Photo by Rhoda Baer

Adding an experimental compound to chemotherapy is a “promising” treatment approach for certain patients with acute myeloid leukemia (AML), according to researchers.

They tested the compound, CPI-613, in combination with high-dose cytarabine and mitoxantrone in a phase 1 trial of patients with relapsed or refractory AML.

The combination produced similar response rates in the overall patient population (50%), patients age 60 and older (47%), and those with poor-risk cytogenetics (46%).

The most common grade 3/4 adverse events (AEs) were hematologic toxicities, and there was 1 fatal AE—hypotension.

Mortality rates in this trial were similar to those observed in historical controls treated with high-dose cytarabine, mitoxantrone, and asparaginase.

“These data are very encouraging, especially for patients 60 years of age or older who have historically done very poorly with this disease,” said Timothy Pardee, MD, PhD, a professor at Wake Forest Baptist Health in Winston-Salem, North Carolina, and chief medical officer of Rafael Pharmaceuticals, Inc., the company developing CPI-613.

Dr Pardee and his colleagues reported these results in Clinical Cancer Research.

The researchers noted that CPI-613 is designed to target mitochondrial metabolism in cancer cells, and preclinical research showed that CPI-613 sensitized AML cells to chemotherapy.

To investigate this further, the team tested CPI-613 in combination with high-dose cytarabine and mitoxantrone in the phase 1 trial. The study included 66 patients with relapsed or refractory AML, as well as a patient with advanced-phase chronic myeloid leukemia (CML) who was mistakenly enrolled.

The patients’ median age was 60 (range, 21-79), and 54% were age 60 and older. Their median percentage of marrow blasts was 43%. Forty percent of patients had poor-risk cytogenetics, and 49% had intermediate-risk cytogenetics.

Most patients (72%) had no prior salvage therapy, 13% had 1 prior line of salvage, 10% had 2 prior lines, and 4% had more than 2. Thirty-one percent of patients had refractory disease.

Seven percent of patients had previously received high-dose cytarabine and mitoxantrone, and 25% had previous salvage including high-dose or intermediate-dose cytarabine.

Treatment

Patients received CPI-613, given over 2 hours, on days 1 to 5 of cycle 1. Doses ranged from 500 mg/m² to 2750 mg/m².

Starting on day 3, patients received 5 doses of cytarabine at 3 gm/m² (for patients younger than 60) or 1.5 gm/m² (for older patients) in 500 mL normal saline, over 3 hours, every 12 hours.

Patients also received 3 daily doses of mitoxantrone at 6 mg/m² in 50 mL normal saline, given over 15 minutes, after the first, third, and fifth doses of cytarabine.

Patients were initially assigned to receive 1 cycle of treatment. Those with at least 5% blasts after the first cycle could receive a second course—either a full course or a 3-day course. And patients who responded to the first course could receive up to 2 cycles of the 3-day course.

Safety

There were 2 dose-limiting toxicities when CPI-613 was given at the 2750 mg/m² dose. One of these toxicities was grade 3 diarrhea that didn’t respond to anti-diarrheals, and the other was grade 3 nausea that didn’t respond to antiemetics.

Because of these events, 2500 mg/m² was deemed the maximum-tolerated dose. However, the recommended phase 2 dose is 2000 mg/m².

The most common AEs—occurring in at least 50% of all patients who received CPI-613 (n=67)—included hemoglobin decrease (67%), hyperglycemia (67%), neutropenia (67%), thrombocytopenia (67%), hypomagnesemia (66%), leukopenia (66%), lymphopenia (66%), hypoalbuminemia (65%), hypokalemia (60%), hypocalcemia (57%), and diarrhea (55%).

All cases of neutropenia, thrombocytopenia, leukopenia, and lymphopenia were grade 3/4. Other common grade 3/4 AEs (occurring in at least 20% of patients) included hemoglobin decrease (62%), febrile neutropenia (28%), hypophosphatemia (24%), and hypokalemia (23%).

The only grade 5 AE was hypotension.

The mortality rate was 12% (n=8) at 30 days and 19% (n=13) at 60 days. The researchers said this was similar to the historical experience with high-dose cytarabine, mitoxantrone, and asparaginase. Mortality rates with this regimen were 13% at 30 days and 22% at 60 days.

Efficacy

Sixty-two patients were evaluable for response. Of the 5 patients who were not evaluable, 1 didn’t complete the first cycle of treatment, 1 was the CML patient, and 3 died before assessment.

The overall response rate was 50% (31/62). This included 26 patients with a complete response (CR) and 5 patients who had a CR with incomplete count recovery (CRi).

The rate of CR/CRi was 47% (15/32) in patients older than 60 years of age, 46% (11/24) in patients who had poor-risk cytogenetics, and 53% (8/15) when CPI-613 was given at the recommended phase 2 dose—2000 mg/m².

The median overall survival (OS) was 6.7 months for all evaluable patients and 13.2 months for patients who achieved a CR/CRi.

The median OS was 6.9 months for patients age 60 and older, which was not significantly different from the median OS in younger patients (P=0.9642).

This study was sponsored by Wake Forest University Health Sciences and the National Cancer Institute.

Photo by Rhoda Baer

Adding an experimental compound to chemotherapy is a “promising” treatment approach for certain patients with acute myeloid leukemia (AML), according to researchers.

They tested the compound, CPI-613, in combination with high-dose cytarabine and mitoxantrone in a phase 1 trial of patients with relapsed or refractory AML.

The combination produced similar response rates in the overall patient population (50%), patients age 60 and older (47%), and those with poor-risk cytogenetics (46%).

The most common grade 3/4 adverse events (AEs) were hematologic toxicities, and there was 1 fatal AE—hypotension.

Mortality rates in this trial were similar to those observed in historical controls treated with high-dose cytarabine, mitoxantrone, and asparaginase.

“These data are very encouraging, especially for patients 60 years of age or older who have historically done very poorly with this disease,” said Timothy Pardee, MD, PhD, a professor at Wake Forest Baptist Health in Winston-Salem, North Carolina, and chief medical officer of Rafael Pharmaceuticals, Inc., the company developing CPI-613.

Dr Pardee and his colleagues reported these results in Clinical Cancer Research.

The researchers noted that CPI-613 is designed to target mitochondrial metabolism in cancer cells, and preclinical research showed that CPI-613 sensitized AML cells to chemotherapy.

To investigate this further, the team tested CPI-613 in combination with high-dose cytarabine and mitoxantrone in the phase 1 trial. The study included 66 patients with relapsed or refractory AML, as well as a patient with advanced-phase chronic myeloid leukemia (CML) who was mistakenly enrolled.

The patients’ median age was 60 (range, 21-79), and 54% were age 60 and older. Their median percentage of marrow blasts was 43%. Forty percent of patients had poor-risk cytogenetics, and 49% had intermediate-risk cytogenetics.

Most patients (72%) had no prior salvage therapy, 13% had 1 prior line of salvage, 10% had 2 prior lines, and 4% had more than 2. Thirty-one percent of patients had refractory disease.

Seven percent of patients had previously received high-dose cytarabine and mitoxantrone, and 25% had previous salvage including high-dose or intermediate-dose cytarabine.

Treatment

Patients received CPI-613, given over 2 hours, on days 1 to 5 of cycle 1. Doses ranged from 500 mg/m² to 2750 mg/m².

Starting on day 3, patients received 5 doses of cytarabine at 3 gm/m² (for patients younger than 60) or 1.5 gm/m² (for older patients) in 500 mL normal saline, over 3 hours, every 12 hours.

Patients also received 3 daily doses of mitoxantrone at 6 mg/m² in 50 mL normal saline, given over 15 minutes, after the first, third, and fifth doses of cytarabine.

Patients were initially assigned to receive 1 cycle of treatment. Those with at least 5% blasts after the first cycle could receive a second course—either a full course or a 3-day course. And patients who responded to the first course could receive up to 2 cycles of the 3-day course.

Safety

There were 2 dose-limiting toxicities when CPI-613 was given at the 2750 mg/m² dose. One of these toxicities was grade 3 diarrhea that didn’t respond to anti-diarrheals, and the other was grade 3 nausea that didn’t respond to antiemetics.

Because of these events, 2500 mg/m² was deemed the maximum-tolerated dose. However, the recommended phase 2 dose is 2000 mg/m².

The most common AEs—occurring in at least 50% of all patients who received CPI-613 (n=67)—included hemoglobin decrease (67%), hyperglycemia (67%), neutropenia (67%), thrombocytopenia (67%), hypomagnesemia (66%), leukopenia (66%), lymphopenia (66%), hypoalbuminemia (65%), hypokalemia (60%), hypocalcemia (57%), and diarrhea (55%).

All cases of neutropenia, thrombocytopenia, leukopenia, and lymphopenia were grade 3/4. Other common grade 3/4 AEs (occurring in at least 20% of patients) included hemoglobin decrease (62%), febrile neutropenia (28%), hypophosphatemia (24%), and hypokalemia (23%).

The only grade 5 AE was hypotension.

The mortality rate was 12% (n=8) at 30 days and 19% (n=13) at 60 days. The researchers said this was similar to the historical experience with high-dose cytarabine, mitoxantrone, and asparaginase. Mortality rates with this regimen were 13% at 30 days and 22% at 60 days.

Efficacy

Sixty-two patients were evaluable for response. Of the 5 patients who were not evaluable, 1 didn’t complete the first cycle of treatment, 1 was the CML patient, and 3 died before assessment.

The overall response rate was 50% (31/62). This included 26 patients with a complete response (CR) and 5 patients who had a CR with incomplete count recovery (CRi).

The rate of CR/CRi was 47% (15/32) in patients older than 60 years of age, 46% (11/24) in patients who had poor-risk cytogenetics, and 53% (8/15) when CPI-613 was given at the recommended phase 2 dose—2000 mg/m².

The median overall survival (OS) was 6.7 months for all evaluable patients and 13.2 months for patients who achieved a CR/CRi.

The median OS was 6.9 months for patients age 60 and older, which was not significantly different from the median OS in younger patients (P=0.9642).

This study was sponsored by Wake Forest University Health Sciences and the National Cancer Institute.

Photo by Rhoda Baer

Adding an experimental compound to chemotherapy is a “promising” treatment approach for certain patients with acute myeloid leukemia (AML), according to researchers.

They tested the compound, CPI-613, in combination with high-dose cytarabine and mitoxantrone in a phase 1 trial of patients with relapsed or refractory AML.

The combination produced similar response rates in the overall patient population (50%), patients age 60 and older (47%), and those with poor-risk cytogenetics (46%).

The most common grade 3/4 adverse events (AEs) were hematologic toxicities, and there was 1 fatal AE—hypotension.

Mortality rates in this trial were similar to those observed in historical controls treated with high-dose cytarabine, mitoxantrone, and asparaginase.

“These data are very encouraging, especially for patients 60 years of age or older who have historically done very poorly with this disease,” said Timothy Pardee, MD, PhD, a professor at Wake Forest Baptist Health in Winston-Salem, North Carolina, and chief medical officer of Rafael Pharmaceuticals, Inc., the company developing CPI-613.

Dr Pardee and his colleagues reported these results in Clinical Cancer Research.

The researchers noted that CPI-613 is designed to target mitochondrial metabolism in cancer cells, and preclinical research showed that CPI-613 sensitized AML cells to chemotherapy.

To investigate this further, the team tested CPI-613 in combination with high-dose cytarabine and mitoxantrone in the phase 1 trial. The study included 66 patients with relapsed or refractory AML, as well as a patient with advanced-phase chronic myeloid leukemia (CML) who was mistakenly enrolled.

The patients’ median age was 60 (range, 21-79), and 54% were age 60 and older. Their median percentage of marrow blasts was 43%. Forty percent of patients had poor-risk cytogenetics, and 49% had intermediate-risk cytogenetics.

Most patients (72%) had no prior salvage therapy, 13% had 1 prior line of salvage, 10% had 2 prior lines, and 4% had more than 2. Thirty-one percent of patients had refractory disease.

Seven percent of patients had previously received high-dose cytarabine and mitoxantrone, and 25% had previous salvage including high-dose or intermediate-dose cytarabine.

Treatment

Patients received CPI-613, given over 2 hours, on days 1 to 5 of cycle 1. Doses ranged from 500 mg/m² to 2750 mg/m².

Starting on day 3, patients received 5 doses of cytarabine at 3 gm/m² (for patients younger than 60) or 1.5 gm/m² (for older patients) in 500 mL normal saline, over 3 hours, every 12 hours.

Patients also received 3 daily doses of mitoxantrone at 6 mg/m² in 50 mL normal saline, given over 15 minutes, after the first, third, and fifth doses of cytarabine.

Patients were initially assigned to receive 1 cycle of treatment. Those with at least 5% blasts after the first cycle could receive a second course—either a full course or a 3-day course. And patients who responded to the first course could receive up to 2 cycles of the 3-day course.

Safety

There were 2 dose-limiting toxicities when CPI-613 was given at the 2750 mg/m² dose. One of these toxicities was grade 3 diarrhea that didn’t respond to anti-diarrheals, and the other was grade 3 nausea that didn’t respond to antiemetics.

Because of these events, 2500 mg/m² was deemed the maximum-tolerated dose. However, the recommended phase 2 dose is 2000 mg/m².

The most common AEs—occurring in at least 50% of all patients who received CPI-613 (n=67)—included hemoglobin decrease (67%), hyperglycemia (67%), neutropenia (67%), thrombocytopenia (67%), hypomagnesemia (66%), leukopenia (66%), lymphopenia (66%), hypoalbuminemia (65%), hypokalemia (60%), hypocalcemia (57%), and diarrhea (55%).

All cases of neutropenia, thrombocytopenia, leukopenia, and lymphopenia were grade 3/4. Other common grade 3/4 AEs (occurring in at least 20% of patients) included hemoglobin decrease (62%), febrile neutropenia (28%), hypophosphatemia (24%), and hypokalemia (23%).

The only grade 5 AE was hypotension.

