SIM image of platelets

Courtesy of Dan Cutler

A proof-of-concept study suggests structured illumination microscopy (SIM) enables accurate diagnosis of Hermansky-Pudlak syndrome (HPS), an autosomal recessive disorder characterized by platelet dysfunction and prolonged bleeding.

Researchers therefore believe SIM could provide a more accessible and cost-effective method for diagnosing platelet disorders.

They also said SIM provides detailed data that may enable personalized treatments.

The researchers described their results with SIM in the Journal of Thrombosis and Haemostasis.

The team noted that electron microscopy can be used to diagnose HPS and other disorders characterized by platelet dysfunction. But the method is costly, requires fresh samples, gives limited information, and is not widely available.

“We’ve found that SIM has a lot of advantages over whole mount electron microscopy as a diagnosis method,” said study author David Westmoreland, of University College London in the UK.

“Samples don’t need to be analyzed live and can be reanalyzed, and automation means analysis is unbiased and less time-consuming. Given about 75% of patients with a bleeding disorder such as Hermansky-Pudlak syndrome are initially misdiagnosed, and 28% need to see between 4 to 6 specialists before receiving the correct diagnosis, there is a demand for a new method of analysis.”

For this proof-of-concept study, Westmoreland and his colleagues used SIM to image platelet granules in blood samples using a marker protein, CD63.

The imaging technology was custom-built by the team to automatically count the number of granules per platelet, thereby identifying patients with HPS, a rare disorder thought to affect 1 in 500,000 people.

The researchers distinguished the 3 patients with HPS from 7 normal controls with 99% confidence. Automated counting of granules showed that individuals with the disorder had a third as many granules as controls.

“Our limited analysis of this new method is extremely promising, and we hope to take it forward to test for multiple parameters with different markers,” said Dan Cutler, PhD, also of University College London.

“In this way, we could use a single super-resolution image to screen for many different platelet-based blood disorders.”

SIM image of platelets

Courtesy of Dan Cutler

A proof-of-concept study suggests structured illumination microscopy (SIM) enables accurate diagnosis of Hermansky-Pudlak syndrome (HPS), an autosomal recessive disorder characterized by platelet dysfunction and prolonged bleeding.

Researchers therefore believe SIM could provide a more accessible and cost-effective method for diagnosing platelet disorders.

They also said SIM provides detailed data that may enable personalized treatments.

The researchers described their results with SIM in the Journal of Thrombosis and Haemostasis.

The team noted that electron microscopy can be used to diagnose HPS and other disorders characterized by platelet dysfunction. But the method is costly, requires fresh samples, gives limited information, and is not widely available.

“We’ve found that SIM has a lot of advantages over whole mount electron microscopy as a diagnosis method,” said study author David Westmoreland, of University College London in the UK.

“Samples don’t need to be analyzed live and can be reanalyzed, and automation means analysis is unbiased and less time-consuming. Given about 75% of patients with a bleeding disorder such as Hermansky-Pudlak syndrome are initially misdiagnosed, and 28% need to see between 4 to 6 specialists before receiving the correct diagnosis, there is a demand for a new method of analysis.”

For this proof-of-concept study, Westmoreland and his colleagues used SIM to image platelet granules in blood samples using a marker protein, CD63.

The imaging technology was custom-built by the team to automatically count the number of granules per platelet, thereby identifying patients with HPS, a rare disorder thought to affect 1 in 500,000 people.

The researchers distinguished the 3 patients with HPS from 7 normal controls with 99% confidence. Automated counting of granules showed that individuals with the disorder had a third as many granules as controls.

“Our limited analysis of this new method is extremely promising, and we hope to take it forward to test for multiple parameters with different markers,” said Dan Cutler, PhD, also of University College London.

“In this way, we could use a single super-resolution image to screen for many different platelet-based blood disorders.”

SIM image of platelets

Courtesy of Dan Cutler

A proof-of-concept study suggests structured illumination microscopy (SIM) enables accurate diagnosis of Hermansky-Pudlak syndrome (HPS), an autosomal recessive disorder characterized by platelet dysfunction and prolonged bleeding.

Researchers therefore believe SIM could provide a more accessible and cost-effective method for diagnosing platelet disorders.

They also said SIM provides detailed data that may enable personalized treatments.

The researchers described their results with SIM in the Journal of Thrombosis and Haemostasis.

The team noted that electron microscopy can be used to diagnose HPS and other disorders characterized by platelet dysfunction. But the method is costly, requires fresh samples, gives limited information, and is not widely available.

