for LDL, with 64% achieving controlled levels. The large majority of patients were controlled on a single statin drug (n = 195, 59%) while those requiring more than a statin drug for control comprised 53% of patients (n = 92).

 

Table 3 shows achievement of BP < 130/80 by anti-hypertensive regimen. The majority of the hypertensive regimens included the use of an ACEI or an ARB, with overall BP control achieved in at least 45% of patients. The highest BP control (49%) was achieved in the diuretic and CCB–containing regimens without an ACEI or ARB, represented by a smaller group of patients (n = 65). There were 32 patients whose hypertension was controlled without antihypertensive therapy. Ninety-three percent of the cohort had data for evaluation in both years.

The numbers of medications needed to achieve control for glycemia, hypertension, and LDL are shown in Table 4. The mean number of glucose medications increased from 1.2 to 2.2 between 2006 and 2012. For BP and LDL management, the mean number of medications nearly doubled over the 6-year period. The highest number of medications was needed to reach BP goals, with 2.7 medications needed for systolic BP and 3.3 medications necessary for diastolic control. Results were similar for number of required medications for patients achieving a goal A1C of < 7% or a relaxed goal of < 8% in this cohort.

Discussion

Despite the availability of evidence-based guidelines and vast knowledge about microvascular and macrovascular complications due to diabetes, clinical goals for diabetes outcomes are not being routinely achieved in practice. More work is needed to achieve national standards of care. NHANES data from 2007 to 2010 revealed that 52.5% of patients with diabetes achieved an A1C of < 7% while 51.1% had a BP < 130/80 and 56.2% had an LDL < 100 mg/dL [8].

Improvement in LDL cholesterol was seen in the current study, and A1C remained constant during the 6-year time period. While mean A1C, BP, and LDL measurements were close to ADA target goals, a smaller proportion of patients were controlled in 2012 compared with 2006. Hoerger and colleagues [11] found using NHANES data 1999 to 2004 that mean A1C levels significantly declined over time, with 55.7% (up from 36.9%) achieving an A1C of < 7% by 2004  [11]. In our sample of patient with diabetes, only 39.6% were at A1C goal in 2012; 8.2% (61/742) achieved control with no medications.

Metformin is first-line therapy according to ADA recommendations. Most regimens in our study included this drug, with a large percentage of patients with controlled A1C taking this very affordable agent [12]. The combination regimens with metformin plus another oral therapy or 2 oral drugs with insulin resulted in a higher percentage of patients controlled  compared to metformin or insulin monotherapy. From our previous chart review [13] of the entire practice of patients with diabetes (n = 1398) from 2006, A1C control was similarly achieved in patients taking insulin (31% vs. 33%) or insulin combinations (19% vs. 20%) from 2006 to 2012, respectively.

For LDL cholesterol control, 9.7% (57/588) of the cohort used no medications to reach goal. Statin use predominated, with 60% of the cohort reaching goal with a single statin agent. Approximately one-third (175/588) of evaluable patients were on  more than 1 cholesterol medication, and about half of these (53%) reached goal. Over the 6-year period, atorvastatin become available generically, which may have impacted the number of patients able to use this statin. Compared with a recent literature review over a 12-year period of LDL attainment in primary care [14], the results of our study show equivalent or better LDL goal achievement among patient with diabetes.

The majority of the patients received an ACEI or ARB. There were a comparable number of patients controlled with ACEI or ARB with a diuretic, versus an ACEI or ARB with a diuretic and CCB. Large-scale clinical trials have shown that using an ACEI or ARB in combination with a CCB is superior to a hydrochlorathiazide-based combination for reducing risk of major cardiovascular events [15]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that serious adverse events attributed to antihypertensive treatment occurred more frequently in the intensive therapy group (< 120/80) than in the standard therapy (< 140/80) group [16]. The stringent systolic BP goal in accord was accomplished using 3.4 medications. Aggressive lowering of BP may be dangerous in patients with diabetes and there is no benefit found in many large-scale studies [17]. The 2013 ADA goal for BP is now < 140/80 mm Hg, and while our data show that a significant increase in BP was seen over a 6-year period, the number of medications needed to control BP will likely be lower with the new ADA target and potentially safer.

In our cohort, over the 6-year period there was an increase in the number of medications needed to achieve glycemic, BP, and LDL goals. During this time, there were no major changes in the way the patients received care in the clinic environment. We cannot comment on whether lifestyle changes or diabetes education may have impacted the need for increased medication use. Limitations to this study include the unavailability of  A1C (17%) and LDL (34%) data at both time points for every patient, inability to verify insurance data for the 2012 time period, and that the data are from a single practice. We also were unable to determine the duration of diabetes diagnosis due to a change in electronic medical record systems and lack of full documentation by providers.

These findings suggest that as patients live longer with type 2 diabetes, they will need increasing numbers of medications to achieve standard of care goals. Research has shown that there are challenges in implementing diabetes guidelines in primary care, including potential inaccuracies contained in electronic patient health information, inadequate coordination among health care providers, physician lack of awareness of guidelines, and clinical inertia [18]. As shown in the current study and other research, intensification of traditional therapies for glycemic control can sustain target outcomes without the risk of significant weight gain [19].

The chronic condition of diabetes is associated with medical complications as well as challenges for providing optimal care, despite advances in pharmacotherapy. As more medications are added to a patient’s regimen, adherence can become challenging. The cost of medications also warrants consideration. Research is needed to understand the impact on quality of life, cost of care, and outcomes of these regimens as well as whether lifestyle modifications can impact the number of medications needed by individual patients. The current study indicates that overall outcome control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications with the primary agent being a statin drug.

 

Acknowledgements: We would like to thank Drs. Elizabeth Strachan and Madhavi Peechara for their past contributions and diligence in the original chart review.

Corresponding author: Julienne K. Kirk, PharmD, CDE, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1084, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JKK, KL, RWL; analysis and interpretation of data, JKK, SWD, KL, CAH, RWL; drafting of article, JKK, KL, RWL; critical revision of the article, JKK, KL, CAH; provision of study materials or patients, JKK, SWD; statistical expertise, SWD; administrative or technical support, CAH; collection and assembly of data, JKK, KL, CAH.

From the Wake Forest School of Medicine, Winston-Salem, NC.

 

Abstract

• Objective: To assess outcomes and pharmacotherapy in a cohort of patients with type 2 diabetes in a university-based family medicine teaching practice.
• Methods: We used ICD-9-CM codes to identify a cohort of patients with diabetes seen in 2006 and 2012. A total of 891 patients were identified who made follow-up visits in both years. We collected data on patient characteristics, pharmacotherapy, and outcomes for glycemia, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol. We determined type and number of medications taken to achieve target outcomes.
• Results: A1C remained constant between 2006 and 2012 (7.6% to 7.7%) along with BMI (34.7 kg/m² to 34.1 kg/m²), while mean LDL cholesterol significantly decreased from 109 mg/dL in 2006 to 98.8 mg/dL in 2012. The number of patients achieving a goal LDL < 100 mg/dL increased from 43.5 % in 2006 to 58.6% in 2012. The largest group with controlled A1C (< 7 %) were taking metformin with a sulfonylurea, DPP-4 inhibitor, glitazone or an injectable GLP-agonist. The majority achieved an LDL goal of < 100 mg/dl. The majority of hypertensive regimens included use of an ACE inhibitor or ARB with overall BP control achieved in at least 45% of patients.
• Conclusion: Multiple medications are necessary to achieve control among patients with type 2 diabetes over time and this cannot be attributed to an increase in BMI. Overall control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications, with the primary agent for LDL reduction being a statin.