The mortality rate was 12% (n=8) at 30 days and 19% (n=13) at 60 days. The researchers said this was similar to the historical experience with high-dose cytarabine, mitoxantrone, and asparaginase. Mortality rates with this regimen were 13% at 30 days and 22% at 60 days.

Efficacy

Sixty-two patients were evaluable for response. Of the 5 patients who were not evaluable, 1 didn’t complete the first cycle of treatment, 1 was the CML patient, and 3 died before assessment.

The overall response rate was 50% (31/62). This included 26 patients with a complete response (CR) and 5 patients who had a CR with incomplete count recovery (CRi).

The rate of CR/CRi was 47% (15/32) in patients older than 60 years of age, 46% (11/24) in patients who had poor-risk cytogenetics, and 53% (8/15) when CPI-613 was given at the recommended phase 2 dose—2000 mg/m².

The median overall survival (OS) was 6.7 months for all evaluable patients and 13.2 months for patients who achieved a CR/CRi.

The median OS was 6.9 months for patients age 60 and older, which was not significantly different from the median OS in younger patients (P=0.9642).

This study was sponsored by Wake Forest University Health Sciences and the National Cancer Institute.

KAUAI, HAWAII – Dermatologists don’t ordinarily peruse the ophthalmology literature. So they may be unaware that the American Academy of Ophthalmology has issued revised recommendations on weight-based dosing of hydroxychloroquine in order to minimize retinopathy risk, Erik J. Stratman, MD, noted at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Most dermatologists routinely dose hydroxychloroquine at 400 mg/day, regardless of body weight. The former AAO recommendation, which dates back to 2011, called for dosing at up to 6.5 mg/kg of ideal body weight or 400 mg/day, whichever is lower. However, the AAO recommendation has changed in light of a large, retrospective case-control study that suggested this practice may be overdosing thin patients – thereby exposing them to increased risk of retinal toxicity and other drug-related adverse events – while at the same time possibly underdosing some obese patients, said Dr. Stratman, chairman of the department of dermatology at the Marshfield (Wisc.) Clinic.

This was one of two dermatology practice gaps he highlighted involving suboptimal medication management, the other being most dermatologists’ failure to protect their patients’ gut when prescribing prednisone.

“I think the push over the last 5 years has been ‘protect the bones, protect the bones, protect the bones.’ We’ve done better and better about protecting the bones and getting that into our conversations with patients on prednisone. But we’re not thinking so much about the gut,” the dermatologist said.

Hydroxychloroquine dosing

The former AAO recommendation was revised in response to a retrospective case-control study of retinal toxicity rates in 2,361 patients on the drug continuously for longer than 5 years. The study demonstrated that the risk of retinopathy jumped 5.7-fold with daily consumption of hydroxychloroquine at more than 5.0 mg/kg (JAMA Ophthalmol. 2014 Dec;132[12]:1453-60).

The current AAO recommendation (Ophthalmology. 2016 Jun;123[6]:1386-94) is to dose hydroxychloroquine at a daily maximum of 5.0 mg/kg of real weight, which correlated better with retinopathy risk in the case-control study than did ideal body weight. Hydroxychloroquine doesn’t accumulate well in fat.

Until now, most dermatologists have not routinely measured patients’ body weight in the office or calculated their body mass index. But Dr. Stratman advised against reliance upon a patient’s self-reported body weight, which may diverge substantially from reality. “Get yourself a good office scale – they’re not that expensive – and use it when prescribing drugs with a tight therapeutic window,” he urged.

Protecting against prednisone-induced gastritis

“We underprotect the gut,” Dr. Stratman asserted.

He referred to a recent comprehensive dermatologic review of the prevention and management of glucocorticoid-related side effects, especially the part on peptic ulcer disease (J Am Acad Dermatol. 2017 Jan;76[1]:11-6). This is an issue that heretofore hadn’t been much emphasized in the dermatology literature.

“I read this and thought, ‘Gosh, I’m not really having a conversation with my patients about a review of systems for gut protection as I should. And I certainly haven’t been thinking about prescribing PPIs [proton pump inhibitors] for my patients,’” he recalled.

Dr. Stratman polled his Hawaii Dermatology Seminar audience as to who had ever prescribed a PPI. Most indicated with their electronic clickers that they had never done so.

“This is what a practice gap is,” he commented. “You read the literature and you say, ‘Oh, I guess that makes sense. Maybe I should be doing that more often, or making sure it gets done.’”

“I don’t want to come across as saying, ‘For everybody we put on prednisone we should be giving vitamin D, calcium, and a PPI.’ That’s not the message. The message is, assess your patient – or make sure your patient is being assessed – for risk of peptic ulcer disease. And if you don’t feel comfortable prescribing a PPI, please get the patient connected with their primary care provider, who should,” Dr. Stratman said.

[email protected]

KAUAI, HAWAII – Dermatologists don’t ordinarily peruse the ophthalmology literature. So they may be unaware that the American Academy of Ophthalmology has issued revised recommendations on weight-based dosing of hydroxychloroquine in order to minimize retinopathy risk, Erik J. Stratman, MD, noted at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Most dermatologists routinely dose hydroxychloroquine at 400 mg/day, regardless of body weight. The former AAO recommendation, which dates back to 2011, called for dosing at up to 6.5 mg/kg of ideal body weight or 400 mg/day, whichever is lower. However, the AAO recommendation has changed in light of a large, retrospective case-control study that suggested this practice may be overdosing thin patients – thereby exposing them to increased risk of retinal toxicity and other drug-related adverse events – while at the same time possibly underdosing some obese patients, said Dr. Stratman, chairman of the department of dermatology at the Marshfield (Wisc.) Clinic.

This was one of two dermatology practice gaps he highlighted involving suboptimal medication management, the other being most dermatologists’ failure to protect their patients’ gut when prescribing prednisone.

“I think the push over the last 5 years has been ‘protect the bones, protect the bones, protect the bones.’ We’ve done better and better about protecting the bones and getting that into our conversations with patients on prednisone. But we’re not thinking so much about the gut,” the dermatologist said.

Hydroxychloroquine dosing

The former AAO recommendation was revised in response to a retrospective case-control study of retinal toxicity rates in 2,361 patients on the drug continuously for longer than 5 years. The study demonstrated that the risk of retinopathy jumped 5.7-fold with daily consumption of hydroxychloroquine at more than 5.0 mg/kg (JAMA Ophthalmol. 2014 Dec;132[12]:1453-60).

The current AAO recommendation (Ophthalmology. 2016 Jun;123[6]:1386-94) is to dose hydroxychloroquine at a daily maximum of 5.0 mg/kg of real weight, which correlated better with retinopathy risk in the case-control study than did ideal body weight. Hydroxychloroquine doesn’t accumulate well in fat.

Until now, most dermatologists have not routinely measured patients’ body weight in the office or calculated their body mass index. But Dr. Stratman advised against reliance upon a patient’s self-reported body weight, which may diverge substantially from reality. “Get yourself a good office scale – they’re not that expensive – and use it when prescribing drugs with a tight therapeutic window,” he urged.

Protecting against prednisone-induced gastritis

“We underprotect the gut,” Dr. Stratman asserted.

He referred to a recent comprehensive dermatologic review of the prevention and management of glucocorticoid-related side effects, especially the part on peptic ulcer disease (J Am Acad Dermatol. 2017 Jan;76[1]:11-6). This is an issue that heretofore hadn’t been much emphasized in the dermatology literature.

“I read this and thought, ‘Gosh, I’m not really having a conversation with my patients about a review of systems for gut protection as I should. And I certainly haven’t been thinking about prescribing PPIs [proton pump inhibitors] for my patients,’” he recalled.

Dr. Stratman polled his Hawaii Dermatology Seminar audience as to who had ever prescribed a PPI. Most indicated with their electronic clickers that they had never done so.

“This is what a practice gap is,” he commented. “You read the literature and you say, ‘Oh, I guess that makes sense. Maybe I should be doing that more often, or making sure it gets done.’”

“I don’t want to come across as saying, ‘For everybody we put on prednisone we should be giving vitamin D, calcium, and a PPI.’ That’s not the message. The message is, assess your patient – or make sure your patient is being assessed – for risk of peptic ulcer disease. And if you don’t feel comfortable prescribing a PPI, please get the patient connected with their primary care provider, who should,” Dr. Stratman said.

[email protected]

KAUAI, HAWAII – Dermatologists don’t ordinarily peruse the ophthalmology literature. So they may be unaware that the American Academy of Ophthalmology has issued revised recommendations on weight-based dosing of hydroxychloroquine in order to minimize retinopathy risk, Erik J. Stratman, MD, noted at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.

Most dermatologists routinely dose hydroxychloroquine at 400 mg/day, regardless of body weight. The former AAO recommendation, which dates back to 2011, called for dosing at up to 6.5 mg/kg of ideal body weight or 400 mg/day, whichever is lower. However, the AAO recommendation has changed in light of a large, retrospective case-control study that suggested this practice may be overdosing thin patients – thereby exposing them to increased risk of retinal toxicity and other drug-related adverse events – while at the same time possibly underdosing some obese patients, said Dr. Stratman, chairman of the department of dermatology at the Marshfield (Wisc.) Clinic.

This was one of two dermatology practice gaps he highlighted involving suboptimal medication management, the other being most dermatologists’ failure to protect their patients’ gut when prescribing prednisone.

“I think the push over the last 5 years has been ‘protect the bones, protect the bones, protect the bones.’ We’ve done better and better about protecting the bones and getting that into our conversations with patients on prednisone. But we’re not thinking so much about the gut,” the dermatologist said.

Hydroxychloroquine dosing

The former AAO recommendation was revised in response to a retrospective case-control study of retinal toxicity rates in 2,361 patients on the drug continuously for longer than 5 years. The study demonstrated that the risk of retinopathy jumped 5.7-fold with daily consumption of hydroxychloroquine at more than 5.0 mg/kg (JAMA Ophthalmol. 2014 Dec;132[12]:1453-60).

The current AAO recommendation (Ophthalmology. 2016 Jun;123[6]:1386-94) is to dose hydroxychloroquine at a daily maximum of 5.0 mg/kg of real weight, which correlated better with retinopathy risk in the case-control study than did ideal body weight. Hydroxychloroquine doesn’t accumulate well in fat.

Until now, most dermatologists have not routinely measured patients’ body weight in the office or calculated their body mass index. But Dr. Stratman advised against reliance upon a patient’s self-reported body weight, which may diverge substantially from reality. “Get yourself a good office scale – they’re not that expensive – and use it when prescribing drugs with a tight therapeutic window,” he urged.

Protecting against prednisone-induced gastritis

“We underprotect the gut,” Dr. Stratman asserted.

He referred to a recent comprehensive dermatologic review of the prevention and management of glucocorticoid-related side effects, especially the part on peptic ulcer disease (J Am Acad Dermatol. 2017 Jan;76[1]:11-6). This is an issue that heretofore hadn’t been much emphasized in the dermatology literature.

“I read this and thought, ‘Gosh, I’m not really having a conversation with my patients about a review of systems for gut protection as I should. And I certainly haven’t been thinking about prescribing PPIs [proton pump inhibitors] for my patients,’” he recalled.

Dr. Stratman polled his Hawaii Dermatology Seminar audience as to who had ever prescribed a PPI. Most indicated with their electronic clickers that they had never done so.

“This is what a practice gap is,” he commented. “You read the literature and you say, ‘Oh, I guess that makes sense. Maybe I should be doing that more often, or making sure it gets done.’”

“I don’t want to come across as saying, ‘For everybody we put on prednisone we should be giving vitamin D, calcium, and a PPI.’ That’s not the message. The message is, assess your patient – or make sure your patient is being assessed – for risk of peptic ulcer disease. And if you don’t feel comfortable prescribing a PPI, please get the patient connected with their primary care provider, who should,” Dr. Stratman said.

[email protected]

Spending on indoor tanning in the United States has dropped considerably since 2011, despite increased overall spending on services by consumers, according to investigators from the University of Pennsylvania.

Since the Affordable Care Act was passed in 2010 with a 10% excise tax on indoor tanning services, consumer spending, as reflected by collections of that tax, has dropped 13% – from $86.3 million in 2011 to $75.1 in 2016. The amount collected actually increased in 2012 and 2013, when revenue was $91.7 million, making the drop since that peak an even larger 18.1%. Overall personal spending on services, in the meantime, rose steadily from $7.1 billion in 2011 to $8.7 billion in 2016, or 22.6%, Kishore L. Jayakumar and Jules B. Lipoff, MD, said in JAMA Dermatology.

[email protected]

SOURCE: Jayakumar KL et al. JAMA Dermatol. 2018 Apr 11. doi: 10.1001/jamadermatol.2018.0161.

Spending on indoor tanning in the United States has dropped considerably since 2011, despite increased overall spending on services by consumers, according to investigators from the University of Pennsylvania.

Since the Affordable Care Act was passed in 2010 with a 10% excise tax on indoor tanning services, consumer spending, as reflected by collections of that tax, has dropped 13% – from $86.3 million in 2011 to $75.1 in 2016. The amount collected actually increased in 2012 and 2013, when revenue was $91.7 million, making the drop since that peak an even larger 18.1%. Overall personal spending on services, in the meantime, rose steadily from $7.1 billion in 2011 to $8.7 billion in 2016, or 22.6%, Kishore L. Jayakumar and Jules B. Lipoff, MD, said in JAMA Dermatology.

[email protected]

SOURCE: Jayakumar KL et al. JAMA Dermatol. 2018 Apr 11. doi: 10.1001/jamadermatol.2018.0161.

Spending on indoor tanning in the United States has dropped considerably since 2011, despite increased overall spending on services by consumers, according to investigators from the University of Pennsylvania.

Since the Affordable Care Act was passed in 2010 with a 10% excise tax on indoor tanning services, consumer spending, as reflected by collections of that tax, has dropped 13% – from $86.3 million in 2011 to $75.1 in 2016. The amount collected actually increased in 2012 and 2013, when revenue was $91.7 million, making the drop since that peak an even larger 18.1%. Overall personal spending on services, in the meantime, rose steadily from $7.1 billion in 2011 to $8.7 billion in 2016, or 22.6%, Kishore L. Jayakumar and Jules B. Lipoff, MD, said in JAMA Dermatology.