“We’ve found that SIM has a lot of advantages over whole mount electron microscopy as a diagnosis method,” said study author David Westmoreland, of University College London in the UK.

“Samples don’t need to be analyzed live and can be reanalyzed, and automation means analysis is unbiased and less time-consuming. Given about 75% of patients with a bleeding disorder such as Hermansky-Pudlak syndrome are initially misdiagnosed, and 28% need to see between 4 to 6 specialists before receiving the correct diagnosis, there is a demand for a new method of analysis.”

For this proof-of-concept study, Westmoreland and his colleagues used SIM to image platelet granules in blood samples using a marker protein, CD63.

The imaging technology was custom-built by the team to automatically count the number of granules per platelet, thereby identifying patients with HPS, a rare disorder thought to affect 1 in 500,000 people.

The researchers distinguished the 3 patients with HPS from 7 normal controls with 99% confidence. Automated counting of granules showed that individuals with the disorder had a third as many granules as controls.

“Our limited analysis of this new method is extremely promising, and we hope to take it forward to test for multiple parameters with different markers,” said Dan Cutler, PhD, also of University College London.

“In this way, we could use a single super-resolution image to screen for many different platelet-based blood disorders.”

NEW YORK (Reuters Health) - Inpatient dermatology consultations for skin disorders are associated with improved diagnostic accuracy and faster intervention, researchers have

found.

Information about the impact of hospitalist dermatology consultative services is limited, Dr. Daniela Kroshinsky from Massachusetts General Hospital in Boston and colleagues note in JAMA  Dermatology, online January 13.

To learn more, the team conducted a cross-sectional study of data from dermatology consult teams at four academic medical centers in the U.S. Full-time inpatient dermatologists with resident teams performed a total of 1,661 inpatient dermatology consultations within 24 to 48 hours of request over 12 months from 2008 to 2009.

All final diagnoses were based on clinical history, examination findings, and laboratory testing. Each service (primary team) that asked for a dermatology consult provided its presumptive diagnosis at the time of its request.

The most common primary teams were Medicine (47%), followed by Surgery (15%), Intensive Care Units (12%), and Hematology-Oncology (9%). The most commonly undiagnosed or misdiagnosed conditions by the primary teams were cellulitis, leg ulcerations, and viral infections. The majority of primary team preliminary diagnoses included rash/unknown (n=814), followed by cellulitis/abscess (n=115), and drug rash (n=111). The majority of primary diagnoses by dermatologists included drug rash (n=292; 18%), psoriasis/eczema (n=170; 10%), and benign neoplasm (n=168; 10%).

The dermatologists identified additional cutaneous issues in 298 (18%) of consults; diagnosis was confirmed by biopsy in 667 (40%) patients. Overall, dermatology consultation changed the final diagnosis in 71% of consultation requests.

Just under a third of the patients were admitted to the hospitals because of their skin conditions. In the remaining cases, the dermatologic issues were found incidentally or developed during hospitalization.

In 40% of cases, dermatology-specific evaluation and treatment recommendations were carried out in a single visit; 29% required one follow-up evaluation and 16% required two.

"This is the first multicenter national study to define the nature of dermatologic issues presenting to academic medical centers and to demonstrate the impact dermatologists have on improving the correct diagnosis of patients with skin issues,"Dr. Kroshinsky told Reuters Health by email.

Hospitalist dermatology is an important and effective subset of dermatology and hospital medicine, she said.

"Ideally," Dr. Kroshinsky added, "hospitals would have access to a dermatologist in real-time or via teledermatology."

NEW YORK (Reuters Health) - Inpatient dermatology consultations for skin disorders are associated with improved diagnostic accuracy and faster intervention, researchers have

found.

Information about the impact of hospitalist dermatology consultative services is limited, Dr. Daniela Kroshinsky from Massachusetts General Hospital in Boston and colleagues note in JAMA  Dermatology, online January 13.

To learn more, the team conducted a cross-sectional study of data from dermatology consult teams at four academic medical centers in the U.S. Full-time inpatient dermatologists with resident teams performed a total of 1,661 inpatient dermatology consultations within 24 to 48 hours of request over 12 months from 2008 to 2009.

All final diagnoses were based on clinical history, examination findings, and laboratory testing. Each service (primary team) that asked for a dermatology consult provided its presumptive diagnosis at the time of its request.