Diabetes is an illness that affects an estimated 25.8 million Americans and is quickly becoming a worldwide epidemic [1,2]. Diabetes is a significant cause of both microvascular and macrovascular sequelae, but its frequent association with the comorbid conditions of hypertension and dyslipidemia further increases the risk of heart disease, stroke, peripheral vascular complications, and renal impairment [3–5]. The American Diabetes Association (ADA) publishes consensus guidelines annually to guide management for patients with diabetes. From 2006 to 2012, the accepted standard of medical care included achieving a hemoglobin A1C (A1C) measurement of < 7%, a low-density lipoprotein (LDL) level of < 100 mg/dL, and a blood pressure (BP) of < 130/80 mm Hg [6,7]. The National Health and Nutrition Examination Survey (NHANES) recently reported that the goal of simultaneous control of A1C, LDL and BP is met in only about 19% of diabetes patients [8]. Target glycemic control is relaxed to an A1C < 8% in some patients with multiple comorbidities, limited life span, or risk for hypoglycemia; and in 2013 the BP goal was modified to < 140/80 based on clinical trial evidence [9].

In combination with lifestyle modification, pharmacotherapy is a critical component of chronic disease management. Initial pharmacotherapy treatment recommendations include metformin for diabetes, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertension, and a statin for dyslipidemia [6,7,9]. In patients who already have a diagnosis of diabetes, achieving control becomes more difficult to accomplish with lifestyle alone, and the benefit of lifestyle intervention on all-cause mortality as well as cardiovascular and microvascular events remains a debated issue [10]. The need for pharmacologic agents in most patients with diabetes is inevitable. Metformin is the agent of choice for initial treatment with drug therapy, with the option of adding a variety of other oral or injectable medications based on clinician decision-making [7]. In this study, we reviewed data from a longitudinal cohort of type 2 diabetes patients and compared medication use and outcomes at 2 different time-points (2006 and 2012) to see how medical management and outcome measures changed over time.

 

Methods

Setting

Data were obtained from an academic family medicine clinic in the southeastern United States. Approximately 56,000 patient visits to this clinic are conducted annually. Family medicine residents in training, fellows, faculty physicians, physician assistants, a nutritionist, and diabetes educators care for patients seen in this practice.

Data Collection

A cohort of patients was identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes for type 2 diabetes. The cohort comprised patients with diabetes in 2006 and 2012 who made follow-up visits in both years.

The data from both time-points were obtained from electronic medical record (EMR) data capture and structured chart review. Two reviewers reviewed 10% of the charts for accuracy after the data was pre-populated from the EMR. The following data were obtained: demographic variables (patient age, gender, and race), height, weight, insurance, smoking status, A1C, LDL, and BP measurements, pharmacotherapy for glycemia, hypertension, and hyperlipidemia, and number of medications needed for control. For variables that had multiple measures, we calculated an average for the year.

The study protocol was approved by the Institutional Review Board at Wake Forest School of Medicine.

Statistical Analysis

Descriptive statistics were performed to compute means, standard deviations, frequencies, and percentages for demographic variables and for glycemia, BP, LDL includ-ing patient characteristics, diabetes outcomes, and pharmacotherapy medication variables. Paired t tests were used to assess for a difference at the level of the patient in the means of the A1C, BP, and LDL between the 2 study time-points (2-sided alpha = 0.05). The non-parametric McNemar test was used to assess for differences in the proportions of patients at the identified goal for A1C, LDL, and BP for 2006 and 2012.

Results

The longitudinal cohort population consisted of 891 patients, 49.5% white and 48.1% African American, with a mean age of 57.9 years (Table 1). The cohort represented 63.7% (891/1398) of the baseline population of patients with diabetes in 2006. Over half of the patients were female and the majority of the sample was overweight or obese. At baseline, almost the entire cohort had some type of insurance including private, Medicare, Medicaid, or a combination.

The number of visits per patient was 5.9 in 2006 and 5.3 in 2012. A1C remained constant between 2006 and 2012 (mean 7.6% vs. 7.7%, ± 1.8) along with body mass index (BMI), while mean LDL cholesterol significantly decreased from 109 ± 36.4 mg/dL in 2006 to 98.8 ± 40.4 mg/dL in 2012 (Table 2). Mean systolic BP marginally increased over the 6-year period from 131.5 ± 14.2 to 134.8 ± 16.1 mm Hg with diastolic BP remaining constant.

The percentage of patients achieving the less stringent A1C goal of < 8% comprised over 50% of the population at both time points; however, compared with 2006, in 2012 there was a lower percentage of patients at the more stringent A1C target of < 7% (43.2% vs. 39.6%). The percentage of patients achieving goal for systolic BP was significantly decreased to 38.6% in 2012 versus 46.5% in 2006 (Table 2). However, the proportion of patients with controlled diastolic BP rose significantly from 70% to 77.6%. The number of patients achieving goal LDL (< 100 mg/dL) increased from 43.5% in 2006 to 58.6% in 2012.

The most common therapeutic regimen was combination therapy with insulin and oral medications, taken by 37% (n = 277) of the cohort (Table 3). Approximately one-third of the study population was taking oral combination therapy using metformin. There were 149 (16.7%) patients who did not have A1C measurements available in both years. The largest group by medication regimen with controlled A1C (< 7 %) were those taking metformin with a combination drug (ie, sulfonylurea, DPP-4 inhibitor, glitazone, or an injectable GLP-agonist). There were 71 patients on no medication, and 86% were at A1C goal.

Table 3 shows number of patients at LDL goal of < 100 mg/dL by lipid-lowering agent. There was a large portion (n = 303 or 34%) of the 891 patients that did not have LDL values available in both 2006 and 2012. A total of 89 patients were taking no medications for LDL, with 64% achieving controlled levels. The large majority of patients were controlled on a single statin drug (n = 195, 59%) while those requiring more than a statin drug for control comprised 53% of patients (n = 92).

 

Table 3 shows achievement of BP < 130/80 by anti-hypertensive regimen. The majority of the hypertensive regimens included the use of an ACEI or an ARB, with overall BP control achieved in at least 45% of patients. The highest BP control (49%) was achieved in the diuretic and CCB–containing regimens without an ACEI or ARB, represented by a smaller group of patients (n = 65). There were 32 patients whose hypertension was controlled without antihypertensive therapy. Ninety-three percent of the cohort had data for evaluation in both years.

The numbers of medications needed to achieve control for glycemia, hypertension, and LDL are shown in Table 4. The mean number of glucose medications increased from 1.2 to 2.2 between 2006 and 2012. For BP and LDL management, the mean number of medications nearly doubled over the 6-year period. The highest number of medications was needed to reach BP goals, with 2.7 medications needed for systolic BP and 3.3 medications necessary for diastolic control. Results were similar for number of required medications for patients achieving a goal A1C of < 7% or a relaxed goal of < 8% in this cohort.

Discussion

Despite the availability of evidence-based guidelines and vast knowledge about microvascular and macrovascular complications due to diabetes, clinical goals for diabetes outcomes are not being routinely achieved in practice. More work is needed to achieve national standards of care. NHANES data from 2007 to 2010 revealed that 52.5% of patients with diabetes achieved an A1C of < 7% while 51.1% had a BP < 130/80 and 56.2% had an LDL < 100 mg/dL [8].

Improvement in LDL cholesterol was seen in the current study, and A1C remained constant during the 6-year time period. While mean A1C, BP, and LDL measurements were close to ADA target goals, a smaller proportion of patients were controlled in 2012 compared with 2006. Hoerger and colleagues [11] found using NHANES data 1999 to 2004 that mean A1C levels significantly declined over time, with 55.7% (up from 36.9%) achieving an A1C of < 7% by 2004  [11]. In our sample of patient with diabetes, only 39.6% were at A1C goal in 2012; 8.2% (61/742) achieved control with no medications.

Metformin is first-line therapy according to ADA recommendations. Most regimens in our study included this drug, with a large percentage of patients with controlled A1C taking this very affordable agent [12]. The combination regimens with metformin plus another oral therapy or 2 oral drugs with insulin resulted in a higher percentage of patients controlled  compared to metformin or insulin monotherapy. From our previous chart review [13] of the entire practice of patients with diabetes (n = 1398) from 2006, A1C control was similarly achieved in patients taking insulin (31% vs. 33%) or insulin combinations (19% vs. 20%) from 2006 to 2012, respectively.