[email protected]

SOURCE: Jayakumar KL et al. JAMA Dermatol. 2018 Apr 11. doi: 10.1001/jamadermatol.2018.0161.

REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and a high burden of autonomic symptoms are associated with increased risk of future psychotic symptoms in patients with Parkinson’s disease, according to research published online ahead of print April 4 in Neurology. These symptoms also correlate with low density of the cholinergic nucleus 4 (Ch4) of the basal forebrain.

Data From the Parkinson’s Progression Markers Initiative

Parkinson’s disease psychosis indicates advanced disease and is associated with dementia and increased mortality. Research indicates that degeneration of the nucleus basalis of Meynert is characteristic of Parkinson’s disease and Parkinson’s disease dementia, but this brain region is difficult to measure with MRI because of its size. It is possible, however, to measure Ch4, which incorporates the nucleus basalis of Meynert.

Matthew J. Barrett, MD, Assistant Professor of Neurology at the University of Virginia in Charlottesville, and colleagues studied a cohort of patients with de novo Parkinson’s disease to identify baseline clinical risk factors for future psychotic symptoms and to assess the relationship between baseline Ch4 density and future psychotic symptoms. All participants were untreated at baseline and had enrolled in the Parkinson’s Progression Markers Initiative (PPMI), a prospective, longitudinal, observational study.

Ch4 Density Could Predict Psychotic Symptoms

The investigators included 423 participants in their analysis. The population’s mean age at enrollment was approximately 61.5, and about 35% of the population was female. Mean disease duration was 0.57 years. The population’s median number of clinical visits was 11, and the median last visit occurred at 54 months after baseline.

In all, 138 participants (32.6%) reported psychotic symptoms at least once, and 84 (19.9%) reported them more than once. Dr. Barrett and colleagues identified 17 patients who, having once reported psychotic symptoms, reported these symptoms at each subsequent visit. Among patients who reported psychotic symptoms, approximately 79% reported them at only one visit.

The investigators categorized patients into three groups according to the number of psychotic events. The groups included participants with no psychotic events, those with one psychotic event, and those with two or more psychotic events.

After performing multivariate logistic regression and adjusting the results for age and sex, Dr. Barrett and colleagues found that greater autonomic symptoms (odds ratio [OR], 1.07 for a one-unit change in SCOPA-AUT), the presence of RBD (OR, 1.9), and EDS (OR, 2.5) at baseline were associated with increased risk of reporting psychotic symptoms on two or more occasions, compared to no or one psychotic event.

A logistic regression model adjusted for age and sex indicated that greater autonomic symptoms (OR, 1.08 for a one-unit change in SCOPA-AUT) and EDS (OR, 1.8) at baseline were associated with increased risk of psychotic symptoms on one or more occasions. A Cox regression model adjusted for EDS (hazard ratio [HR], 1.5) indicated that greater autonomic symptoms (HR, 1.03 for a one-unit change in SCOPA-AUT) and presence of RBD (HR, 1.47) were associated with increased risk of having a first psychotic event.

At the last assessment, patients with Parkinson’s disease and two or more psychotic events were more likely to have the postural instability and gait difficulty motor phenotype and lower scores on the Montreal Cognitive Assessment, Letter Number Sequencing test, and Symbol Digit Modalities Test.

The investigators had data about cholinergic nuclei densities at baseline for 228 participants with Parkinson’s disease and 101 controls. Ch4 density in Parkinson’s disease was associated with lower risk of reporting psychotic symptoms on two or more occasions (OR, 0.96 for an increase in density of one unit). Mean Ch4 densities were 1.7% greater for the control group, compared with the Parkinson’s disease group. Participants with Parkinson’s disease and two or more psychotic events had lower baseline Ch4 density, compared with healthy controls, but participants with Parkinson’s disease with no or one psychotic event did not.

In linear regression models adjusted for age and sex, autonomic symptoms were associated with baseline Ch4 density, but EDS and RBD were not. Having comorbid EDS and RBD was associated with lower Ch4 density.

Results Do Not Establish Causation

“Prior studies reported that EDS was associated with hallucinations in Parkinson’s disease, but we are not aware of other studies that found EDS to be a predictor of future psychotic symptoms,” said Dr. Barrett and colleagues.

“In univariate comparisons, participants with Parkinson’s disease with three or more psychotic events had worse visuospatial function, compared with those with two psychotic events. Considering the greater impairment in visuospatial and visuoperceptive function reported in Parkinson’s disease with visual hallucinations, this association should be evaluated in the future in the PPMI Parkinson’s disease cohort as additional follow-up visits occur.”

The current study’s finding of an association between autonomic dysfunction, RBD, and EDS and baseline Ch4 density in Parkinson’s disease is consistent with a recent analysis that found that the same symptoms were associated with a diffuse malignant subtype of Parkinson’s disease, said the authors. “Our finding that these three nonmotor symptoms are linked to future psychotic symptoms validates the prognostic value of these symptoms in predicting worse outcomes early in disease.”

Evidence does not support a causal relationship between lower Ch4 density and autonomic dysfunction, RBD, and EDS. These four characteristics may be associated with widespread subcortical pathology. “The relationship between this triad of clinical symptoms and lower Ch4 density supports the potential utility of this neuroimaging biomarker to identify a diffuse malignant subtype of Parkinson’s disease and to predict more rapid disease progression,” said Dr. Barrett and colleagues.

—Erik Greb

Suggested Reading

Barrett MJ, Blair JC, Sperling SA, et al. Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. Neurology. 2018 Apr 4 [Epub ahead of print].

Bohnen NI, Teipel SJ. Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. Neurology. 2018 Apr 4 [Epub ahead of print].

REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and a high burden of autonomic symptoms are associated with increased risk of future psychotic symptoms in patients with Parkinson’s disease, according to research published online ahead of print April 4 in Neurology. These symptoms also correlate with low density of the cholinergic nucleus 4 (Ch4) of the basal forebrain.

Data From the Parkinson’s Progression Markers Initiative

Parkinson’s disease psychosis indicates advanced disease and is associated with dementia and increased mortality. Research indicates that degeneration of the nucleus basalis of Meynert is characteristic of Parkinson’s disease and Parkinson’s disease dementia, but this brain region is difficult to measure with MRI because of its size. It is possible, however, to measure Ch4, which incorporates the nucleus basalis of Meynert.

Matthew J. Barrett, MD, Assistant Professor of Neurology at the University of Virginia in Charlottesville, and colleagues studied a cohort of patients with de novo Parkinson’s disease to identify baseline clinical risk factors for future psychotic symptoms and to assess the relationship between baseline Ch4 density and future psychotic symptoms. All participants were untreated at baseline and had enrolled in the Parkinson’s Progression Markers Initiative (PPMI), a prospective, longitudinal, observational study.

Ch4 Density Could Predict Psychotic Symptoms

The investigators included 423 participants in their analysis. The population’s mean age at enrollment was approximately 61.5, and about 35% of the population was female. Mean disease duration was 0.57 years. The population’s median number of clinical visits was 11, and the median last visit occurred at 54 months after baseline.

In all, 138 participants (32.6%) reported psychotic symptoms at least once, and 84 (19.9%) reported them more than once. Dr. Barrett and colleagues identified 17 patients who, having once reported psychotic symptoms, reported these symptoms at each subsequent visit. Among patients who reported psychotic symptoms, approximately 79% reported them at only one visit.

The investigators categorized patients into three groups according to the number of psychotic events. The groups included participants with no psychotic events, those with one psychotic event, and those with two or more psychotic events.

After performing multivariate logistic regression and adjusting the results for age and sex, Dr. Barrett and colleagues found that greater autonomic symptoms (odds ratio [OR], 1.07 for a one-unit change in SCOPA-AUT), the presence of RBD (OR, 1.9), and EDS (OR, 2.5) at baseline were associated with increased risk of reporting psychotic symptoms on two or more occasions, compared to no or one psychotic event.

A logistic regression model adjusted for age and sex indicated that greater autonomic symptoms (OR, 1.08 for a one-unit change in SCOPA-AUT) and EDS (OR, 1.8) at baseline were associated with increased risk of psychotic symptoms on one or more occasions. A Cox regression model adjusted for EDS (hazard ratio [HR], 1.5) indicated that greater autonomic symptoms (HR, 1.03 for a one-unit change in SCOPA-AUT) and presence of RBD (HR, 1.47) were associated with increased risk of having a first psychotic event.

At the last assessment, patients with Parkinson’s disease and two or more psychotic events were more likely to have the postural instability and gait difficulty motor phenotype and lower scores on the Montreal Cognitive Assessment, Letter Number Sequencing test, and Symbol Digit Modalities Test.

The investigators had data about cholinergic nuclei densities at baseline for 228 participants with Parkinson’s disease and 101 controls. Ch4 density in Parkinson’s disease was associated with lower risk of reporting psychotic symptoms on two or more occasions (OR, 0.96 for an increase in density of one unit). Mean Ch4 densities were 1.7% greater for the control group, compared with the Parkinson’s disease group. Participants with Parkinson’s disease and two or more psychotic events had lower baseline Ch4 density, compared with healthy controls, but participants with Parkinson’s disease with no or one psychotic event did not.

In linear regression models adjusted for age and sex, autonomic symptoms were associated with baseline Ch4 density, but EDS and RBD were not. Having comorbid EDS and RBD was associated with lower Ch4 density.

Results Do Not Establish Causation

“Prior studies reported that EDS was associated with hallucinations in Parkinson’s disease, but we are not aware of other studies that found EDS to be a predictor of future psychotic symptoms,” said Dr. Barrett and colleagues.

“In univariate comparisons, participants with Parkinson’s disease with three or more psychotic events had worse visuospatial function, compared with those with two psychotic events. Considering the greater impairment in visuospatial and visuoperceptive function reported in Parkinson’s disease with visual hallucinations, this association should be evaluated in the future in the PPMI Parkinson’s disease cohort as additional follow-up visits occur.”

The current study’s finding of an association between autonomic dysfunction, RBD, and EDS and baseline Ch4 density in Parkinson’s disease is consistent with a recent analysis that found that the same symptoms were associated with a diffuse malignant subtype of Parkinson’s disease, said the authors. “Our finding that these three nonmotor symptoms are linked to future psychotic symptoms validates the prognostic value of these symptoms in predicting worse outcomes early in disease.”

Evidence does not support a causal relationship between lower Ch4 density and autonomic dysfunction, RBD, and EDS. These four characteristics may be associated with widespread subcortical pathology. “The relationship between this triad of clinical symptoms and lower Ch4 density supports the potential utility of this neuroimaging biomarker to identify a diffuse malignant subtype of Parkinson’s disease and to predict more rapid disease progression,” said Dr. Barrett and colleagues.

—Erik Greb

Suggested Reading

Barrett MJ, Blair JC, Sperling SA, et al. Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. Neurology. 2018 Apr 4 [Epub ahead of print].

Bohnen NI, Teipel SJ. Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. Neurology. 2018 Apr 4 [Epub ahead of print].

REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and a high burden of autonomic symptoms are associated with increased risk of future psychotic symptoms in patients with Parkinson’s disease, according to research published online ahead of print April 4 in Neurology. These symptoms also correlate with low density of the cholinergic nucleus 4 (Ch4) of the basal forebrain.

Data From the Parkinson’s Progression Markers Initiative

Parkinson’s disease psychosis indicates advanced disease and is associated with dementia and increased mortality. Research indicates that degeneration of the nucleus basalis of Meynert is characteristic of Parkinson’s disease and Parkinson’s disease dementia, but this brain region is difficult to measure with MRI because of its size. It is possible, however, to measure Ch4, which incorporates the nucleus basalis of Meynert.

Matthew J. Barrett, MD, Assistant Professor of Neurology at the University of Virginia in Charlottesville, and colleagues studied a cohort of patients with de novo Parkinson’s disease to identify baseline clinical risk factors for future psychotic symptoms and to assess the relationship between baseline Ch4 density and future psychotic symptoms. All participants were untreated at baseline and had enrolled in the Parkinson’s Progression Markers Initiative (PPMI), a prospective, longitudinal, observational study.

Ch4 Density Could Predict Psychotic Symptoms

The investigators included 423 participants in their analysis. The population’s mean age at enrollment was approximately 61.5, and about 35% of the population was female. Mean disease duration was 0.57 years. The population’s median number of clinical visits was 11, and the median last visit occurred at 54 months after baseline.

In all, 138 participants (32.6%) reported psychotic symptoms at least once, and 84 (19.9%) reported them more than once. Dr. Barrett and colleagues identified 17 patients who, having once reported psychotic symptoms, reported these symptoms at each subsequent visit. Among patients who reported psychotic symptoms, approximately 79% reported them at only one visit.

The investigators categorized patients into three groups according to the number of psychotic events. The groups included participants with no psychotic events, those with one psychotic event, and those with two or more psychotic events.

After performing multivariate logistic regression and adjusting the results for age and sex, Dr. Barrett and colleagues found that greater autonomic symptoms (odds ratio [OR], 1.07 for a one-unit change in SCOPA-AUT), the presence of RBD (OR, 1.9), and EDS (OR, 2.5) at baseline were associated with increased risk of reporting psychotic symptoms on two or more occasions, compared to no or one psychotic event.

A logistic regression model adjusted for age and sex indicated that greater autonomic symptoms (OR, 1.08 for a one-unit change in SCOPA-AUT) and EDS (OR, 1.8) at baseline were associated with increased risk of psychotic symptoms on one or more occasions. A Cox regression model adjusted for EDS (hazard ratio [HR], 1.5) indicated that greater autonomic symptoms (HR, 1.03 for a one-unit change in SCOPA-AUT) and presence of RBD (HR, 1.47) were associated with increased risk of having a first psychotic event.