The most common primary teams were Medicine (47%), followed by Surgery (15%), Intensive Care Units (12%), and Hematology-Oncology (9%). The most commonly undiagnosed or misdiagnosed conditions by the primary teams were cellulitis, leg ulcerations, and viral infections. The majority of primary team preliminary diagnoses included rash/unknown (n=814), followed by cellulitis/abscess (n=115), and drug rash (n=111). The majority of primary diagnoses by dermatologists included drug rash (n=292; 18%), psoriasis/eczema (n=170; 10%), and benign neoplasm (n=168; 10%).

The dermatologists identified additional cutaneous issues in 298 (18%) of consults; diagnosis was confirmed by biopsy in 667 (40%) patients. Overall, dermatology consultation changed the final diagnosis in 71% of consultation requests.

Just under a third of the patients were admitted to the hospitals because of their skin conditions. In the remaining cases, the dermatologic issues were found incidentally or developed during hospitalization.

In 40% of cases, dermatology-specific evaluation and treatment recommendations were carried out in a single visit; 29% required one follow-up evaluation and 16% required two.

"This is the first multicenter national study to define the nature of dermatologic issues presenting to academic medical centers and to demonstrate the impact dermatologists have on improving the correct diagnosis of patients with skin issues,"Dr. Kroshinsky told Reuters Health by email.

Hospitalist dermatology is an important and effective subset of dermatology and hospital medicine, she said.

"Ideally," Dr. Kroshinsky added, "hospitals would have access to a dermatologist in real-time or via teledermatology."

NEW YORK (Reuters Health) - Inpatient dermatology consultations for skin disorders are associated with improved diagnostic accuracy and faster intervention, researchers have

found.

Information about the impact of hospitalist dermatology consultative services is limited, Dr. Daniela Kroshinsky from Massachusetts General Hospital in Boston and colleagues note in JAMA  Dermatology, online January 13.

To learn more, the team conducted a cross-sectional study of data from dermatology consult teams at four academic medical centers in the U.S. Full-time inpatient dermatologists with resident teams performed a total of 1,661 inpatient dermatology consultations within 24 to 48 hours of request over 12 months from 2008 to 2009.

All final diagnoses were based on clinical history, examination findings, and laboratory testing. Each service (primary team) that asked for a dermatology consult provided its presumptive diagnosis at the time of its request.

The most common primary teams were Medicine (47%), followed by Surgery (15%), Intensive Care Units (12%), and Hematology-Oncology (9%). The most commonly undiagnosed or misdiagnosed conditions by the primary teams were cellulitis, leg ulcerations, and viral infections. The majority of primary team preliminary diagnoses included rash/unknown (n=814), followed by cellulitis/abscess (n=115), and drug rash (n=111). The majority of primary diagnoses by dermatologists included drug rash (n=292; 18%), psoriasis/eczema (n=170; 10%), and benign neoplasm (n=168; 10%).

The dermatologists identified additional cutaneous issues in 298 (18%) of consults; diagnosis was confirmed by biopsy in 667 (40%) patients. Overall, dermatology consultation changed the final diagnosis in 71% of consultation requests.

Just under a third of the patients were admitted to the hospitals because of their skin conditions. In the remaining cases, the dermatologic issues were found incidentally or developed during hospitalization.

In 40% of cases, dermatology-specific evaluation and treatment recommendations were carried out in a single visit; 29% required one follow-up evaluation and 16% required two.

"This is the first multicenter national study to define the nature of dermatologic issues presenting to academic medical centers and to demonstrate the impact dermatologists have on improving the correct diagnosis of patients with skin issues,"Dr. Kroshinsky told Reuters Health by email.

Hospitalist dermatology is an important and effective subset of dermatology and hospital medicine, she said.

"Ideally," Dr. Kroshinsky added, "hospitals would have access to a dermatologist in real-time or via teledermatology."

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted orphan designation for cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs) to treat EBV post-transplant lymphoproliferative disorder (EBV-PTLD) occurring after solid organ or hematopoietic stem cell transplant.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases, which may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and a 7-year period of marketing exclusivity if the product is approved.

The EBV-CTL product is under development by Atara Biotherapeutics, Inc. It is produced by collecting T cells from third-party donors and exposing the cells to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, Atara’s EBV-CTLs find the cancer cells expressing EBV and kill them. EBV-CTLs are currently being studied in phase 2 trials.

Results of a phase 1/2 study were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

The FDA previously granted EBV-CTLs breakthrough designation to treat EBV-PTLD. This designation is intended to expedite the development and review of new drugs for serious or life-threatening conditions.