For LDL cholesterol control, 9.7% (57/588) of the cohort used no medications to reach goal. Statin use predominated, with 60% of the cohort reaching goal with a single statin agent. Approximately one-third (175/588) of evaluable patients were on  more than 1 cholesterol medication, and about half of these (53%) reached goal. Over the 6-year period, atorvastatin become available generically, which may have impacted the number of patients able to use this statin. Compared with a recent literature review over a 12-year period of LDL attainment in primary care [14], the results of our study show equivalent or better LDL goal achievement among patient with diabetes.

The majority of the patients received an ACEI or ARB. There were a comparable number of patients controlled with ACEI or ARB with a diuretic, versus an ACEI or ARB with a diuretic and CCB. Large-scale clinical trials have shown that using an ACEI or ARB in combination with a CCB is superior to a hydrochlorathiazide-based combination for reducing risk of major cardiovascular events [15]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that serious adverse events attributed to antihypertensive treatment occurred more frequently in the intensive therapy group (< 120/80) than in the standard therapy (< 140/80) group [16]. The stringent systolic BP goal in accord was accomplished using 3.4 medications. Aggressive lowering of BP may be dangerous in patients with diabetes and there is no benefit found in many large-scale studies [17]. The 2013 ADA goal for BP is now < 140/80 mm Hg, and while our data show that a significant increase in BP was seen over a 6-year period, the number of medications needed to control BP will likely be lower with the new ADA target and potentially safer.

In our cohort, over the 6-year period there was an increase in the number of medications needed to achieve glycemic, BP, and LDL goals. During this time, there were no major changes in the way the patients received care in the clinic environment. We cannot comment on whether lifestyle changes or diabetes education may have impacted the need for increased medication use. Limitations to this study include the unavailability of  A1C (17%) and LDL (34%) data at both time points for every patient, inability to verify insurance data for the 2012 time period, and that the data are from a single practice. We also were unable to determine the duration of diabetes diagnosis due to a change in electronic medical record systems and lack of full documentation by providers.

These findings suggest that as patients live longer with type 2 diabetes, they will need increasing numbers of medications to achieve standard of care goals. Research has shown that there are challenges in implementing diabetes guidelines in primary care, including potential inaccuracies contained in electronic patient health information, inadequate coordination among health care providers, physician lack of awareness of guidelines, and clinical inertia [18]. As shown in the current study and other research, intensification of traditional therapies for glycemic control can sustain target outcomes without the risk of significant weight gain [19].

The chronic condition of diabetes is associated with medical complications as well as challenges for providing optimal care, despite advances in pharmacotherapy. As more medications are added to a patient’s regimen, adherence can become challenging. The cost of medications also warrants consideration. Research is needed to understand the impact on quality of life, cost of care, and outcomes of these regimens as well as whether lifestyle modifications can impact the number of medications needed by individual patients. The current study indicates that overall outcome control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications with the primary agent being a statin drug.

 

Acknowledgements: We would like to thank Drs. Elizabeth Strachan and Madhavi Peechara for their past contributions and diligence in the original chart review.

Corresponding author: Julienne K. Kirk, PharmD, CDE, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1084, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JKK, KL, RWL; analysis and interpretation of data, JKK, SWD, KL, CAH, RWL; drafting of article, JKK, KL, RWL; critical revision of the article, JKK, KL, CAH; provision of study materials or patients, JKK, SWD; statistical expertise, SWD; administrative or technical support, CAH; collection and assembly of data, JKK, KL, CAH.

Targeting CXCL12/CXCR4 signaling could be a “powerful” approach to treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.

Results of their preclinical experiments indicate that deleting CXCL12 from vascular endothelial cells can stall T-ALL progression.

And inhibiting or deleting CXCR4 can halt tumor growth and induce remission in mice with T-ALL.

The researchers reported these findings in Cancer Cell.

“Our experiments showed that blocking CXCR4 decimated leukemia cells,” said study author Susan Schwab, PhD, of the New York University School of Medicine in New York, New York.

This suggests CXCR4 antagonists could treat T-ALL, she added, noting that such drugs are already in preliminary testing for myeloid leukemia and have proven well-tolerated thus far.

Dr Schwab and her colleagues conducted this research to build upon previous work, which showed that leukemia-initiating cells concentrate in the bone marrow near CXCL12-producing blood vessels.

This finding inspired the researchers to investigate the expression and function of CXCR4 because it binds to CXCL12, as well as the role CXCR4-CXCL12 molecular signaling plays in disease growth.

With this study, the team found that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma.

They showed that deleting CXCL12 in vascular endothelial cells suppressed T-ALL. But they did not observe the same benefit when they deleted CXCL12 from perivascular cells.

The researchers also found that T-ALL cells express high surface levels of CXCR4, and deleting CXCR4 can produce sustained remission in mice with T-ALL.

Similarly, a small-molecule inhibitor of CXCR4, AMD3465, exhibited antileukemic activity in murine T-ALL and human xenografts.

Experiments with CXCR4-deficient T-ALL cells showed that CXCR4 expression and signaling influences leukemic cell localization and survival. And further investigation revealed that the loss of CXCR4 expression is associated with decreased levels of MYC.

The researchers said additional work is needed to determine exactly how CXCR4 is able to promote and sustain T-ALL.

Targeting CXCL12/CXCR4 signaling could be a “powerful” approach to treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.

Results of their preclinical experiments indicate that deleting CXCL12 from vascular endothelial cells can stall T-ALL progression.

And inhibiting or deleting CXCR4 can halt tumor growth and induce remission in mice with T-ALL.

The researchers reported these findings in Cancer Cell.

“Our experiments showed that blocking CXCR4 decimated leukemia cells,” said study author Susan Schwab, PhD, of the New York University School of Medicine in New York, New York.

This suggests CXCR4 antagonists could treat T-ALL, she added, noting that such drugs are already in preliminary testing for myeloid leukemia and have proven well-tolerated thus far.

Dr Schwab and her colleagues conducted this research to build upon previous work, which showed that leukemia-initiating cells concentrate in the bone marrow near CXCL12-producing blood vessels.

This finding inspired the researchers to investigate the expression and function of CXCR4 because it binds to CXCL12, as well as the role CXCR4-CXCL12 molecular signaling plays in disease growth.

With this study, the team found that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma.

They showed that deleting CXCL12 in vascular endothelial cells suppressed T-ALL. But they did not observe the same benefit when they deleted CXCL12 from perivascular cells.

The researchers also found that T-ALL cells express high surface levels of CXCR4, and deleting CXCR4 can produce sustained remission in mice with T-ALL.

Similarly, a small-molecule inhibitor of CXCR4, AMD3465, exhibited antileukemic activity in murine T-ALL and human xenografts.

Experiments with CXCR4-deficient T-ALL cells showed that CXCR4 expression and signaling influences leukemic cell localization and survival. And further investigation revealed that the loss of CXCR4 expression is associated with decreased levels of MYC.

The researchers said additional work is needed to determine exactly how CXCR4 is able to promote and sustain T-ALL.

Targeting CXCL12/CXCR4 signaling could be a “powerful” approach to treating T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.

Results of their preclinical experiments indicate that deleting CXCL12 from vascular endothelial cells can stall T-ALL progression.

And inhibiting or deleting CXCR4 can halt tumor growth and induce remission in mice with T-ALL.

The researchers reported these findings in Cancer Cell.

“Our experiments showed that blocking CXCR4 decimated leukemia cells,” said study author Susan Schwab, PhD, of the New York University School of Medicine in New York, New York.

This suggests CXCR4 antagonists could treat T-ALL, she added, noting that such drugs are already in preliminary testing for myeloid leukemia and have proven well-tolerated thus far.

Dr Schwab and her colleagues conducted this research to build upon previous work, which showed that leukemia-initiating cells concentrate in the bone marrow near CXCL12-producing blood vessels.

This finding inspired the researchers to investigate the expression and function of CXCR4 because it binds to CXCL12, as well as the role CXCR4-CXCL12 molecular signaling plays in disease growth.

With this study, the team found that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma.

They showed that deleting CXCL12 in vascular endothelial cells suppressed T-ALL. But they did not observe the same benefit when they deleted CXCL12 from perivascular cells.

The researchers also found that T-ALL cells express high surface levels of CXCR4, and deleting CXCR4 can produce sustained remission in mice with T-ALL.