At the last assessment, patients with Parkinson’s disease and two or more psychotic events were more likely to have the postural instability and gait difficulty motor phenotype and lower scores on the Montreal Cognitive Assessment, Letter Number Sequencing test, and Symbol Digit Modalities Test.

The investigators had data about cholinergic nuclei densities at baseline for 228 participants with Parkinson’s disease and 101 controls. Ch4 density in Parkinson’s disease was associated with lower risk of reporting psychotic symptoms on two or more occasions (OR, 0.96 for an increase in density of one unit). Mean Ch4 densities were 1.7% greater for the control group, compared with the Parkinson’s disease group. Participants with Parkinson’s disease and two or more psychotic events had lower baseline Ch4 density, compared with healthy controls, but participants with Parkinson’s disease with no or one psychotic event did not.

In linear regression models adjusted for age and sex, autonomic symptoms were associated with baseline Ch4 density, but EDS and RBD were not. Having comorbid EDS and RBD was associated with lower Ch4 density.

Results Do Not Establish Causation

“Prior studies reported that EDS was associated with hallucinations in Parkinson’s disease, but we are not aware of other studies that found EDS to be a predictor of future psychotic symptoms,” said Dr. Barrett and colleagues.

“In univariate comparisons, participants with Parkinson’s disease with three or more psychotic events had worse visuospatial function, compared with those with two psychotic events. Considering the greater impairment in visuospatial and visuoperceptive function reported in Parkinson’s disease with visual hallucinations, this association should be evaluated in the future in the PPMI Parkinson’s disease cohort as additional follow-up visits occur.”

The current study’s finding of an association between autonomic dysfunction, RBD, and EDS and baseline Ch4 density in Parkinson’s disease is consistent with a recent analysis that found that the same symptoms were associated with a diffuse malignant subtype of Parkinson’s disease, said the authors. “Our finding that these three nonmotor symptoms are linked to future psychotic symptoms validates the prognostic value of these symptoms in predicting worse outcomes early in disease.”

Evidence does not support a causal relationship between lower Ch4 density and autonomic dysfunction, RBD, and EDS. These four characteristics may be associated with widespread subcortical pathology. “The relationship between this triad of clinical symptoms and lower Ch4 density supports the potential utility of this neuroimaging biomarker to identify a diffuse malignant subtype of Parkinson’s disease and to predict more rapid disease progression,” said Dr. Barrett and colleagues.

—Erik Greb

Suggested Reading

Barrett MJ, Blair JC, Sperling SA, et al. Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. Neurology. 2018 Apr 4 [Epub ahead of print].

Bohnen NI, Teipel SJ. Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. Neurology. 2018 Apr 4 [Epub ahead of print].

ORLANDO – A respiratory or urinary tract infection severe enough to land a patient in the hospital constitutes a novel independent risk factor for subsequent ischemic heart disease and ischemic stroke, according to a “big data” registry study from the United Kingdom.

“Our data show infection was just as much a risk factor or more compared with the traditional atherosclerotic cardiovascular disease risk factors,” Paul Carter, MD, said at the annual meeting of the American College of Cardiology.

Bruce Jancin/MDedge News

Dr. Carter of Aston Medical School in Birmingham, England, presented a retrospective analysis from the ACALM (Algorithm for Comorbidities Associated with Length of stay and Mortality) study of administrative data on all of the more than 1.22 million patients admitted to seven U.K. hospitals in 2000-2013. His analysis included all 34,027 adults aged 40 years or older admitted with a urinary tract or respiratory infection on their index hospitalization who had no history of ischemic heart disease or ischemic stroke.

These patients, with a mean age of 73 years, 59% of whom were women, were compared with an equal number of age- and gender-matched adults whose index hospitalization was for reasons other than ischemic heart disease, stroke, urinary tract infection (UTI), or respiratory infection – the two most common infections resulting in hospitalization in the United Kingdom.

Patients with a respiratory infection or UTI had a 9.9% incidence of new-onset ischemic heart disease and a 4.1% rate of ischemic stroke during follow-up starting upon discharge from their index hospitalization, significantly higher than the 5.9% and 1.5% rates in controls. In a multivariate logistic regression analysis adjusted for demographics, standard cardiovascular risk factors, and the top 10 causes of mortality in the United Kingdom, patients with respiratory infection or UTI as their admitting diagnosis had a 1.36-fold increased likelihood of developing ischemic heart disease post discharge and a 2.5-fold greater risk of ischemic stroke than matched controls.

Moreover, mortality following diagnosis of ischemic heart disease was 75.2% in patients whose index hospitalization was for infection, compared with 51.1% in controls who developed ischemic heart disease without a history of hospitalization for infection, for an adjusted 2.98-fold increased likelihood of death. Similarly, mortality after an ischemic stroke was 59.8% in patients with a prior severe infection, compared with 30.8% in controls, which translated to an adjusted 3.1-fold increased risk of death post stroke in patients with a prior hospitalization for infection.

In the multivariate analysis, hospitalization for infection was a stronger risk factor for subsequent ischemic stroke than was atrial fibrillation, heart failure, type 1 or type 2 diabetes, hypertension, or hyperlipidemia. The risk of ischemic heart disease in patients with an infectious disease hospitalization was similar to the risks associated with most of those recognized risk factors.

Two possible mechanisms by which infection might predispose to subsequent ischemic heart disease and stroke are via a direct effect whereby pathogens such as Chlamydia pneumoniae are taken up into arterial plaques, where they cause a local inflammatory response, or an indirect effect in which systemic inflammation primes the atherosclerotic plaque through distribution of inflammatory cytokines, according to Dr. Carter.

He said the ACALM findings are particularly intriguing when considered in the context of the 2017 results of the landmark CANTOS trial, in which canakinumab (Ilaris), a targeted anti-inflammatory agent that inhibits the interleukin-1 beta innate immunity pathway, reduced recurrent ischemic events in post-MI patients who had high systemic inflammation as evidenced by their elevated C-reactive protein level but a normal-range LDL cholesterol (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914).

“If atherosclerosis is an inflammatory condition, this begs the question of whether other inflammatory conditions, like infection, which induces a large systemic inflammatory response, might drive atherosclerosis,” Dr. Carter commented.

“It’s now very well understood that inflammatory mediators, cells, and processes are involved in every step from the initial endothelial dysfunction that leads to uptake of LDL, inflammatory cells, and monocytes all the way through to plaque progression and rupture, where Th1 cytokines have been implicated in causing that rupture, and ultimately in patient presentation at the hospital,” he added.

He sees the ACALM findings as hypothesis generating, serving to help lay the groundwork for future clinical trials of vaccine or anti-inflammatory antibiotic therapies.

Dr. Carter reported having no financial conflicts related to his presentation.

[email protected]

SOURCE: Carter P. ACC 2018, Abstract 1325M-0.

ORLANDO – A respiratory or urinary tract infection severe enough to land a patient in the hospital constitutes a novel independent risk factor for subsequent ischemic heart disease and ischemic stroke, according to a “big data” registry study from the United Kingdom.

“Our data show infection was just as much a risk factor or more compared with the traditional atherosclerotic cardiovascular disease risk factors,” Paul Carter, MD, said at the annual meeting of the American College of Cardiology.

Bruce Jancin/MDedge News

Dr. Carter of Aston Medical School in Birmingham, England, presented a retrospective analysis from the ACALM (Algorithm for Comorbidities Associated with Length of stay and Mortality) study of administrative data on all of the more than 1.22 million patients admitted to seven U.K. hospitals in 2000-2013. His analysis included all 34,027 adults aged 40 years or older admitted with a urinary tract or respiratory infection on their index hospitalization who had no history of ischemic heart disease or ischemic stroke.

These patients, with a mean age of 73 years, 59% of whom were women, were compared with an equal number of age- and gender-matched adults whose index hospitalization was for reasons other than ischemic heart disease, stroke, urinary tract infection (UTI), or respiratory infection – the two most common infections resulting in hospitalization in the United Kingdom.

Patients with a respiratory infection or UTI had a 9.9% incidence of new-onset ischemic heart disease and a 4.1% rate of ischemic stroke during follow-up starting upon discharge from their index hospitalization, significantly higher than the 5.9% and 1.5% rates in controls. In a multivariate logistic regression analysis adjusted for demographics, standard cardiovascular risk factors, and the top 10 causes of mortality in the United Kingdom, patients with respiratory infection or UTI as their admitting diagnosis had a 1.36-fold increased likelihood of developing ischemic heart disease post discharge and a 2.5-fold greater risk of ischemic stroke than matched controls.

Moreover, mortality following diagnosis of ischemic heart disease was 75.2% in patients whose index hospitalization was for infection, compared with 51.1% in controls who developed ischemic heart disease without a history of hospitalization for infection, for an adjusted 2.98-fold increased likelihood of death. Similarly, mortality after an ischemic stroke was 59.8% in patients with a prior severe infection, compared with 30.8% in controls, which translated to an adjusted 3.1-fold increased risk of death post stroke in patients with a prior hospitalization for infection.

In the multivariate analysis, hospitalization for infection was a stronger risk factor for subsequent ischemic stroke than was atrial fibrillation, heart failure, type 1 or type 2 diabetes, hypertension, or hyperlipidemia. The risk of ischemic heart disease in patients with an infectious disease hospitalization was similar to the risks associated with most of those recognized risk factors.

Two possible mechanisms by which infection might predispose to subsequent ischemic heart disease and stroke are via a direct effect whereby pathogens such as Chlamydia pneumoniae are taken up into arterial plaques, where they cause a local inflammatory response, or an indirect effect in which systemic inflammation primes the atherosclerotic plaque through distribution of inflammatory cytokines, according to Dr. Carter.

He said the ACALM findings are particularly intriguing when considered in the context of the 2017 results of the landmark CANTOS trial, in which canakinumab (Ilaris), a targeted anti-inflammatory agent that inhibits the interleukin-1 beta innate immunity pathway, reduced recurrent ischemic events in post-MI patients who had high systemic inflammation as evidenced by their elevated C-reactive protein level but a normal-range LDL cholesterol (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914).

“If atherosclerosis is an inflammatory condition, this begs the question of whether other inflammatory conditions, like infection, which induces a large systemic inflammatory response, might drive atherosclerosis,” Dr. Carter commented.

“It’s now very well understood that inflammatory mediators, cells, and processes are involved in every step from the initial endothelial dysfunction that leads to uptake of LDL, inflammatory cells, and monocytes all the way through to plaque progression and rupture, where Th1 cytokines have been implicated in causing that rupture, and ultimately in patient presentation at the hospital,” he added.

He sees the ACALM findings as hypothesis generating, serving to help lay the groundwork for future clinical trials of vaccine or anti-inflammatory antibiotic therapies.

Dr. Carter reported having no financial conflicts related to his presentation.

[email protected]

SOURCE: Carter P. ACC 2018, Abstract 1325M-0.

ORLANDO – A respiratory or urinary tract infection severe enough to land a patient in the hospital constitutes a novel independent risk factor for subsequent ischemic heart disease and ischemic stroke, according to a “big data” registry study from the United Kingdom.

“Our data show infection was just as much a risk factor or more compared with the traditional atherosclerotic cardiovascular disease risk factors,” Paul Carter, MD, said at the annual meeting of the American College of Cardiology.

Bruce Jancin/MDedge News

Dr. Carter of Aston Medical School in Birmingham, England, presented a retrospective analysis from the ACALM (Algorithm for Comorbidities Associated with Length of stay and Mortality) study of administrative data on all of the more than 1.22 million patients admitted to seven U.K. hospitals in 2000-2013. His analysis included all 34,027 adults aged 40 years or older admitted with a urinary tract or respiratory infection on their index hospitalization who had no history of ischemic heart disease or ischemic stroke.

These patients, with a mean age of 73 years, 59% of whom were women, were compared with an equal number of age- and gender-matched adults whose index hospitalization was for reasons other than ischemic heart disease, stroke, urinary tract infection (UTI), or respiratory infection – the two most common infections resulting in hospitalization in the United Kingdom.

Patients with a respiratory infection or UTI had a 9.9% incidence of new-onset ischemic heart disease and a 4.1% rate of ischemic stroke during follow-up starting upon discharge from their index hospitalization, significantly higher than the 5.9% and 1.5% rates in controls. In a multivariate logistic regression analysis adjusted for demographics, standard cardiovascular risk factors, and the top 10 causes of mortality in the United Kingdom, patients with respiratory infection or UTI as their admitting diagnosis had a 1.36-fold increased likelihood of developing ischemic heart disease post discharge and a 2.5-fold greater risk of ischemic stroke than matched controls.

Moreover, mortality following diagnosis of ischemic heart disease was 75.2% in patients whose index hospitalization was for infection, compared with 51.1% in controls who developed ischemic heart disease without a history of hospitalization for infection, for an adjusted 2.98-fold increased likelihood of death. Similarly, mortality after an ischemic stroke was 59.8% in patients with a prior severe infection, compared with 30.8% in controls, which translated to an adjusted 3.1-fold increased risk of death post stroke in patients with a prior hospitalization for infection.

In the multivariate analysis, hospitalization for infection was a stronger risk factor for subsequent ischemic stroke than was atrial fibrillation, heart failure, type 1 or type 2 diabetes, hypertension, or hyperlipidemia. The risk of ischemic heart disease in patients with an infectious disease hospitalization was similar to the risks associated with most of those recognized risk factors.

Two possible mechanisms by which infection might predispose to subsequent ischemic heart disease and stroke are via a direct effect whereby pathogens such as Chlamydia pneumoniae are taken up into arterial plaques, where they cause a local inflammatory response, or an indirect effect in which systemic inflammation primes the atherosclerotic plaque through distribution of inflammatory cytokines, according to Dr. Carter.

He said the ACALM findings are particularly intriguing when considered in the context of the 2017 results of the landmark CANTOS trial, in which canakinumab (Ilaris), a targeted anti-inflammatory agent that inhibits the interleukin-1 beta innate immunity pathway, reduced recurrent ischemic events in post-MI patients who had high systemic inflammation as evidenced by their elevated C-reactive protein level but a normal-range LDL cholesterol (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914).