To qualify for breakthrough designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted orphan designation for cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs) to treat EBV post-transplant lymphoproliferative disorder (EBV-PTLD) occurring after solid organ or hematopoietic stem cell transplant.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases, which may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and a 7-year period of marketing exclusivity if the product is approved.

The EBV-CTL product is under development by Atara Biotherapeutics, Inc. It is produced by collecting T cells from third-party donors and exposing the cells to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, Atara’s EBV-CTLs find the cancer cells expressing EBV and kill them. EBV-CTLs are currently being studied in phase 2 trials.

Results of a phase 1/2 study were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

The FDA previously granted EBV-CTLs breakthrough designation to treat EBV-PTLD. This designation is intended to expedite the development and review of new drugs for serious or life-threatening conditions.

To qualify for breakthrough designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of

Benjamin Chaigne-Delalande

The US Food and Drug Administration (FDA) has granted orphan designation for cytotoxic T lymphocytes activated against Epstein-Barr virus (EBV-CTLs) to treat EBV post-transplant lymphoproliferative disorder (EBV-PTLD) occurring after solid organ or hematopoietic stem cell transplant.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases, which may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and a 7-year period of marketing exclusivity if the product is approved.

The EBV-CTL product is under development by Atara Biotherapeutics, Inc. It is produced by collecting T cells from third-party donors and exposing the cells to EBV antigens.

The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient, providing an “off-the-shelf,” allogeneic, cellular therapeutic option for patients.

In the context of EBV-PTLD, Atara’s EBV-CTLs find the cancer cells expressing EBV and kill them. EBV-CTLs are currently being studied in phase 2 trials.

Results of a phase 1/2 study were presented at the APHON 37th Annual Conference and Exhibit and at the 2015 ASCO Annual Meeting.

The FDA previously granted EBV-CTLs breakthrough designation to treat EBV-PTLD. This designation is intended to expedite the development and review of new drugs for serious or life-threatening conditions.

To qualify for breakthrough designation, a drug must show credible evidence of a substantial improvement on a clinically significant endpoint over available therapies, or over placebo if there is no available therapy, or in a study that compares the new treatment plus the standard of care to the standard alone.

The designation confers several benefits, including intensive FDA guidance and eligibility for submission of a rolling biologic license application.

Gut bacteria

Microorganisms in the gut play a role in the severity of malaria, according to a study published in PNAS.

Investigators examined the gut microbiomes of mice and found evidence to suggest that malaria severity  is not only a function of the parasite or the host. It is also influenced by the microbes in the infected organism.

And 2 types of bacteria—Bifidobacterium and Lactobacillus—were associated with reduced malaria severity.

“The research provides a potential new avenue to investigate factors that control the severity of malaria,” said study author Steven Wilhelm, PhD, of the University of Tennessee at Knoxville.

“With 1 million people dying [of malaria] each year, many of whom are young children, any approach that may save even a few lives is worth following up on.”

With this study, Dr Wilhelm and his colleagues found that genetically similar mice acquired from different vendors had differences in pathology after malaria infection. There were significant differences in both parasite burden and mortality after infection with multiple Plasmodium species.

The investigators measured gut microbiomes in the mice by sequencing bacteria in the digestive tract and noted significant differences within the different mouse populations.

So the team transferred cecal content from the first set of mice into germ-free mice and found that differences in malaria severity were transferred.

The mice that received transplants from donors that were more resistant to malaria had low parasite burdens. And mice that received transplants from donors that were more susceptible to malaria had high parasite burdens.

The investigators also observed an increased abundance of Bifidobacterium and Lactobacillus bacteria in the mice that exhibited reduced malaria pathology.

So the team took mice that were more susceptible to malaria, treated them with antibiotics, and fed them yogurt containing Bifidobacterium and Lactobacillus. As expected, the severity of malaria in these mice decreased.

“These results demonstrate the possibility of modifying the gut microbiome to prevent severe malaria,” said study author Nathan Schmidt, PhD, of the University of Louisville in Kentucky.

Dr Wilhelm noted that, although the research interventions lessened the severity of malaria in mice, it did not prevent or cure it. And the investigators are a long way from perfecting similar treatments in humans but are working on understanding the mechanism.

“A way to help people who are infected—and especially a simple and cheap way, as much of the infection occurs in the developing world—would be a great service to society,” Dr Wilhelm said.

Gut bacteria

Microorganisms in the gut play a role in the severity of malaria, according to a study published in PNAS.