Similarly, a small-molecule inhibitor of CXCR4, AMD3465, exhibited antileukemic activity in murine T-ALL and human xenografts.

Experiments with CXCR4-deficient T-ALL cells showed that CXCR4 expression and signaling influences leukemic cell localization and survival. And further investigation revealed that the loss of CXCR4 expression is associated with decreased levels of MYC.

The researchers said additional work is needed to determine exactly how CXCR4 is able to promote and sustain T-ALL.

A novel approach to genome analysis can provide a clearer picture of cancer genomes, according to research published in PNAS.

Investigators used this approach, which combines optical mapping and DNA sequencing, to analyze samples from a patient with multiple myeloma (MM).

They found “widespread structural variation” in the tumor genome and observed an increase in mutational burden that correlated with disease

progression.

“Cancer genomes are complicated, but we found that, using an approach like this, you can begin to understand them at every level,” said study author David Schwartz, PhD, of the University of Wisconsin-Madison.

“The approach allows an intimate view of a cancer genome. You get to see it, you get to measure it, and you get to see it evolve at many levels. This is what we should be doing with every cancer genome, and the goal here is to make the system fast enough so this becomes a routine tool.”

To test the approach, the investigators obtained cancerous and noncancerous samples from a patient with MM at two different time points: while the patient was still responding to treatment and after the patient’s disease had progressed and become resistant to chemotherapy.

The team performed standard DNA sequencing to read each of the letters spelling out the genomic code of the disease. Then, isolating the individual DNA molecules, they performed optical mapping.

This involves stretching single strands of DNA and placing them in a device. The strands are given specific landmarks and marked with a fluorescent dye. An automated system takes images of each of these marked segments, cataloging the molecules into large datasets that are then pieced together to provide a larger view of the genome.

The investigators said the information provided by DNA sequencing and the “bigger picture” provided by optical mapping allowed for a comprehensive view of the patient’s MM genome.

“It’s a rare, near-complete characterization of the complexity of a myeloma genome, from the smallest variance all the way to big chunks of chromosomal material that differ between the tumor DNA and the normal DNA of the patient,” said study author Fotis Asimakopoulos, MD, PhD, of the University of Wisconsin Carbone Cancer Center.

The approach allowed the investigators to see that, compared to the patient’s noncancerous genome, and across the two time points, the MM genome was marked by an increase in notable mutations and larger-scale changes.

The team highlighted the changes they believe are most worthy of further exploration and that yield the greatest potential for future therapies. They hope this approach could help prevent drug resistance or at least help scientists and physicians develop ways to work around it.

It could allow them to examine changes in a patient’s cancer over the progression of the illness, monitor for signs of resistance, and fine-tune treatments, Dr Schwartz said.

“To cure myeloma, we need to understand how genomes evolve with progression and treatment,” Dr Asimakopoulos added. “The more we can understand the drivers in cancer in significant depth, and in each individual, the better we can tailor treatment to each patient’s disease biology.”

“Instead of [calling the disease] grade 1, we can say, ‘This is Joe’s myeloma, and, given this list of mutations and other info, this is the treatment.’ No two myeloma are alike.”

The investigators are now working toward advancing the system, making it higher-resolution, more cost-effective, and scalable. Ultimately, they would like to build a system capable of analyzing 1000 genomes in 24 hours.

A novel approach to genome analysis can provide a clearer picture of cancer genomes, according to research published in PNAS.

Investigators used this approach, which combines optical mapping and DNA sequencing, to analyze samples from a patient with multiple myeloma (MM).

They found “widespread structural variation” in the tumor genome and observed an increase in mutational burden that correlated with disease

progression.

“Cancer genomes are complicated, but we found that, using an approach like this, you can begin to understand them at every level,” said study author David Schwartz, PhD, of the University of Wisconsin-Madison.

“The approach allows an intimate view of a cancer genome. You get to see it, you get to measure it, and you get to see it evolve at many levels. This is what we should be doing with every cancer genome, and the goal here is to make the system fast enough so this becomes a routine tool.”

To test the approach, the investigators obtained cancerous and noncancerous samples from a patient with MM at two different time points: while the patient was still responding to treatment and after the patient’s disease had progressed and become resistant to chemotherapy.

The team performed standard DNA sequencing to read each of the letters spelling out the genomic code of the disease. Then, isolating the individual DNA molecules, they performed optical mapping.

This involves stretching single strands of DNA and placing them in a device. The strands are given specific landmarks and marked with a fluorescent dye. An automated system takes images of each of these marked segments, cataloging the molecules into large datasets that are then pieced together to provide a larger view of the genome.

The investigators said the information provided by DNA sequencing and the “bigger picture” provided by optical mapping allowed for a comprehensive view of the patient’s MM genome.

“It’s a rare, near-complete characterization of the complexity of a myeloma genome, from the smallest variance all the way to big chunks of chromosomal material that differ between the tumor DNA and the normal DNA of the patient,” said study author Fotis Asimakopoulos, MD, PhD, of the University of Wisconsin Carbone Cancer Center.

The approach allowed the investigators to see that, compared to the patient’s noncancerous genome, and across the two time points, the MM genome was marked by an increase in notable mutations and larger-scale changes.

The team highlighted the changes they believe are most worthy of further exploration and that yield the greatest potential for future therapies. They hope this approach could help prevent drug resistance or at least help scientists and physicians develop ways to work around it.

It could allow them to examine changes in a patient’s cancer over the progression of the illness, monitor for signs of resistance, and fine-tune treatments, Dr Schwartz said.

“To cure myeloma, we need to understand how genomes evolve with progression and treatment,” Dr Asimakopoulos added. “The more we can understand the drivers in cancer in significant depth, and in each individual, the better we can tailor treatment to each patient’s disease biology.”

“Instead of [calling the disease] grade 1, we can say, ‘This is Joe’s myeloma, and, given this list of mutations and other info, this is the treatment.’ No two myeloma are alike.”

The investigators are now working toward advancing the system, making it higher-resolution, more cost-effective, and scalable. Ultimately, they would like to build a system capable of analyzing 1000 genomes in 24 hours.

A novel approach to genome analysis can provide a clearer picture of cancer genomes, according to research published in PNAS.

Investigators used this approach, which combines optical mapping and DNA sequencing, to analyze samples from a patient with multiple myeloma (MM).

They found “widespread structural variation” in the tumor genome and observed an increase in mutational burden that correlated with disease

progression.

“Cancer genomes are complicated, but we found that, using an approach like this, you can begin to understand them at every level,” said study author David Schwartz, PhD, of the University of Wisconsin-Madison.

“The approach allows an intimate view of a cancer genome. You get to see it, you get to measure it, and you get to see it evolve at many levels. This is what we should be doing with every cancer genome, and the goal here is to make the system fast enough so this becomes a routine tool.”

To test the approach, the investigators obtained cancerous and noncancerous samples from a patient with MM at two different time points: while the patient was still responding to treatment and after the patient’s disease had progressed and become resistant to chemotherapy.

The team performed standard DNA sequencing to read each of the letters spelling out the genomic code of the disease. Then, isolating the individual DNA molecules, they performed optical mapping.

This involves stretching single strands of DNA and placing them in a device. The strands are given specific landmarks and marked with a fluorescent dye. An automated system takes images of each of these marked segments, cataloging the molecules into large datasets that are then pieced together to provide a larger view of the genome.

The investigators said the information provided by DNA sequencing and the “bigger picture” provided by optical mapping allowed for a comprehensive view of the patient’s MM genome.

“It’s a rare, near-complete characterization of the complexity of a myeloma genome, from the smallest variance all the way to big chunks of chromosomal material that differ between the tumor DNA and the normal DNA of the patient,” said study author Fotis Asimakopoulos, MD, PhD, of the University of Wisconsin Carbone Cancer Center.

The approach allowed the investigators to see that, compared to the patient’s noncancerous genome, and across the two time points, the MM genome was marked by an increase in notable mutations and larger-scale changes.

The team highlighted the changes they believe are most worthy of further exploration and that yield the greatest potential for future therapies. They hope this approach could help prevent drug resistance or at least help scientists and physicians develop ways to work around it.