“If atherosclerosis is an inflammatory condition, this begs the question of whether other inflammatory conditions, like infection, which induces a large systemic inflammatory response, might drive atherosclerosis,” Dr. Carter commented.

“It’s now very well understood that inflammatory mediators, cells, and processes are involved in every step from the initial endothelial dysfunction that leads to uptake of LDL, inflammatory cells, and monocytes all the way through to plaque progression and rupture, where Th1 cytokines have been implicated in causing that rupture, and ultimately in patient presentation at the hospital,” he added.

He sees the ACALM findings as hypothesis generating, serving to help lay the groundwork for future clinical trials of vaccine or anti-inflammatory antibiotic therapies.

Dr. Carter reported having no financial conflicts related to his presentation.

[email protected]

SOURCE: Carter P. ACC 2018, Abstract 1325M-0.

DALLAS – Carboxytherapy – the insufflation of carbon dioxide gas into the skin layers – may provide a small but transient decrease in subcutaneous fat, a small randomized, controlled trial demonstrated.

“Carboxytherapy has been previously used therapeutically to reduce fat, and studies of carboxytherapy have been done in the past as well,” the study’s senior author, Murad Alam, MD, said in an interview in advance of a poster session at the annual conference of the American Society for Laser Medicine and Surgery Inc. “However, earlier studies have not been controlled trials.”

For the split-body study, he and his associates enrolled 16 adults and randomized one side of their body to receive infusions of 1,000 cc of CO₂ every week for 5 weeks in the flank region, while the contralateral side received sham treatments. Outcomes of interest included fat layer thickness using a diagnostic ultrasound, total circumference, and body weight, said Dr. Alam, vice-chair of the department of dermatology and chief of the division of cutaneous and aesthetic surgery at Northwestern University, Chicago. He reported that a significant difference in fat thickness was observed in the carboxytherapy-treated side 1 week after the last treatment (P = .011), but this difference was not maintained at 28 weeks as measured by diagnostic ultrasound. Total circumference decreased nominally but not significantly. Body weights did not significantly change throughout the study.

[email protected]

DALLAS – Carboxytherapy – the insufflation of carbon dioxide gas into the skin layers – may provide a small but transient decrease in subcutaneous fat, a small randomized, controlled trial demonstrated.

“Carboxytherapy has been previously used therapeutically to reduce fat, and studies of carboxytherapy have been done in the past as well,” the study’s senior author, Murad Alam, MD, said in an interview in advance of a poster session at the annual conference of the American Society for Laser Medicine and Surgery Inc. “However, earlier studies have not been controlled trials.”

For the split-body study, he and his associates enrolled 16 adults and randomized one side of their body to receive infusions of 1,000 cc of CO₂ every week for 5 weeks in the flank region, while the contralateral side received sham treatments. Outcomes of interest included fat layer thickness using a diagnostic ultrasound, total circumference, and body weight, said Dr. Alam, vice-chair of the department of dermatology and chief of the division of cutaneous and aesthetic surgery at Northwestern University, Chicago. He reported that a significant difference in fat thickness was observed in the carboxytherapy-treated side 1 week after the last treatment (P = .011), but this difference was not maintained at 28 weeks as measured by diagnostic ultrasound. Total circumference decreased nominally but not significantly. Body weights did not significantly change throughout the study.

[email protected]

DALLAS – Carboxytherapy – the insufflation of carbon dioxide gas into the skin layers – may provide a small but transient decrease in subcutaneous fat, a small randomized, controlled trial demonstrated.

“Carboxytherapy has been previously used therapeutically to reduce fat, and studies of carboxytherapy have been done in the past as well,” the study’s senior author, Murad Alam, MD, said in an interview in advance of a poster session at the annual conference of the American Society for Laser Medicine and Surgery Inc. “However, earlier studies have not been controlled trials.”

For the split-body study, he and his associates enrolled 16 adults and randomized one side of their body to receive infusions of 1,000 cc of CO₂ every week for 5 weeks in the flank region, while the contralateral side received sham treatments. Outcomes of interest included fat layer thickness using a diagnostic ultrasound, total circumference, and body weight, said Dr. Alam, vice-chair of the department of dermatology and chief of the division of cutaneous and aesthetic surgery at Northwestern University, Chicago. He reported that a significant difference in fat thickness was observed in the carboxytherapy-treated side 1 week after the last treatment (P = .011), but this difference was not maintained at 28 weeks as measured by diagnostic ultrasound. Total circumference decreased nominally but not significantly. Body weights did not significantly change throughout the study.

[email protected]

ABSTRACT

The aim of this study was to provide clinical recommendations about the use of platelet-rich plasma (PRP) that was subjected to short-term storage at room temperature. We determined bioactive growth factor and cytokine concentrations as indicators of platelet and white blood cell degranulation in blood and PRP. Additionally, this study sought to validate the use of manual, direct smear analysis as an alternative to automated methods for platelet quantification in PRP.

Blood was used to generate low-leukocyte PRP (L^lo PRP) or high-leukocyte PRP (L^hi PRP). Blood was either processed immediately or kept at room temperature for 2 or 4 hours prior to generation of PRP, which was then held at room temperature for 0, 1, 2, or 4 hours. Subsequently, bioactive transforming growth factor beta-1 and matrix metalloproteinase-9 were measured by ELISA (enzyme-linked immunosorbent assay). Manual and automated platelet counts were performed on all blood and PRP samples.

There were no differences in growth factor or cytokine concentration when blood or L^lo PRP or L^hi PRP was retained at room temperature for up to 4 hours. Manual, direct smear analysis for platelet quantification was not different from the use of automated machine counting for PRP samples, but in the starting blood samples, manual platelet counts were significantly higher than those generated using automated technology.

When there is a delay of up to 4 hours in the generation of PRP from blood or in the application of PRP to the patient, bioactive growth factor and cytokine concentrations remain stable in both blood and PRP. A manual direct counting method is a simple, cost-effective, and valid method to measure the contents of the PRP product being delivered to the patient.

Platelet-rich plasma (PRP) is used to promote healing in many areas of medicine, such as dental surgery,^1,2 soft-tissue injury,^3,4 orthopedic surgery,^5,6 wound healing,⁷ and veterinary medicine.^8,9 Despite its extensive use, there are still questions about the clinical efficacy of PRP.^10-12 Due to biological heterogeneity between patients^13,14 and differences between available manufacturing kits,^13,15 PRP can be highly variable between patients. There are classification schemes to categorize the various types of PRP,^16-18 which can be divided broadly into low-leukocyte PRP (L^lo PRP) and high-leukocyte PRP (L^hi PRP). PRP can be used as a point of care therapy, prepared and used immediately, or it can be used during a surgical procedure. In some institutions, blood is drawn by a phlebotomist, processed in the hospital laboratory, and then delivered to the operating room. In other instances, PRP is generated patient-side by the primary attending physician’s team, who draws the blood and processes it for immediate use.^5,19 Delays at any step in these various scenarios could lead to the blood or the resultant PRP remaining at room temperature from minutes to several hours prior to administration to the patient. This variability in PRP protocols between clinical and surgical settings adds to concerns regarding the stability and efficacy of the biologic.

Continue to: When performing clinical or research...

The primary aim of this study was to determine if retention of blood or PRP at room temperature for various time intervals had an effect on final growth factor or catabolic cytokine concentration. Bioactive transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase-9 (MMP-9) were measured as representatives of growth factors and catabolic cytokines, respectively. The secondary aim was to identify if manual platelet counts were an accurate reflection of automated counts. The outcomes of these experiments should provide immediately relevant information for the clinical application of PRP.

MATERIALS AND METHODS

Blood Collection and Generation of PRP

Under Institutional Review Board approval, blood (105 mL) was collected from healthy human volunteers (N = 5) into a syringe containing acid citrate dextrose anticoagulant to a final concentration of 10% acid citrate dextrose. Three 15-mL aliquots of blood were used to generate L^lo PRP (Autologous Conditioned Plasma Double Syringe, Arthrex) and three 20-mL aliquots were used to generate L^hi PRP (SmartPReP 2, Harvest Technologies) (Figure 1). 

Automated and Manual Counts

Automated complete blood counts were performed by a board certified clinical pathologist in the clinical pathology department of Cornell University on all blood, L^lo PRP, and L^hi PRP samples. A manual platelet count, using a modified Giemsa stain,²² was performed on smears of all blood and PRP samples (Video). Slides were scanned at 10x magnification to identify an area where many red blood cells were present while maintaining a clear field of view (Figure 2A). The magnification was then increased to 100x using oil immersion, and the total number of platelets was counted in 10 fields of view (Figure 2B). 

Growth Factor and Catabolic Cytokine Measurements

Blood and PRP samples were thawed for ELISA (enzyme-linked immunosorbent assay) analysis. TGF-β1 concentration was determined using the TGF-β1 Emax ImmunoAssay System (Promega Corporation), which measures biologically active TGF-β1. We chose TGF-β1 because it is commonly measured in PRP studies as an anabolic cytokine with multiple effects on tissue healing. The functions of TGF-β1 include stimulation of undifferentiated mesenchymal cell proliferation; regulation of endothelial, fibroblast, and osteoblast mitogenesis; coordination of collagen synthesis; promotion of endothelial chemotaxis and angiogenesis; activation of extracellular matrix synthesis in cartilage; and reduction of the catabolic activity of interluekin-1 and MMPs.^23-25 In addition, TGF-β1 concentration strongly correlates with platelet concentration.²⁶ MMP-9 concentration was determined using the MMP-9 Biotrak Activity Assay (GE Healthcare Biosciences) which measures both active and pro- forms of MMP-9. In PRP, MMP-9 was measured as an indicator of white blood cell (WBC) concentration.²⁶ A catabolic cytokine capable of degrading collagen,^13,27 MMP-9 has been linked to poor healing.²⁸ For both assays, samples were measured in duplicate using a multiple detection plate reader (Tecan Safire).

Continue to: Statistical Analysis...

Statistical Analysis

Data were tested for the normal distribution to determine the appropriate statistical test. Manual and automated platelet counts were compared to each other in whole blood, L^lo PRP, and L^hi PRP samples using a paired t test. Bioactive TGF-β1 concentrations in blood, L^lo PRP, and L^hi PRP, were compared using a Kruskal-Wallis one-way analysis of variance (ANOVA) with Dunn’s all-pairwise comparison. Bioactive and pro-MMP-9 concentrations measured in the retained blood or PRP samples were compared using a one-way ANOVA with Tukey’s all-pairwise comparison. Statistical analyses were performed using Statistix 9 software (Analytical Software). A P value of <0.05 was considered significant.

RESULTS

Validation of PRP

PRP, as defined by an increase in platelet concentration in PRP compared with blood, was successfully generated in all samples by both systems. There was an average 1.98 ± 0.14-fold increase in platelet concentration in L^lo PRP and an average 3.06 ± 0.24-fold increase in L^hi PRP. Platelet concentration was significantly higher in L^hi PRP than in L^lo PRP (P = 0.001). Compared to whole blood, WBC concentration was 0.47 ± 0.07-fold lower in L^lo PRP and 1.98 ± 0.14-fold greater in L^hi PRP. Similar to platelets, WBCs were significantly greater in L^hi PRP than in L^lo PRP (P = 0.02).

Bioactive TGF-β1 and MMP-9 Concentration in Blood Retained at Room Temperature

To reflect the clinical situation where blood would be drawn from a patient, but there would be a delay in processing the blood to generate PRP, blood samples were retained at room temperature for up to 4 hours prior to analysis. Neither bioactive TGF-β1 (Figure 3) nor bioactive/pro-MMP-9 concentrations (Figure 4) changed significantly over time when blood was retained at room temperature prior to centrifugation to generate PRP.

Bioactive TGF-β1 and MMP-9 Concentration in PRP Retained at Room Temperature

In order to mimic the clinical situation where PRP would be generated but might sit out prior to being administered to the patient, PRP samples were retained at room temperature for up to 4 hours prior to analysis. In these samples, bioactive TGF-β1 concentrations were not significantly different between PRP products analyzed immediately and those samples retained at room temperature for up to 4 hours (Figure 5). 

Automatic vs Manual Platelet Count

Manual platelet counts were compared to automated platelet counts to determine if a manual platelet smear analysis could be a reliable method for analyzing PRP in clinical and pre-clinical studies. There was a significant difference between the automated and manual platelet counts in blood samples (Table) (P = 0.05, N = 5) with the manual platelet count having a higher average (99.1 thou/uL) platelet concentration than automated counts. Platelet clumping was identified in 2 automated counts, which falsely decreased platelet concentration by an unknown quantity. Manual platelet counts for both L^lo PRP (n = 30) and L^hi PRP (n = 30) were not different from automated platelet counts. Platelet clumping was not reported on any manual platelet counts performed on PRP samples.

Table. Platelet Concentrations of Whole Blood, L^lo PRP, and L^hi PRP (N = 5)

A paired t test was performed to compare results obtained from an automated platelet count and those obtained from a manual count.

Abbreviations: L^hi PRP, high-leukocyte platelet-rich plasma; L^lo PRP, low-leukocyte platelet-rich plasma; SD, standard deviation.

Continue to:The primary aim of this study...

DISCUSSION

The primary aim of this study was to improve the clinical use of PRP by characterizing changes that might occur due to extended preparation times. Physicians commonly question the stability of blood or PRP if it is retained at room temperature prior to being administered to the patient. Clinical recommendations to optimize PRP preparation can be derived from a better understanding of the stability of platelets and WBCs, which contribute to the anabolic and catabolic cytokines in PRP.