It could allow them to examine changes in a patient’s cancer over the progression of the illness, monitor for signs of resistance, and fine-tune treatments, Dr Schwartz said.

“To cure myeloma, we need to understand how genomes evolve with progression and treatment,” Dr Asimakopoulos added. “The more we can understand the drivers in cancer in significant depth, and in each individual, the better we can tailor treatment to each patient’s disease biology.”

“Instead of [calling the disease] grade 1, we can say, ‘This is Joe’s myeloma, and, given this list of mutations and other info, this is the treatment.’ No two myeloma are alike.”

The investigators are now working toward advancing the system, making it higher-resolution, more cost-effective, and scalable. Ultimately, they would like to build a system capable of analyzing 1000 genomes in 24 hours.

BALTIMORE—Scientists say they have synthesized an imaging agent that allows them to detect blood clots throughout the body and estimate the fibrin content of those clots.

In murine experiments, the fibrin-specific PET probe FBP8 detected arterial and venous thrombi with high accuracy.

The tracer also proved sensitive to changes in the fibrin content of clots, which correlated with their age.

Francesco Blasi, PhD, of Massachusetts General Hospital in Charlestown, presented these findings at the 2015 SNMMI Annual Meeting (abstract 78).

Dr Blasi and his colleagues synthesized FBP8 by conjugating a short cyclic peptide with high affinity for fibrin to a macrocyclic chelator (NODAGA) and labeling it with 64Cu.

The researchers then performed FBP8-PET 1, 3, or 7 days after inducing thrombosis in 30 Sprague-Dawley rats (by applying ferric chloride on the carotid artery and femoral vein). The team also performed FBP8-PET in an animal model of deep vein thrombosis and pulmonary embolism.

FBP8-PET was more than 97% accurate for pinpointing arterial and venous thrombi in the rats. It also detected lung and venous thrombi in the model of deep vein thrombosis and pulmonary embolism. And probe uptake was significantly greater in fresh blood clots than in older ones (P<0.01).

“If approved, fibrin-specific PET could facilitate diagnosis, guide therapeutic choices, and help physicians monitor their patients’ treatment,” said study investigator Peter Caravan, PhD, of Massachusetts General Hospital.

“This technique also offers full-body detection of thrombi with a single injection of probe, instead of the current imaging standards, which are limited to specific parts of the body. A one-time, whole-body scan could prevent unnecessary procedures and uncover hidden thrombi before they generate a deadly embolism.”

Contingent on approval by the US Food and Drug Administration, the researchers expect to conduct a first-in-human study of FBP8-PET as soon as this fall.

BALTIMORE—Scientists say they have synthesized an imaging agent that allows them to detect blood clots throughout the body and estimate the fibrin content of those clots.

In murine experiments, the fibrin-specific PET probe FBP8 detected arterial and venous thrombi with high accuracy.

The tracer also proved sensitive to changes in the fibrin content of clots, which correlated with their age.

Francesco Blasi, PhD, of Massachusetts General Hospital in Charlestown, presented these findings at the 2015 SNMMI Annual Meeting (abstract 78).

Dr Blasi and his colleagues synthesized FBP8 by conjugating a short cyclic peptide with high affinity for fibrin to a macrocyclic chelator (NODAGA) and labeling it with 64Cu.

The researchers then performed FBP8-PET 1, 3, or 7 days after inducing thrombosis in 30 Sprague-Dawley rats (by applying ferric chloride on the carotid artery and femoral vein). The team also performed FBP8-PET in an animal model of deep vein thrombosis and pulmonary embolism.

FBP8-PET was more than 97% accurate for pinpointing arterial and venous thrombi in the rats. It also detected lung and venous thrombi in the model of deep vein thrombosis and pulmonary embolism. And probe uptake was significantly greater in fresh blood clots than in older ones (P<0.01).

“If approved, fibrin-specific PET could facilitate diagnosis, guide therapeutic choices, and help physicians monitor their patients’ treatment,” said study investigator Peter Caravan, PhD, of Massachusetts General Hospital.

“This technique also offers full-body detection of thrombi with a single injection of probe, instead of the current imaging standards, which are limited to specific parts of the body. A one-time, whole-body scan could prevent unnecessary procedures and uncover hidden thrombi before they generate a deadly embolism.”

Contingent on approval by the US Food and Drug Administration, the researchers expect to conduct a first-in-human study of FBP8-PET as soon as this fall.

BALTIMORE—Scientists say they have synthesized an imaging agent that allows them to detect blood clots throughout the body and estimate the fibrin content of those clots.

In murine experiments, the fibrin-specific PET probe FBP8 detected arterial and venous thrombi with high accuracy.

The tracer also proved sensitive to changes in the fibrin content of clots, which correlated with their age.

Francesco Blasi, PhD, of Massachusetts General Hospital in Charlestown, presented these findings at the 2015 SNMMI Annual Meeting (abstract 78).

Dr Blasi and his colleagues synthesized FBP8 by conjugating a short cyclic peptide with high affinity for fibrin to a macrocyclic chelator (NODAGA) and labeling it with 64Cu.

The researchers then performed FBP8-PET 1, 3, or 7 days after inducing thrombosis in 30 Sprague-Dawley rats (by applying ferric chloride on the carotid artery and femoral vein). The team also performed FBP8-PET in an animal model of deep vein thrombosis and pulmonary embolism.

FBP8-PET was more than 97% accurate for pinpointing arterial and venous thrombi in the rats. It also detected lung and venous thrombi in the model of deep vein thrombosis and pulmonary embolism. And probe uptake was significantly greater in fresh blood clots than in older ones (P<0.01).

“If approved, fibrin-specific PET could facilitate diagnosis, guide therapeutic choices, and help physicians monitor their patients’ treatment,” said study investigator Peter Caravan, PhD, of Massachusetts General Hospital.

“This technique also offers full-body detection of thrombi with a single injection of probe, instead of the current imaging standards, which are limited to specific parts of the body. A one-time, whole-body scan could prevent unnecessary procedures and uncover hidden thrombi before they generate a deadly embolism.”

Contingent on approval by the US Food and Drug Administration, the researchers expect to conduct a first-in-human study of FBP8-PET as soon as this fall.

Mylan N.V. is conducting a US-wide recall of injectable products due to the presence of visible foreign particulate matter observed in retention samples.

This voluntary recall includes select lots of gemcitabine and a single lot of methotrexate.

Although administration of a sterile injectable containing foreign particulates can cause severe health consequences, Mylan has not received any reports of adverse events related to this recall.

The recall includes the following products:

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 0069-3857-10; Lot number: 7801084; Expiration date: 07/2015

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 0069-3857-10; Lot number: 7801110; Expiration date: 08/2015

Gemcitabine for Injection, USP 2 g; Package size: 100 mL; NDC number: 67457-463-02; Lot number: 7801221; Expiration date: 03/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801398; Expiration date: 08/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801406; Expiration date: 08/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801427; Expiration date: 09/2016

Gemcitabine for Injection, USP 1 g; Package size: 50 mL; NDC number: 67457-462-01; Lot number: 7801284; Expiration date: 05/2016

Methotrexate Injection, USP 50 mg/2 mL (25 mg/mL); Package size: 5 x 2 mL; NDC number: 67457-467-99; Lot number: 7801421; Expiration date: 09/2016

Gemcitabine for Injection, USP is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between January 8, 2014, and February 10, 2015. They were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801084 and 7801110 are packaged with a Pfizer Injectable label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between December 8, 2014, and December 19, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with products included in this recall should stop use and return the products to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST. Consumers should contact their physician or healthcare provider if they have experienced any problems that may be related to using these products.

Adverse reactions or quality problems experienced with the use of this product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Mylan N.V. is conducting a US-wide recall of injectable products due to the presence of visible foreign particulate matter observed in retention samples.

This voluntary recall includes select lots of gemcitabine and a single lot of methotrexate.

Although administration of a sterile injectable containing foreign particulates can cause severe health consequences, Mylan has not received any reports of adverse events related to this recall.

The recall includes the following products:

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 0069-3857-10; Lot number: 7801084; Expiration date: 07/2015

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 0069-3857-10; Lot number: 7801110; Expiration date: 08/2015

Gemcitabine for Injection, USP 2 g; Package size: 100 mL; NDC number: 67457-463-02; Lot number: 7801221; Expiration date: 03/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801398; Expiration date: 08/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801406; Expiration date: 08/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801427; Expiration date: 09/2016

Gemcitabine for Injection, USP 1 g; Package size: 50 mL; NDC number: 67457-462-01; Lot number: 7801284; Expiration date: 05/2016

Methotrexate Injection, USP 50 mg/2 mL (25 mg/mL); Package size: 5 x 2 mL; NDC number: 67457-467-99; Lot number: 7801421; Expiration date: 09/2016

Gemcitabine for Injection, USP is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between January 8, 2014, and February 10, 2015. They were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801084 and 7801110 are packaged with a Pfizer Injectable label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between December 8, 2014, and December 19, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with products included in this recall should stop use and return the products to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST. Consumers should contact their physician or healthcare provider if they have experienced any problems that may be related to using these products.

Adverse reactions or quality problems experienced with the use of this product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Mylan N.V. is conducting a US-wide recall of injectable products due to the presence of visible foreign particulate matter observed in retention samples.

This voluntary recall includes select lots of gemcitabine and a single lot of methotrexate.

Although administration of a sterile injectable containing foreign particulates can cause severe health consequences, Mylan has not received any reports of adverse events related to this recall.

The recall includes the following products:

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 0069-3857-10; Lot number: 7801084; Expiration date: 07/2015

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 0069-3857-10; Lot number: 7801110; Expiration date: 08/2015

Gemcitabine for Injection, USP 2 g; Package size: 100 mL; NDC number: 67457-463-02; Lot number: 7801221; Expiration date: 03/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801398; Expiration date: 08/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801406; Expiration date: 08/2016

Gemcitabine for Injection, USP 200 mg; Package size: 10 mL; NDC number: 67457-464-20; Lot number: 7801427; Expiration date: 09/2016

Gemcitabine for Injection, USP 1 g; Package size: 50 mL; NDC number: 67457-462-01; Lot number: 7801284; Expiration date: 05/2016

Methotrexate Injection, USP 50 mg/2 mL (25 mg/mL); Package size: 5 x 2 mL; NDC number: 67457-467-99; Lot number: 7801421; Expiration date: 09/2016

Gemcitabine for Injection, USP is an intravenously administered product indicated for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, and pancreatic cancer. These lots were distributed in the US between January 8, 2014, and February 10, 2015. They were manufactured and packaged by Agila Onco Therapies Limited, a Mylan company. Lot 7801084 and 7801110 are packaged with a Pfizer Injectable label.

Methotrexate Injection, USP 25 mg/mL can be administered intramuscularly, intravenously, intra-arterially, or intrathecally and is indicated for certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. The lot was distributed in the US between December 8, 2014, and December 19, 2014, and was packaged by Agila Onco Therapies Limited, a Mylan company.

Mylan is notifying its distributors and customers by letter and is arranging for the return of all recalled products. Distributors, retailers, hospitals, clinics, and physicians with products included in this recall should stop use and return the products to the place of purchase.

Consumers with questions regarding this recall can contact Mylan Customer Relations at 800-796-9526 or [email protected], Monday through Friday from 8 am to 5 pm EST. Consumers should contact their physician or healthcare provider if they have experienced any problems that may be related to using these products.

Adverse reactions or quality problems experienced with the use of this product may be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Black salve is composed of various ingredients, many of which are inert; however, some black salves contain escharotics, the 2 most common are zinc chloride and bloodroot (Sanguinaria canadensis) extract. In high doses, such as those contained in most black salve products, these corrosive agents can indiscriminately damage both healthy and diseased tissue.¹ Nevertheless, many black salve products currently are advertised as safe and natural methods for curing skin cancer^2-4 or treating a variety of other skin conditions (eg, moles, warts, skin tags, boils, abscesses, bee stings, other minor wounds)^1,5 and even nondermatologic conditions such as a sore throat.⁶ Despite the information and testimonials that are widely available on the Internet, black salve use has not been validated by rigorous studies. Black salve is not regulated by the US Food and Drug Administration, resulting in poor quality control and inconsistent user instructions. We report the case of application of black salve to a biopsy site of a compound nevus with moderate atypia that resulted in the formation of a dermatitis plaque with subsequent scarring and basal layer pigmentation.

Case Report

A 35-year-old woman with a family history of melanoma presented for follow-up of a compound nevus with moderate atypia on the right anterior thigh that had been biopsied 6 months prior. Complete excision of the lesion was recommended at the initial presentation but was not performed due to scheduling conflicts. The patient reported applying black salve to the biopsy site and also to the left thigh 3 months later. There was no reaction on the left thigh after one 24-hour application of black salve, but an area around the biopsy site on the right thigh became thickened and irritated with superficial erosion of the skin following 2 applications of black salve, each of 24 hours’ duration. Physical examination revealed a granulomatous plaque at the biopsy site that was approximately 5 cm in diameter (Figure 1A). One year later the lesion had completely healed (Figure 1B) and a biopsy revealed scarring with basal layer pigmentation (Figure 2).

Figure 1. A 5-cm granulomatous reaction surrounding a biopsy site on the right anterior thigh 3 months after application of black salve (A). One year later, the lesion had completely healed (B).					Figure 2. A biopsy one year following application of black salve demonstrated scarring with basal layer pigmentation (H&E, original magnification ×4).

Comment

A Web search using the term black salve yields a large number of products labeled as skin cancer salves, many showing glowing reviews and some being sold by major US retailers. The ingredients in black salves often vary in the innocuous substances they contain, but most products include the escharotics zinc chloride and bloodroot extract, which is derived from the plant S canadensis.^1,3 For example, the ingredients of one popular black salve product include zinc chloride, chaparral (active ingredient is nordihydroguaiaretic acid), graviola leaf extract, oleander leaf extract, bloodroot extract, and glycerine,⁷ while another product includes bloodroot extract, zinc chloride, chaparral, cayenne pepper, red clover, birch bark, dimethyl sulfoxide, and burdock root.⁴

Bloodroot extract’s antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory effects derive from its benzylisoquinoline alkaloids including sanguinarine, allocryptopine, berberine, coptisine, protopine, and stylopine.^3,8 Bloodroot extract possesses some degree of tumoricidal potency, with one study finding that it selectively targets cancer cells.⁹ However, this differential response is seen only at low doses and not at the high concentrations contained in most black salve products.¹ According to fluorometric assays, sanguinarine is not selective for tumor cells and therefore damages healthy tissue in addition to the unwanted lesions.^6,10,11 The US Food and Drug Administration includes black salve products on its list of fake cancer cures that consumers should avoid.¹² Reports of extensive damage from black salve use include skin ulceration^2,10 and complete loss of a naris¹ and nasal ala.⁵ Our case suggests the possible association between black salve use and an irritant reaction and erosion of the skin.

Furthermore, reliance on black salve alone in the treatment of skin cancer poses the threat of recurrence or metastasis of cancer because there is no way to know if the salve completely removed the cancer without a biopsy. Self-treatment can delay more effective therapy and may require further treatments.

Black salve should be subject to standarddrug regulations and its use discouraged by dermatologists due to the associated harmful effects and the availability of safer treatments. To better treat and inform their patients, dermatologists should be aware that patients may be attracted to alternative treatments such as black salves.

Black salve is composed of various ingredients, many of which are inert; however, some black salves contain escharotics, the 2 most common are zinc chloride and bloodroot (Sanguinaria canadensis) extract. In high doses, such as those contained in most black salve products, these corrosive agents can indiscriminately damage both healthy and diseased tissue.¹ Nevertheless, many black salve products currently are advertised as safe and natural methods for curing skin cancer^2-4 or treating a variety of other skin conditions (eg, moles, warts, skin tags, boils, abscesses, bee stings, other minor wounds)^1,5 and even nondermatologic conditions such as a sore throat.⁶ Despite the information and testimonials that are widely available on the Internet, black salve use has not been validated by rigorous studies. Black salve is not regulated by the US Food and Drug Administration, resulting in poor quality control and inconsistent user instructions. We report the case of application of black salve to a biopsy site of a compound nevus with moderate atypia that resulted in the formation of a dermatitis plaque with subsequent scarring and basal layer pigmentation.