The results of this study suggest that platelets and WBCs remain stable in blood and both L^lo PRP and L^hi PRP for up to 4 hours. The use of bioactive ELISAs to measure TGF-β1 and MMP-9 allows for determination of stability of the PRP product retained at room temperature for up to 4 hours. This provides a time buffer to allow for delays from either institutional logistics or unanticipated clinical delays, without adverse effects on the generation of the final PRP product. As with all biologics, there are many factors that contribute to variability, but a relatively short delay of up to 4 hours in either generation of PRP from blood or in administration of PRP to the patient does not appear to contribute to that variability. Similar studies have been performed on equine PRP and suggest that growth factor concentrations remain stable for up to 6 hours after preparation of PRP²⁹ and in human PRP, which implies that although samples degrade over time, platelet integrity might be acceptable for clinical use for up to 5 days after preparation, particularly if stored in oxygen.³⁰ In contrast to this study, neither of the previously published reports used assays to measure biological activity in the stored PRP. Regardless of the variability between the studies with respect to the type of PRP evaluated and the outcome measures used, all of the studies support the concept that PRP can be stored at room temperature for at least a few hours before clinical use.

Centrifugation of blood does not guarantee the generation of PRP.^13,14 In some cases, platelet counts in PRP are similar to or even less than that in the starting whole blood sample. To determine whether a clinical outcome is attributed to PRP, it is vital to know the platelet concentration and, arguably, the WBC concentration in the blood used to generate PRP and in the PRP sample administered to the patient. The platelet concentration in blood and PRP samples can be quantified using automated or manual methods. The use of automated methods can add significant cost to a study or procedure. Manually evaluating a blood smear is an accepted, though more time consuming, method of analyzing cellular components of a blood sample. Depending on the standard operating procedure of the laboratory, manual smears are often done in conjunction with an automated count. This identifies abnormalities in cellular shape or size, or platelet clumping, which are not consistently recognized by automated methods. Manually evaluating a blood smear does take some training, but the material cost is very low, which has added value for clinical or preclinical research studies. Interestingly, the results of this study indicate that manual platelet counts in blood may be more accurate than the count generated from an automated counter because the automated platelet counts were falsely low due to platelet clumping. Platelet clumping can occur as early as 1 hour after blood collection, regardless of the type of anticoagulant used.³¹

LIMITATIONS

The sample size of this study was small. However, variability in PRP has been well documented in multiple other studies using slightly larger sample sizes.^13,14,16 Another potential limitation of this study could be that only one growth factor, TGF-β1, and one catabolic cytokine, MMP-9, were used as surrogate measures to represent platelet and WBC stability, respectively. We chose TGF-β1 because it is correlated with platelet concentrations^14,15,26 and MMP-9 because it is an indicator of catabolic factors in PRP that have been correlated with WBC concentrations.²⁶

CONCLUSION

This study illustrated that growth factor and cytokine concentrations in both L^lo PRP and L^hi PRP are stable for up to 4 hours. The clinical implications of these results suggest that if the generation or administration of PRP is delayed by up to 4 hours, the resultant PRP retains its bioactivity and is acceptable for clinical application. However, given the known variability of PRP generated due to patient and manufacturer variability,^13,14 it is still important to ensure that the product is indeed PRP, with an increase in platelet number over the starting sample of blood. This validation can be performed with a simple and cost-effective manual smear analysis of blood and PRP. The results of this study provide information that can be immediately translated into clinical, surgical, and research practices.

ABSTRACT

The aim of this study was to provide clinical recommendations about the use of platelet-rich plasma (PRP) that was subjected to short-term storage at room temperature. We determined bioactive growth factor and cytokine concentrations as indicators of platelet and white blood cell degranulation in blood and PRP. Additionally, this study sought to validate the use of manual, direct smear analysis as an alternative to automated methods for platelet quantification in PRP.

Blood was used to generate low-leukocyte PRP (L^lo PRP) or high-leukocyte PRP (L^hi PRP). Blood was either processed immediately or kept at room temperature for 2 or 4 hours prior to generation of PRP, which was then held at room temperature for 0, 1, 2, or 4 hours. Subsequently, bioactive transforming growth factor beta-1 and matrix metalloproteinase-9 were measured by ELISA (enzyme-linked immunosorbent assay). Manual and automated platelet counts were performed on all blood and PRP samples.

There were no differences in growth factor or cytokine concentration when blood or L^lo PRP or L^hi PRP was retained at room temperature for up to 4 hours. Manual, direct smear analysis for platelet quantification was not different from the use of automated machine counting for PRP samples, but in the starting blood samples, manual platelet counts were significantly higher than those generated using automated technology.

When there is a delay of up to 4 hours in the generation of PRP from blood or in the application of PRP to the patient, bioactive growth factor and cytokine concentrations remain stable in both blood and PRP. A manual direct counting method is a simple, cost-effective, and valid method to measure the contents of the PRP product being delivered to the patient.

Platelet-rich plasma (PRP) is used to promote healing in many areas of medicine, such as dental surgery,^1,2 soft-tissue injury,^3,4 orthopedic surgery,^5,6 wound healing,⁷ and veterinary medicine.^8,9 Despite its extensive use, there are still questions about the clinical efficacy of PRP.^10-12 Due to biological heterogeneity between patients^13,14 and differences between available manufacturing kits,^13,15 PRP can be highly variable between patients. There are classification schemes to categorize the various types of PRP,^16-18 which can be divided broadly into low-leukocyte PRP (L^lo PRP) and high-leukocyte PRP (L^hi PRP). PRP can be used as a point of care therapy, prepared and used immediately, or it can be used during a surgical procedure. In some institutions, blood is drawn by a phlebotomist, processed in the hospital laboratory, and then delivered to the operating room. In other instances, PRP is generated patient-side by the primary attending physician’s team, who draws the blood and processes it for immediate use.^5,19 Delays at any step in these various scenarios could lead to the blood or the resultant PRP remaining at room temperature from minutes to several hours prior to administration to the patient. This variability in PRP protocols between clinical and surgical settings adds to concerns regarding the stability and efficacy of the biologic.

Continue to: When performing clinical or research...

The primary aim of this study was to determine if retention of blood or PRP at room temperature for various time intervals had an effect on final growth factor or catabolic cytokine concentration. Bioactive transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase-9 (MMP-9) were measured as representatives of growth factors and catabolic cytokines, respectively. The secondary aim was to identify if manual platelet counts were an accurate reflection of automated counts. The outcomes of these experiments should provide immediately relevant information for the clinical application of PRP.

MATERIALS AND METHODS

Blood Collection and Generation of PRP

Under Institutional Review Board approval, blood (105 mL) was collected from healthy human volunteers (N = 5) into a syringe containing acid citrate dextrose anticoagulant to a final concentration of 10% acid citrate dextrose. Three 15-mL aliquots of blood were used to generate L^lo PRP (Autologous Conditioned Plasma Double Syringe, Arthrex) and three 20-mL aliquots were used to generate L^hi PRP (SmartPReP 2, Harvest Technologies) (Figure 1). 

Automated and Manual Counts

Automated complete blood counts were performed by a board certified clinical pathologist in the clinical pathology department of Cornell University on all blood, L^lo PRP, and L^hi PRP samples. A manual platelet count, using a modified Giemsa stain,²² was performed on smears of all blood and PRP samples (Video). Slides were scanned at 10x magnification to identify an area where many red blood cells were present while maintaining a clear field of view (Figure 2A). The magnification was then increased to 100x using oil immersion, and the total number of platelets was counted in 10 fields of view (Figure 2B). 

Growth Factor and Catabolic Cytokine Measurements

Blood and PRP samples were thawed for ELISA (enzyme-linked immunosorbent assay) analysis. TGF-β1 concentration was determined using the TGF-β1 Emax ImmunoAssay System (Promega Corporation), which measures biologically active TGF-β1. We chose TGF-β1 because it is commonly measured in PRP studies as an anabolic cytokine with multiple effects on tissue healing. The functions of TGF-β1 include stimulation of undifferentiated mesenchymal cell proliferation; regulation of endothelial, fibroblast, and osteoblast mitogenesis; coordination of collagen synthesis; promotion of endothelial chemotaxis and angiogenesis; activation of extracellular matrix synthesis in cartilage; and reduction of the catabolic activity of interluekin-1 and MMPs.^23-25 In addition, TGF-β1 concentration strongly correlates with platelet concentration.²⁶ MMP-9 concentration was determined using the MMP-9 Biotrak Activity Assay (GE Healthcare Biosciences) which measures both active and pro- forms of MMP-9. In PRP, MMP-9 was measured as an indicator of white blood cell (WBC) concentration.²⁶ A catabolic cytokine capable of degrading collagen,^13,27 MMP-9 has been linked to poor healing.²⁸ For both assays, samples were measured in duplicate using a multiple detection plate reader (Tecan Safire).

Continue to: Statistical Analysis...

Statistical Analysis

Data were tested for the normal distribution to determine the appropriate statistical test. Manual and automated platelet counts were compared to each other in whole blood, L^lo PRP, and L^hi PRP samples using a paired t test. Bioactive TGF-β1 concentrations in blood, L^lo PRP, and L^hi PRP, were compared using a Kruskal-Wallis one-way analysis of variance (ANOVA) with Dunn’s all-pairwise comparison. Bioactive and pro-MMP-9 concentrations measured in the retained blood or PRP samples were compared using a one-way ANOVA with Tukey’s all-pairwise comparison. Statistical analyses were performed using Statistix 9 software (Analytical Software). A P value of <0.05 was considered significant.

RESULTS

Validation of PRP

PRP, as defined by an increase in platelet concentration in PRP compared with blood, was successfully generated in all samples by both systems. There was an average 1.98 ± 0.14-fold increase in platelet concentration in L^lo PRP and an average 3.06 ± 0.24-fold increase in L^hi PRP. Platelet concentration was significantly higher in L^hi PRP than in L^lo PRP (P = 0.001). Compared to whole blood, WBC concentration was 0.47 ± 0.07-fold lower in L^lo PRP and 1.98 ± 0.14-fold greater in L^hi PRP. Similar to platelets, WBCs were significantly greater in L^hi PRP than in L^lo PRP (P = 0.02).

Bioactive TGF-β1 and MMP-9 Concentration in Blood Retained at Room Temperature

To reflect the clinical situation where blood would be drawn from a patient, but there would be a delay in processing the blood to generate PRP, blood samples were retained at room temperature for up to 4 hours prior to analysis. Neither bioactive TGF-β1 (Figure 3) nor bioactive/pro-MMP-9 concentrations (Figure 4) changed significantly over time when blood was retained at room temperature prior to centrifugation to generate PRP.

Bioactive TGF-β1 and MMP-9 Concentration in PRP Retained at Room Temperature

In order to mimic the clinical situation where PRP would be generated but might sit out prior to being administered to the patient, PRP samples were retained at room temperature for up to 4 hours prior to analysis. In these samples, bioactive TGF-β1 concentrations were not significantly different between PRP products analyzed immediately and those samples retained at room temperature for up to 4 hours (Figure 5). 

Automatic vs Manual Platelet Count

Manual platelet counts were compared to automated platelet counts to determine if a manual platelet smear analysis could be a reliable method for analyzing PRP in clinical and pre-clinical studies. There was a significant difference between the automated and manual platelet counts in blood samples (Table) (P = 0.05, N = 5) with the manual platelet count having a higher average (99.1 thou/uL) platelet concentration than automated counts. Platelet clumping was identified in 2 automated counts, which falsely decreased platelet concentration by an unknown quantity. Manual platelet counts for both L^lo PRP (n = 30) and L^hi PRP (n = 30) were not different from automated platelet counts. Platelet clumping was not reported on any manual platelet counts performed on PRP samples.

Table. Platelet Concentrations of Whole Blood, L^lo PRP, and L^hi PRP (N = 5)

A paired t test was performed to compare results obtained from an automated platelet count and those obtained from a manual count.

Abbreviations: L^hi PRP, high-leukocyte platelet-rich plasma; L^lo PRP, low-leukocyte platelet-rich plasma; SD, standard deviation.

Continue to:The primary aim of this study...

DISCUSSION

The primary aim of this study was to improve the clinical use of PRP by characterizing changes that might occur due to extended preparation times. Physicians commonly question the stability of blood or PRP if it is retained at room temperature prior to being administered to the patient. Clinical recommendations to optimize PRP preparation can be derived from a better understanding of the stability of platelets and WBCs, which contribute to the anabolic and catabolic cytokines in PRP.

The results of this study suggest that platelets and WBCs remain stable in blood and both L^lo PRP and L^hi PRP for up to 4 hours. The use of bioactive ELISAs to measure TGF-β1 and MMP-9 allows for determination of stability of the PRP product retained at room temperature for up to 4 hours. This provides a time buffer to allow for delays from either institutional logistics or unanticipated clinical delays, without adverse effects on the generation of the final PRP product. As with all biologics, there are many factors that contribute to variability, but a relatively short delay of up to 4 hours in either generation of PRP from blood or in administration of PRP to the patient does not appear to contribute to that variability. Similar studies have been performed on equine PRP and suggest that growth factor concentrations remain stable for up to 6 hours after preparation of PRP²⁹ and in human PRP, which implies that although samples degrade over time, platelet integrity might be acceptable for clinical use for up to 5 days after preparation, particularly if stored in oxygen.³⁰ In contrast to this study, neither of the previously published reports used assays to measure biological activity in the stored PRP. Regardless of the variability between the studies with respect to the type of PRP evaluated and the outcome measures used, all of the studies support the concept that PRP can be stored at room temperature for at least a few hours before clinical use.