Case Report

A 35-year-old woman with a family history of melanoma presented for follow-up of a compound nevus with moderate atypia on the right anterior thigh that had been biopsied 6 months prior. Complete excision of the lesion was recommended at the initial presentation but was not performed due to scheduling conflicts. The patient reported applying black salve to the biopsy site and also to the left thigh 3 months later. There was no reaction on the left thigh after one 24-hour application of black salve, but an area around the biopsy site on the right thigh became thickened and irritated with superficial erosion of the skin following 2 applications of black salve, each of 24 hours’ duration. Physical examination revealed a granulomatous plaque at the biopsy site that was approximately 5 cm in diameter (Figure 1A). One year later the lesion had completely healed (Figure 1B) and a biopsy revealed scarring with basal layer pigmentation (Figure 2).

Figure 1. A 5-cm granulomatous reaction surrounding a biopsy site on the right anterior thigh 3 months after application of black salve (A). One year later, the lesion had completely healed (B).					Figure 2. A biopsy one year following application of black salve demonstrated scarring with basal layer pigmentation (H&E, original magnification ×4).

Comment

A Web search using the term black salve yields a large number of products labeled as skin cancer salves, many showing glowing reviews and some being sold by major US retailers. The ingredients in black salves often vary in the innocuous substances they contain, but most products include the escharotics zinc chloride and bloodroot extract, which is derived from the plant S canadensis.^1,3 For example, the ingredients of one popular black salve product include zinc chloride, chaparral (active ingredient is nordihydroguaiaretic acid), graviola leaf extract, oleander leaf extract, bloodroot extract, and glycerine,⁷ while another product includes bloodroot extract, zinc chloride, chaparral, cayenne pepper, red clover, birch bark, dimethyl sulfoxide, and burdock root.⁴

Bloodroot extract’s antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory effects derive from its benzylisoquinoline alkaloids including sanguinarine, allocryptopine, berberine, coptisine, protopine, and stylopine.^3,8 Bloodroot extract possesses some degree of tumoricidal potency, with one study finding that it selectively targets cancer cells.⁹ However, this differential response is seen only at low doses and not at the high concentrations contained in most black salve products.¹ According to fluorometric assays, sanguinarine is not selective for tumor cells and therefore damages healthy tissue in addition to the unwanted lesions.^6,10,11 The US Food and Drug Administration includes black salve products on its list of fake cancer cures that consumers should avoid.¹² Reports of extensive damage from black salve use include skin ulceration^2,10 and complete loss of a naris¹ and nasal ala.⁵ Our case suggests the possible association between black salve use and an irritant reaction and erosion of the skin.

Furthermore, reliance on black salve alone in the treatment of skin cancer poses the threat of recurrence or metastasis of cancer because there is no way to know if the salve completely removed the cancer without a biopsy. Self-treatment can delay more effective therapy and may require further treatments.

Black salve should be subject to standarddrug regulations and its use discouraged by dermatologists due to the associated harmful effects and the availability of safer treatments. To better treat and inform their patients, dermatologists should be aware that patients may be attracted to alternative treatments such as black salves.

Black salve is composed of various ingredients, many of which are inert; however, some black salves contain escharotics, the 2 most common are zinc chloride and bloodroot (Sanguinaria canadensis) extract. In high doses, such as those contained in most black salve products, these corrosive agents can indiscriminately damage both healthy and diseased tissue.¹ Nevertheless, many black salve products currently are advertised as safe and natural methods for curing skin cancer^2-4 or treating a variety of other skin conditions (eg, moles, warts, skin tags, boils, abscesses, bee stings, other minor wounds)^1,5 and even nondermatologic conditions such as a sore throat.⁶ Despite the information and testimonials that are widely available on the Internet, black salve use has not been validated by rigorous studies. Black salve is not regulated by the US Food and Drug Administration, resulting in poor quality control and inconsistent user instructions. We report the case of application of black salve to a biopsy site of a compound nevus with moderate atypia that resulted in the formation of a dermatitis plaque with subsequent scarring and basal layer pigmentation.

Case Report

A 35-year-old woman with a family history of melanoma presented for follow-up of a compound nevus with moderate atypia on the right anterior thigh that had been biopsied 6 months prior. Complete excision of the lesion was recommended at the initial presentation but was not performed due to scheduling conflicts. The patient reported applying black salve to the biopsy site and also to the left thigh 3 months later. There was no reaction on the left thigh after one 24-hour application of black salve, but an area around the biopsy site on the right thigh became thickened and irritated with superficial erosion of the skin following 2 applications of black salve, each of 24 hours’ duration. Physical examination revealed a granulomatous plaque at the biopsy site that was approximately 5 cm in diameter (Figure 1A). One year later the lesion had completely healed (Figure 1B) and a biopsy revealed scarring with basal layer pigmentation (Figure 2).

Figure 1. A 5-cm granulomatous reaction surrounding a biopsy site on the right anterior thigh 3 months after application of black salve (A). One year later, the lesion had completely healed (B).					Figure 2. A biopsy one year following application of black salve demonstrated scarring with basal layer pigmentation (H&E, original magnification ×4).

Comment

A Web search using the term black salve yields a large number of products labeled as skin cancer salves, many showing glowing reviews and some being sold by major US retailers. The ingredients in black salves often vary in the innocuous substances they contain, but most products include the escharotics zinc chloride and bloodroot extract, which is derived from the plant S canadensis.^1,3 For example, the ingredients of one popular black salve product include zinc chloride, chaparral (active ingredient is nordihydroguaiaretic acid), graviola leaf extract, oleander leaf extract, bloodroot extract, and glycerine,⁷ while another product includes bloodroot extract, zinc chloride, chaparral, cayenne pepper, red clover, birch bark, dimethyl sulfoxide, and burdock root.⁴

Bloodroot extract’s antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory effects derive from its benzylisoquinoline alkaloids including sanguinarine, allocryptopine, berberine, coptisine, protopine, and stylopine.^3,8 Bloodroot extract possesses some degree of tumoricidal potency, with one study finding that it selectively targets cancer cells.⁹ However, this differential response is seen only at low doses and not at the high concentrations contained in most black salve products.¹ According to fluorometric assays, sanguinarine is not selective for tumor cells and therefore damages healthy tissue in addition to the unwanted lesions.^6,10,11 The US Food and Drug Administration includes black salve products on its list of fake cancer cures that consumers should avoid.¹² Reports of extensive damage from black salve use include skin ulceration^2,10 and complete loss of a naris¹ and nasal ala.⁵ Our case suggests the possible association between black salve use and an irritant reaction and erosion of the skin.

Furthermore, reliance on black salve alone in the treatment of skin cancer poses the threat of recurrence or metastasis of cancer because there is no way to know if the salve completely removed the cancer without a biopsy. Self-treatment can delay more effective therapy and may require further treatments.

Black salve should be subject to standarddrug regulations and its use discouraged by dermatologists due to the associated harmful effects and the availability of safer treatments. To better treat and inform their patients, dermatologists should be aware that patients may be attracted to alternative treatments such as black salves.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

BOSTON – Patients with atrial fibrillation who also require hemodialysis receive no added antistroke benefit from warfarin treatment and may be more likely to have a major bleeding episode while on warfarin, based on a retrospective study of 302 patients at a single U.S. center.

“The safety and effectiveness of warfarin in patients with atrial fibrillation and chronic hemodialysis is questionable,” Dr. Lohit Garg said at the annual scientific sessions of the Heart Rhythm Society.

Dr. Garg noted that about 90% of patients in the review received aspirin, and they would also receive heparin three times a week as part of their hemodialysis protocol. ”It’s a good hypothesis” that aspirin plus heparin during hemodialysis might provide enough anticoagulation, but without warfarin the rate of stroke or transient ischemic attack was “pretty high,” 11%, “higher than [in] the general population, so aspirin and heparin may not be enough,” he said. The thromboembolic event rate with warfarin was 8%, not a statistically significant difference.