Centrifugation of blood does not guarantee the generation of PRP.^13,14 In some cases, platelet counts in PRP are similar to or even less than that in the starting whole blood sample. To determine whether a clinical outcome is attributed to PRP, it is vital to know the platelet concentration and, arguably, the WBC concentration in the blood used to generate PRP and in the PRP sample administered to the patient. The platelet concentration in blood and PRP samples can be quantified using automated or manual methods. The use of automated methods can add significant cost to a study or procedure. Manually evaluating a blood smear is an accepted, though more time consuming, method of analyzing cellular components of a blood sample. Depending on the standard operating procedure of the laboratory, manual smears are often done in conjunction with an automated count. This identifies abnormalities in cellular shape or size, or platelet clumping, which are not consistently recognized by automated methods. Manually evaluating a blood smear does take some training, but the material cost is very low, which has added value for clinical or preclinical research studies. Interestingly, the results of this study indicate that manual platelet counts in blood may be more accurate than the count generated from an automated counter because the automated platelet counts were falsely low due to platelet clumping. Platelet clumping can occur as early as 1 hour after blood collection, regardless of the type of anticoagulant used.³¹

LIMITATIONS

The sample size of this study was small. However, variability in PRP has been well documented in multiple other studies using slightly larger sample sizes.^13,14,16 Another potential limitation of this study could be that only one growth factor, TGF-β1, and one catabolic cytokine, MMP-9, were used as surrogate measures to represent platelet and WBC stability, respectively. We chose TGF-β1 because it is correlated with platelet concentrations^14,15,26 and MMP-9 because it is an indicator of catabolic factors in PRP that have been correlated with WBC concentrations.²⁶

CONCLUSION

This study illustrated that growth factor and cytokine concentrations in both L^lo PRP and L^hi PRP are stable for up to 4 hours. The clinical implications of these results suggest that if the generation or administration of PRP is delayed by up to 4 hours, the resultant PRP retains its bioactivity and is acceptable for clinical application. However, given the known variability of PRP generated due to patient and manufacturer variability,^13,14 it is still important to ensure that the product is indeed PRP, with an increase in platelet number over the starting sample of blood. This validation can be performed with a simple and cost-effective manual smear analysis of blood and PRP. The results of this study provide information that can be immediately translated into clinical, surgical, and research practices.

ABSTRACT

The aim of this study was to provide clinical recommendations about the use of platelet-rich plasma (PRP) that was subjected to short-term storage at room temperature. We determined bioactive growth factor and cytokine concentrations as indicators of platelet and white blood cell degranulation in blood and PRP. Additionally, this study sought to validate the use of manual, direct smear analysis as an alternative to automated methods for platelet quantification in PRP.

Blood was used to generate low-leukocyte PRP (L^lo PRP) or high-leukocyte PRP (L^hi PRP). Blood was either processed immediately or kept at room temperature for 2 or 4 hours prior to generation of PRP, which was then held at room temperature for 0, 1, 2, or 4 hours. Subsequently, bioactive transforming growth factor beta-1 and matrix metalloproteinase-9 were measured by ELISA (enzyme-linked immunosorbent assay). Manual and automated platelet counts were performed on all blood and PRP samples.

There were no differences in growth factor or cytokine concentration when blood or L^lo PRP or L^hi PRP was retained at room temperature for up to 4 hours. Manual, direct smear analysis for platelet quantification was not different from the use of automated machine counting for PRP samples, but in the starting blood samples, manual platelet counts were significantly higher than those generated using automated technology.

When there is a delay of up to 4 hours in the generation of PRP from blood or in the application of PRP to the patient, bioactive growth factor and cytokine concentrations remain stable in both blood and PRP. A manual direct counting method is a simple, cost-effective, and valid method to measure the contents of the PRP product being delivered to the patient.

Platelet-rich plasma (PRP) is used to promote healing in many areas of medicine, such as dental surgery,^1,2 soft-tissue injury,^3,4 orthopedic surgery,^5,6 wound healing,⁷ and veterinary medicine.^8,9 Despite its extensive use, there are still questions about the clinical efficacy of PRP.^10-12 Due to biological heterogeneity between patients^13,14 and differences between available manufacturing kits,^13,15 PRP can be highly variable between patients. There are classification schemes to categorize the various types of PRP,^16-18 which can be divided broadly into low-leukocyte PRP (L^lo PRP) and high-leukocyte PRP (L^hi PRP). PRP can be used as a point of care therapy, prepared and used immediately, or it can be used during a surgical procedure. In some institutions, blood is drawn by a phlebotomist, processed in the hospital laboratory, and then delivered to the operating room. In other instances, PRP is generated patient-side by the primary attending physician’s team, who draws the blood and processes it for immediate use.^5,19 Delays at any step in these various scenarios could lead to the blood or the resultant PRP remaining at room temperature from minutes to several hours prior to administration to the patient. This variability in PRP protocols between clinical and surgical settings adds to concerns regarding the stability and efficacy of the biologic.

Continue to: When performing clinical or research...

The primary aim of this study was to determine if retention of blood or PRP at room temperature for various time intervals had an effect on final growth factor or catabolic cytokine concentration. Bioactive transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase-9 (MMP-9) were measured as representatives of growth factors and catabolic cytokines, respectively. The secondary aim was to identify if manual platelet counts were an accurate reflection of automated counts. The outcomes of these experiments should provide immediately relevant information for the clinical application of PRP.

MATERIALS AND METHODS

Blood Collection and Generation of PRP

Under Institutional Review Board approval, blood (105 mL) was collected from healthy human volunteers (N = 5) into a syringe containing acid citrate dextrose anticoagulant to a final concentration of 10% acid citrate dextrose. Three 15-mL aliquots of blood were used to generate L^lo PRP (Autologous Conditioned Plasma Double Syringe, Arthrex) and three 20-mL aliquots were used to generate L^hi PRP (SmartPReP 2, Harvest Technologies) (Figure 1). 

Automated and Manual Counts

Automated complete blood counts were performed by a board certified clinical pathologist in the clinical pathology department of Cornell University on all blood, L^lo PRP, and L^hi PRP samples. A manual platelet count, using a modified Giemsa stain,²² was performed on smears of all blood and PRP samples (Video). Slides were scanned at 10x magnification to identify an area where many red blood cells were present while maintaining a clear field of view (Figure 2A). The magnification was then increased to 100x using oil immersion, and the total number of platelets was counted in 10 fields of view (Figure 2B). 

Growth Factor and Catabolic Cytokine Measurements

Blood and PRP samples were thawed for ELISA (enzyme-linked immunosorbent assay) analysis. TGF-β1 concentration was determined using the TGF-β1 Emax ImmunoAssay System (Promega Corporation), which measures biologically active TGF-β1. We chose TGF-β1 because it is commonly measured in PRP studies as an anabolic cytokine with multiple effects on tissue healing. The functions of TGF-β1 include stimulation of undifferentiated mesenchymal cell proliferation; regulation of endothelial, fibroblast, and osteoblast mitogenesis; coordination of collagen synthesis; promotion of endothelial chemotaxis and angiogenesis; activation of extracellular matrix synthesis in cartilage; and reduction of the catabolic activity of interluekin-1 and MMPs.^23-25 In addition, TGF-β1 concentration strongly correlates with platelet concentration.²⁶ MMP-9 concentration was determined using the MMP-9 Biotrak Activity Assay (GE Healthcare Biosciences) which measures both active and pro- forms of MMP-9. In PRP, MMP-9 was measured as an indicator of white blood cell (WBC) concentration.²⁶ A catabolic cytokine capable of degrading collagen,^13,27 MMP-9 has been linked to poor healing.²⁸ For both assays, samples were measured in duplicate using a multiple detection plate reader (Tecan Safire).

Continue to: Statistical Analysis...

Statistical Analysis

Data were tested for the normal distribution to determine the appropriate statistical test. Manual and automated platelet counts were compared to each other in whole blood, L^lo PRP, and L^hi PRP samples using a paired t test. Bioactive TGF-β1 concentrations in blood, L^lo PRP, and L^hi PRP, were compared using a Kruskal-Wallis one-way analysis of variance (ANOVA) with Dunn’s all-pairwise comparison. Bioactive and pro-MMP-9 concentrations measured in the retained blood or PRP samples were compared using a one-way ANOVA with Tukey’s all-pairwise comparison. Statistical analyses were performed using Statistix 9 software (Analytical Software). A P value of <0.05 was considered significant.

RESULTS

Validation of PRP

PRP, as defined by an increase in platelet concentration in PRP compared with blood, was successfully generated in all samples by both systems. There was an average 1.98 ± 0.14-fold increase in platelet concentration in L^lo PRP and an average 3.06 ± 0.24-fold increase in L^hi PRP. Platelet concentration was significantly higher in L^hi PRP than in L^lo PRP (P = 0.001). Compared to whole blood, WBC concentration was 0.47 ± 0.07-fold lower in L^lo PRP and 1.98 ± 0.14-fold greater in L^hi PRP. Similar to platelets, WBCs were significantly greater in L^hi PRP than in L^lo PRP (P = 0.02).

Bioactive TGF-β1 and MMP-9 Concentration in Blood Retained at Room Temperature

To reflect the clinical situation where blood would be drawn from a patient, but there would be a delay in processing the blood to generate PRP, blood samples were retained at room temperature for up to 4 hours prior to analysis. Neither bioactive TGF-β1 (Figure 3) nor bioactive/pro-MMP-9 concentrations (Figure 4) changed significantly over time when blood was retained at room temperature prior to centrifugation to generate PRP.

Bioactive TGF-β1 and MMP-9 Concentration in PRP Retained at Room Temperature

In order to mimic the clinical situation where PRP would be generated but might sit out prior to being administered to the patient, PRP samples were retained at room temperature for up to 4 hours prior to analysis. In these samples, bioactive TGF-β1 concentrations were not significantly different between PRP products analyzed immediately and those samples retained at room temperature for up to 4 hours (Figure 5). 

Automatic vs Manual Platelet Count

Manual platelet counts were compared to automated platelet counts to determine if a manual platelet smear analysis could be a reliable method for analyzing PRP in clinical and pre-clinical studies. There was a significant difference between the automated and manual platelet counts in blood samples (Table) (P = 0.05, N = 5) with the manual platelet count having a higher average (99.1 thou/uL) platelet concentration than automated counts. Platelet clumping was identified in 2 automated counts, which falsely decreased platelet concentration by an unknown quantity. Manual platelet counts for both L^lo PRP (n = 30) and L^hi PRP (n = 30) were not different from automated platelet counts. Platelet clumping was not reported on any manual platelet counts performed on PRP samples.

Table. Platelet Concentrations of Whole Blood, L^lo PRP, and L^hi PRP (N = 5)

A paired t test was performed to compare results obtained from an automated platelet count and those obtained from a manual count.

Abbreviations: L^hi PRP, high-leukocyte platelet-rich plasma; L^lo PRP, low-leukocyte platelet-rich plasma; SD, standard deviation.

Continue to:The primary aim of this study...

DISCUSSION

The primary aim of this study was to improve the clinical use of PRP by characterizing changes that might occur due to extended preparation times. Physicians commonly question the stability of blood or PRP if it is retained at room temperature prior to being administered to the patient. Clinical recommendations to optimize PRP preparation can be derived from a better understanding of the stability of platelets and WBCs, which contribute to the anabolic and catabolic cytokines in PRP.

The results of this study suggest that platelets and WBCs remain stable in blood and both L^lo PRP and L^hi PRP for up to 4 hours. The use of bioactive ELISAs to measure TGF-β1 and MMP-9 allows for determination of stability of the PRP product retained at room temperature for up to 4 hours. This provides a time buffer to allow for delays from either institutional logistics or unanticipated clinical delays, without adverse effects on the generation of the final PRP product. As with all biologics, there are many factors that contribute to variability, but a relatively short delay of up to 4 hours in either generation of PRP from blood or in administration of PRP to the patient does not appear to contribute to that variability. Similar studies have been performed on equine PRP and suggest that growth factor concentrations remain stable for up to 6 hours after preparation of PRP²⁹ and in human PRP, which implies that although samples degrade over time, platelet integrity might be acceptable for clinical use for up to 5 days after preparation, particularly if stored in oxygen.³⁰ In contrast to this study, neither of the previously published reports used assays to measure biological activity in the stored PRP. Regardless of the variability between the studies with respect to the type of PRP evaluated and the outcome measures used, all of the studies support the concept that PRP can be stored at room temperature for at least a few hours before clinical use.

Centrifugation of blood does not guarantee the generation of PRP.^13,14 In some cases, platelet counts in PRP are similar to or even less than that in the starting whole blood sample. To determine whether a clinical outcome is attributed to PRP, it is vital to know the platelet concentration and, arguably, the WBC concentration in the blood used to generate PRP and in the PRP sample administered to the patient. The platelet concentration in blood and PRP samples can be quantified using automated or manual methods. The use of automated methods can add significant cost to a study or procedure. Manually evaluating a blood smear is an accepted, though more time consuming, method of analyzing cellular components of a blood sample. Depending on the standard operating procedure of the laboratory, manual smears are often done in conjunction with an automated count. This identifies abnormalities in cellular shape or size, or platelet clumping, which are not consistently recognized by automated methods. Manually evaluating a blood smear does take some training, but the material cost is very low, which has added value for clinical or preclinical research studies. Interestingly, the results of this study indicate that manual platelet counts in blood may be more accurate than the count generated from an automated counter because the automated platelet counts were falsely low due to platelet clumping. Platelet clumping can occur as early as 1 hour after blood collection, regardless of the type of anticoagulant used.³¹

LIMITATIONS

The sample size of this study was small. However, variability in PRP has been well documented in multiple other studies using slightly larger sample sizes.^13,14,16 Another potential limitation of this study could be that only one growth factor, TGF-β1, and one catabolic cytokine, MMP-9, were used as surrogate measures to represent platelet and WBC stability, respectively. We chose TGF-β1 because it is correlated with platelet concentrations^14,15,26 and MMP-9 because it is an indicator of catabolic factors in PRP that have been correlated with WBC concentrations.²⁶

CONCLUSION

This study illustrated that growth factor and cytokine concentrations in both L^lo PRP and L^hi PRP are stable for up to 4 hours. The clinical implications of these results suggest that if the generation or administration of PRP is delayed by up to 4 hours, the resultant PRP retains its bioactivity and is acceptable for clinical application. However, given the known variability of PRP generated due to patient and manufacturer variability,^13,14 it is still important to ensure that the product is indeed PRP, with an increase in platelet number over the starting sample of blood. This validation can be performed with a simple and cost-effective manual smear analysis of blood and PRP. The results of this study provide information that can be immediately translated into clinical, surgical, and research practices.

CHICAGO – Investigators have identified four genes that are overexpressed in primary melanoma, including one, CXCL1, that holds promise as a strong predictor of future metastatic disease, according to study results presented at the Society of Surgical Oncology Annual Cancer Symposium.

The study implicated four genes strongly expressed in primary melanoma tumors of patients who develop distant metastases – CXCL1, CXCL2, CBL, and CD276 – said Jennifer Erdrich, MD, MPH, of Cedars Sinai Medical Center, Los Angeles. However, CXCL1 stood out. “CXCL1 overexpression is an independent predictor of developing metastatic disease. Patients with CXCL1 overexpression in the primary tumor in our study had decreased overall 5-year survival.” CXCL1 may be a useful predictive marker in primary melanoma and a potential target for immunotherapy, she said.

copyright Kativ/iStockphoto

SOURCE: Erdrich J et al. SSO 2018, Abstract 82.

CHICAGO – Investigators have identified four genes that are overexpressed in primary melanoma, including one, CXCL1, that holds promise as a strong predictor of future metastatic disease, according to study results presented at the Society of Surgical Oncology Annual Cancer Symposium.

The study implicated four genes strongly expressed in primary melanoma tumors of patients who develop distant metastases – CXCL1, CXCL2, CBL, and CD276 – said Jennifer Erdrich, MD, MPH, of Cedars Sinai Medical Center, Los Angeles. However, CXCL1 stood out. “CXCL1 overexpression is an independent predictor of developing metastatic disease. Patients with CXCL1 overexpression in the primary tumor in our study had decreased overall 5-year survival.” CXCL1 may be a useful predictive marker in primary melanoma and a potential target for immunotherapy, she said.

copyright Kativ/iStockphoto

SOURCE: Erdrich J et al. SSO 2018, Abstract 82.

CHICAGO – Investigators have identified four genes that are overexpressed in primary melanoma, including one, CXCL1, that holds promise as a strong predictor of future metastatic disease, according to study results presented at the Society of Surgical Oncology Annual Cancer Symposium.

The study implicated four genes strongly expressed in primary melanoma tumors of patients who develop distant metastases – CXCL1, CXCL2, CBL, and CD276 – said Jennifer Erdrich, MD, MPH, of Cedars Sinai Medical Center, Los Angeles. However, CXCL1 stood out. “CXCL1 overexpression is an independent predictor of developing metastatic disease. Patients with CXCL1 overexpression in the primary tumor in our study had decreased overall 5-year survival.” CXCL1 may be a useful predictive marker in primary melanoma and a potential target for immunotherapy, she said.

copyright Kativ/iStockphoto

SOURCE: Erdrich J et al. SSO 2018, Abstract 82.

ORLANDO – More than one-third of patients with treatment-resistant hypertension in U.S. cardiology practices are eligible for preferential consideration of spironolactone as their fourth-line agent in accord with the practice-changing findings of the PATHWAY-2 trial, Lauren Thompson, MD, said at the annual meeting of the American College of Cardiology.

She presented a study that harnessed the ACC’s National Cardiovascular Data Registry PINNACLE Registry – the largest observational outpatient cardiovascular registry in the world – to assess the potential impact of PATHWAY-2 on the management of treatment-resistant hypertension (TRH) in U.S. cardiology practices. And as she discovered, the potential implications for daily practice are huge.

Bruce Jancin/MDedge News

The most widely prescribed antihypertensive agents in PINNACLE registry patients with TRH were beta-blockers, in 87%; ACE inhibitors, in 72%; calcium channel blockers, in 71%; and thiazide diuretics, in 69%. Of note, 27% of patients with TRH were already on spironolactone.

Audience discussion centered around the uncertainties regarding treatment adherence in patients labeled as having TRH.

“I think sometimes clinicians are afraid to prescribe spironolactone in patients that they think might be nonadherent,” one cardiologist observed.

Dr. Thompson noted that it’s not possible to look at prescription-filling rates in the PINNACLE registry.

“Unfortunately, we can’t exclude white coat hypertension or nonadherence as reasons why patients in PINNACLE end up on multiple antihypertensive medication classes. We can see that a prescription was written, but we have no way to know if it was actually filled or not,” she observed.

Also, since patients in cardiology clinics typically have multiple cardiovascular comorbidities, it’s quite possible that patients with TRH who are on a beta-blocker, for example, might not have received that drug for blood pressure control.

Dr. Thompson’s study was supported by the ACC’s National Cardiovascular Disease Registry. She reported having no financial conflicts of interest.

[email protected]

Source: Thompson L. ACC 18. Abstract 1324M-09.

ORLANDO – More than one-third of patients with treatment-resistant hypertension in U.S. cardiology practices are eligible for preferential consideration of spironolactone as their fourth-line agent in accord with the practice-changing findings of the PATHWAY-2 trial, Lauren Thompson, MD, said at the annual meeting of the American College of Cardiology.

She presented a study that harnessed the ACC’s National Cardiovascular Data Registry PINNACLE Registry – the largest observational outpatient cardiovascular registry in the world – to assess the potential impact of PATHWAY-2 on the management of treatment-resistant hypertension (TRH) in U.S. cardiology practices. And as she discovered, the potential implications for daily practice are huge.

Bruce Jancin/MDedge News

The most widely prescribed antihypertensive agents in PINNACLE registry patients with TRH were beta-blockers, in 87%; ACE inhibitors, in 72%; calcium channel blockers, in 71%; and thiazide diuretics, in 69%. Of note, 27% of patients with TRH were already on spironolactone.

Audience discussion centered around the uncertainties regarding treatment adherence in patients labeled as having TRH.

“I think sometimes clinicians are afraid to prescribe spironolactone in patients that they think might be nonadherent,” one cardiologist observed.

Dr. Thompson noted that it’s not possible to look at prescription-filling rates in the PINNACLE registry.

“Unfortunately, we can’t exclude white coat hypertension or nonadherence as reasons why patients in PINNACLE end up on multiple antihypertensive medication classes. We can see that a prescription was written, but we have no way to know if it was actually filled or not,” she observed.

Also, since patients in cardiology clinics typically have multiple cardiovascular comorbidities, it’s quite possible that patients with TRH who are on a beta-blocker, for example, might not have received that drug for blood pressure control.

Dr. Thompson’s study was supported by the ACC’s National Cardiovascular Disease Registry. She reported having no financial conflicts of interest.

[email protected]

Source: Thompson L. ACC 18. Abstract 1324M-09.

ORLANDO – More than one-third of patients with treatment-resistant hypertension in U.S. cardiology practices are eligible for preferential consideration of spironolactone as their fourth-line agent in accord with the practice-changing findings of the PATHWAY-2 trial, Lauren Thompson, MD, said at the annual meeting of the American College of Cardiology.

She presented a study that harnessed the ACC’s National Cardiovascular Data Registry PINNACLE Registry – the largest observational outpatient cardiovascular registry in the world – to assess the potential impact of PATHWAY-2 on the management of treatment-resistant hypertension (TRH) in U.S. cardiology practices. And as she discovered, the potential implications for daily practice are huge.

Bruce Jancin/MDedge News

The most widely prescribed antihypertensive agents in PINNACLE registry patients with TRH were beta-blockers, in 87%; ACE inhibitors, in 72%; calcium channel blockers, in 71%; and thiazide diuretics, in 69%. Of note, 27% of patients with TRH were already on spironolactone.

Audience discussion centered around the uncertainties regarding treatment adherence in patients labeled as having TRH.

“I think sometimes clinicians are afraid to prescribe spironolactone in patients that they think might be nonadherent,” one cardiologist observed.

Dr. Thompson noted that it’s not possible to look at prescription-filling rates in the PINNACLE registry.

“Unfortunately, we can’t exclude white coat hypertension or nonadherence as reasons why patients in PINNACLE end up on multiple antihypertensive medication classes. We can see that a prescription was written, but we have no way to know if it was actually filled or not,” she observed.

Also, since patients in cardiology clinics typically have multiple cardiovascular comorbidities, it’s quite possible that patients with TRH who are on a beta-blocker, for example, might not have received that drug for blood pressure control.

Dr. Thompson’s study was supported by the ACC’s National Cardiovascular Disease Registry. She reported having no financial conflicts of interest.

[email protected]

Source: Thompson L. ACC 18. Abstract 1324M-09.

How do you summarize a year’s worth of hospitalist-relevant research in an hour? If you’re Cynthia Cooper, MD, and Barbara Slawski, MD, MS, SFHM, you do it with teamwork, rigor, and style.

When the two physicians signed on for the 2018 “Update in Hospital Medicine” talk, they knew the bar was high. The updates talk is a perennial crowd favorite at the Society of Hospital Medicine annual conferences, and this year’s talk, which touched on topics from #MeToo to kidney injury, didn’t disappoint.

MDedge News

Among the highlights of the 20 studies reviewed in concise fashion by Dr. Cooper and Dr. Slawski was work that revealed a startling amount of gender bias when speakers are introduced at medical grand rounds. “One of the things that made the news a lot this last year is gender bias, so we thought we’d start out with that,” said Dr. Slawski, chief of the section of perioperative medicine at the Medical College of Wisconsin in Milwaukee.

In a retrospective observational study, the investigators looked at archived grand rounds video to see how often speakers with doctoral degrees were introduced by title, rather than by first name. Mixed-gender evaluators found that females were much more likely than were males to introduce either females or males by title (P less than .001).

“Have any of you ever had this experience? Me, too,” said Dr. Slawski, to wide and prolonged applause.

Females introducing males were almost twice as likely to use the speaker’s title as when males introduced females (95% vs. 49%; P less than .001). These revelations, said Dr. Slawski, present an “opportunity for improving professional interactions in an environment of mutual respect,” a comment that the room again greeted with a round of applause.

The inpatient syncope evaluation was made a little easier with another top study presented by Dr. Slawski. Using a large multinational database, investigators looked at a subgroup of patients with syncope who were admitted to the hospital. They found that fewer than 2% of patients with syncope were diagnosed with pulmonary embolus (PE) or deep venous thrombosis within 90 days of the index admission. For Dr. Slawski, this means clinicians may be able to relax their worry about thromboembolic events just a bit: “Although this diagnosis should be considered, not all patients need evaluation,” she said.

How do you summarize a year’s worth of hospitalist-relevant research in an hour? If you’re Cynthia Cooper, MD, and Barbara Slawski, MD, MS, SFHM, you do it with teamwork, rigor, and style.

When the two physicians signed on for the 2018 “Update in Hospital Medicine” talk, they knew the bar was high. The updates talk is a perennial crowd favorite at the Society of Hospital Medicine annual conferences, and this year’s talk, which touched on topics from #MeToo to kidney injury, didn’t disappoint.

MDedge News

Among the highlights of the 20 studies reviewed in concise fashion by Dr. Cooper and Dr. Slawski was work that revealed a startling amount of gender bias when speakers are introduced at medical grand rounds. “One of the things that made the news a lot this last year is gender bias, so we thought we’d start out with that,” said Dr. Slawski, chief of the section of perioperative medicine at the Medical College of Wisconsin in Milwaukee.

In a retrospective observational study, the investigators looked at archived grand rounds video to see how often speakers with doctoral degrees were introduced by title, rather than by first name. Mixed-gender evaluators found that females were much more likely than were males to introduce either females or males by title (P less than .001).

“Have any of you ever had this experience? Me, too,” said Dr. Slawski, to wide and prolonged applause.

Females introducing males were almost twice as likely to use the speaker’s title as when males introduced females (95% vs. 49%; P less than .001). These revelations, said Dr. Slawski, present an “opportunity for improving professional interactions in an environment of mutual respect,” a comment that the room again greeted with a round of applause.

The inpatient syncope evaluation was made a little easier with another top study presented by Dr. Slawski. Using a large multinational database, investigators looked at a subgroup of patients with syncope who were admitted to the hospital. They found that fewer than 2% of patients with syncope were diagnosed with pulmonary embolus (PE) or deep venous thrombosis within 90 days of the index admission. For Dr. Slawski, this means clinicians may be able to relax their worry about thromboembolic events just a bit: “Although this diagnosis should be considered, not all patients need evaluation,” she said.

How do you summarize a year’s worth of hospitalist-relevant research in an hour? If you’re Cynthia Cooper, MD, and Barbara Slawski, MD, MS, SFHM, you do it with teamwork, rigor, and style.

When the two physicians signed on for the 2018 “Update in Hospital Medicine” talk, they knew the bar was high. The updates talk is a perennial crowd favorite at the Society of Hospital Medicine annual conferences, and this year’s talk, which touched on topics from #MeToo to kidney injury, didn’t disappoint.

MDedge News

Among the highlights of the 20 studies reviewed in concise fashion by Dr. Cooper and Dr. Slawski was work that revealed a startling amount of gender bias when speakers are introduced at medical grand rounds. “One of the things that made the news a lot this last year is gender bias, so we thought we’d start out with that,” said Dr. Slawski, chief of the section of perioperative medicine at the Medical College of Wisconsin in Milwaukee.

In a retrospective observational study, the investigators looked at archived grand rounds video to see how often speakers with doctoral degrees were introduced by title, rather than by first name. Mixed-gender evaluators found that females were much more likely than were males to introduce either females or males by title (P less than .001).

“Have any of you ever had this experience? Me, too,” said Dr. Slawski, to wide and prolonged applause.

Females introducing males were almost twice as likely to use the speaker’s title as when males introduced females (95% vs. 49%; P less than .001). These revelations, said Dr. Slawski, present an “opportunity for improving professional interactions in an environment of mutual respect,” a comment that the room again greeted with a round of applause.

The inpatient syncope evaluation was made a little easier with another top study presented by Dr. Slawski. Using a large multinational database, investigators looked at a subgroup of patients with syncope who were admitted to the hospital. They found that fewer than 2% of patients with syncope were diagnosed with pulmonary embolus (PE) or deep venous thrombosis within 90 days of the index admission. For Dr. Slawski, this means clinicians may be able to relax their worry about thromboembolic events just a bit: “Although this diagnosis should be considered, not all patients need evaluation,” she said.