Bruce Jancin/Frontline Medical News

Dr. Garg and his associates reviewed patient charts at Beaumont Health System in Royal Oak, Mich., from 2009 to 2012 to find patients on chronic hemodialysis just diagnosed with new-onset atrial fibrillation (AF), and patients with chronic AF newly started on hemodialysis. They identified 724 such patients, and narrowed this down to 302 when they excluded those with valve disease or prosthesis, venous thromboembolic disease, coagulation or bleeding disorder, cancer, renal transplant, and a few other exclusions.

The study group included 119 patients (39%) who received warfarin and 183 (61%) who did not, at the discretion of their treating physicians. Patients averaged 77 years of age, and those who received warfarin and those who didn’t showed roughly similar rates of comorbidities, with no statistically significant differences between the two subgroups.

During an average follow-up of 2 years, the rates of thromboembolic events showed no statistically significant difference between the patients on warfarin and those not receiving the drug. Major bleeds occurred in 22% of the warfarin patients and 14% of those not on warfarin, a relative 53% increased risk with warfarin use that approached but did not reach statistical significance, reported Dr. Garg of the Heart Rhythm Center of Beaumont Hospital in Royal Oak, Mich.

Further, the major bleed subcategory of intracranial bleeds occurred in 10% of patients on warfarin and 4% of those off warfarin, a greater than doubled rate with warfarin, again a difference that approached but did achieve statistical significance. All the intracranial bleeds were fatal.

Dr. Garg also highlighted that these were high-risk patients, with 1.8-year average survival, and a median survival of about 2 years for both patients on warfarin and those off. During follow-up that extended as long as 5 years, 80% of patients died with similar mortality rates in the two treatment subgroups, 82% for those on warfarin and 79% for those who did not receive warfarin.

“We as cardiologists tend to prescribe warfarin” to patients like these, “but obviously we have to rethink this because it seems to harm patients without adding benefit,” commented Dr. Philipp Sommer, an electrophysiologist at the University of Leipzig (Germany).

Dr. Garg had no relevant financial disclosures.

[email protected]


On Twitter @mitchelzoler

BOSTON – Patients with atrial fibrillation who also require hemodialysis receive no added antistroke benefit from warfarin treatment and may be more likely to have a major bleeding episode while on warfarin, based on a retrospective study of 302 patients at a single U.S. center.

“The safety and effectiveness of warfarin in patients with atrial fibrillation and chronic hemodialysis is questionable,” Dr. Lohit Garg said at the annual scientific sessions of the Heart Rhythm Society.

Dr. Garg noted that about 90% of patients in the review received aspirin, and they would also receive heparin three times a week as part of their hemodialysis protocol. ”It’s a good hypothesis” that aspirin plus heparin during hemodialysis might provide enough anticoagulation, but without warfarin the rate of stroke or transient ischemic attack was “pretty high,” 11%, “higher than [in] the general population, so aspirin and heparin may not be enough,” he said. The thromboembolic event rate with warfarin was 8%, not a statistically significant difference.

Bruce Jancin/Frontline Medical News

Dr. Garg and his associates reviewed patient charts at Beaumont Health System in Royal Oak, Mich., from 2009 to 2012 to find patients on chronic hemodialysis just diagnosed with new-onset atrial fibrillation (AF), and patients with chronic AF newly started on hemodialysis. They identified 724 such patients, and narrowed this down to 302 when they excluded those with valve disease or prosthesis, venous thromboembolic disease, coagulation or bleeding disorder, cancer, renal transplant, and a few other exclusions.

The study group included 119 patients (39%) who received warfarin and 183 (61%) who did not, at the discretion of their treating physicians. Patients averaged 77 years of age, and those who received warfarin and those who didn’t showed roughly similar rates of comorbidities, with no statistically significant differences between the two subgroups.

During an average follow-up of 2 years, the rates of thromboembolic events showed no statistically significant difference between the patients on warfarin and those not receiving the drug. Major bleeds occurred in 22% of the warfarin patients and 14% of those not on warfarin, a relative 53% increased risk with warfarin use that approached but did not reach statistical significance, reported Dr. Garg of the Heart Rhythm Center of Beaumont Hospital in Royal Oak, Mich.

Further, the major bleed subcategory of intracranial bleeds occurred in 10% of patients on warfarin and 4% of those off warfarin, a greater than doubled rate with warfarin, again a difference that approached but did achieve statistical significance. All the intracranial bleeds were fatal.

Dr. Garg also highlighted that these were high-risk patients, with 1.8-year average survival, and a median survival of about 2 years for both patients on warfarin and those off. During follow-up that extended as long as 5 years, 80% of patients died with similar mortality rates in the two treatment subgroups, 82% for those on warfarin and 79% for those who did not receive warfarin.

“We as cardiologists tend to prescribe warfarin” to patients like these, “but obviously we have to rethink this because it seems to harm patients without adding benefit,” commented Dr. Philipp Sommer, an electrophysiologist at the University of Leipzig (Germany).

Dr. Garg had no relevant financial disclosures.

[email protected]


On Twitter @mitchelzoler

BOSTON – Patients with atrial fibrillation who also require hemodialysis receive no added antistroke benefit from warfarin treatment and may be more likely to have a major bleeding episode while on warfarin, based on a retrospective study of 302 patients at a single U.S. center.

“The safety and effectiveness of warfarin in patients with atrial fibrillation and chronic hemodialysis is questionable,” Dr. Lohit Garg said at the annual scientific sessions of the Heart Rhythm Society.

Dr. Garg noted that about 90% of patients in the review received aspirin, and they would also receive heparin three times a week as part of their hemodialysis protocol. ”It’s a good hypothesis” that aspirin plus heparin during hemodialysis might provide enough anticoagulation, but without warfarin the rate of stroke or transient ischemic attack was “pretty high,” 11%, “higher than [in] the general population, so aspirin and heparin may not be enough,” he said. The thromboembolic event rate with warfarin was 8%, not a statistically significant difference.

Bruce Jancin/Frontline Medical News

Dr. Garg and his associates reviewed patient charts at Beaumont Health System in Royal Oak, Mich., from 2009 to 2012 to find patients on chronic hemodialysis just diagnosed with new-onset atrial fibrillation (AF), and patients with chronic AF newly started on hemodialysis. They identified 724 such patients, and narrowed this down to 302 when they excluded those with valve disease or prosthesis, venous thromboembolic disease, coagulation or bleeding disorder, cancer, renal transplant, and a few other exclusions.

The study group included 119 patients (39%) who received warfarin and 183 (61%) who did not, at the discretion of their treating physicians. Patients averaged 77 years of age, and those who received warfarin and those who didn’t showed roughly similar rates of comorbidities, with no statistically significant differences between the two subgroups.

During an average follow-up of 2 years, the rates of thromboembolic events showed no statistically significant difference between the patients on warfarin and those not receiving the drug. Major bleeds occurred in 22% of the warfarin patients and 14% of those not on warfarin, a relative 53% increased risk with warfarin use that approached but did not reach statistical significance, reported Dr. Garg of the Heart Rhythm Center of Beaumont Hospital in Royal Oak, Mich.

Further, the major bleed subcategory of intracranial bleeds occurred in 10% of patients on warfarin and 4% of those off warfarin, a greater than doubled rate with warfarin, again a difference that approached but did achieve statistical significance. All the intracranial bleeds were fatal.

Dr. Garg also highlighted that these were high-risk patients, with 1.8-year average survival, and a median survival of about 2 years for both patients on warfarin and those off. During follow-up that extended as long as 5 years, 80% of patients died with similar mortality rates in the two treatment subgroups, 82% for those on warfarin and 79% for those who did not receive warfarin.

“We as cardiologists tend to prescribe warfarin” to patients like these, “but obviously we have to rethink this because it seems to harm patients without adding benefit,” commented Dr. Philipp Sommer, an electrophysiologist at the University of Leipzig (Germany).

Dr. Garg had no relevant financial disclosures.

[email protected]


On Twitter @mitchelzoler