Investigators examined the gut microbiomes of mice and found evidence to suggest that malaria severity  is not only a function of the parasite or the host. It is also influenced by the microbes in the infected organism.

And 2 types of bacteria—Bifidobacterium and Lactobacillus—were associated with reduced malaria severity.

“The research provides a potential new avenue to investigate factors that control the severity of malaria,” said study author Steven Wilhelm, PhD, of the University of Tennessee at Knoxville.

“With 1 million people dying [of malaria] each year, many of whom are young children, any approach that may save even a few lives is worth following up on.”

With this study, Dr Wilhelm and his colleagues found that genetically similar mice acquired from different vendors had differences in pathology after malaria infection. There were significant differences in both parasite burden and mortality after infection with multiple Plasmodium species.

The investigators measured gut microbiomes in the mice by sequencing bacteria in the digestive tract and noted significant differences within the different mouse populations.

So the team transferred cecal content from the first set of mice into germ-free mice and found that differences in malaria severity were transferred.

The mice that received transplants from donors that were more resistant to malaria had low parasite burdens. And mice that received transplants from donors that were more susceptible to malaria had high parasite burdens.

The investigators also observed an increased abundance of Bifidobacterium and Lactobacillus bacteria in the mice that exhibited reduced malaria pathology.

So the team took mice that were more susceptible to malaria, treated them with antibiotics, and fed them yogurt containing Bifidobacterium and Lactobacillus. As expected, the severity of malaria in these mice decreased.

“These results demonstrate the possibility of modifying the gut microbiome to prevent severe malaria,” said study author Nathan Schmidt, PhD, of the University of Louisville in Kentucky.

Dr Wilhelm noted that, although the research interventions lessened the severity of malaria in mice, it did not prevent or cure it. And the investigators are a long way from perfecting similar treatments in humans but are working on understanding the mechanism.

“A way to help people who are infected—and especially a simple and cheap way, as much of the infection occurs in the developing world—would be a great service to society,” Dr Wilhelm said.

Gut bacteria

Microorganisms in the gut play a role in the severity of malaria, according to a study published in PNAS.

Investigators examined the gut microbiomes of mice and found evidence to suggest that malaria severity  is not only a function of the parasite or the host. It is also influenced by the microbes in the infected organism.

And 2 types of bacteria—Bifidobacterium and Lactobacillus—were associated with reduced malaria severity.

“The research provides a potential new avenue to investigate factors that control the severity of malaria,” said study author Steven Wilhelm, PhD, of the University of Tennessee at Knoxville.

“With 1 million people dying [of malaria] each year, many of whom are young children, any approach that may save even a few lives is worth following up on.”

With this study, Dr Wilhelm and his colleagues found that genetically similar mice acquired from different vendors had differences in pathology after malaria infection. There were significant differences in both parasite burden and mortality after infection with multiple Plasmodium species.

The investigators measured gut microbiomes in the mice by sequencing bacteria in the digestive tract and noted significant differences within the different mouse populations.

So the team transferred cecal content from the first set of mice into germ-free mice and found that differences in malaria severity were transferred.

The mice that received transplants from donors that were more resistant to malaria had low parasite burdens. And mice that received transplants from donors that were more susceptible to malaria had high parasite burdens.

The investigators also observed an increased abundance of Bifidobacterium and Lactobacillus bacteria in the mice that exhibited reduced malaria pathology.

So the team took mice that were more susceptible to malaria, treated them with antibiotics, and fed them yogurt containing Bifidobacterium and Lactobacillus. As expected, the severity of malaria in these mice decreased.

“These results demonstrate the possibility of modifying the gut microbiome to prevent severe malaria,” said study author Nathan Schmidt, PhD, of the University of Louisville in Kentucky.

Dr Wilhelm noted that, although the research interventions lessened the severity of malaria in mice, it did not prevent or cure it. And the investigators are a long way from perfecting similar treatments in humans but are working on understanding the mechanism.

“A way to help people who are infected—and especially a simple and cheap way, as much of the infection occurs in the developing world—would be a great service to society,” Dr Wilhelm said.

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

A biosimilar agent to Remicade, the brand-name and reference form of infliximab, stayed on track to become the second biosimilar drug to enter the U.S. market when the Arthritis Advisory Committee of the Food and Drug Administration voted overwhelmingly in favor of licensure of the biosimilar at a meeting on Feb. 9.

The vote was 21 in favor and 3 against, with no abstentions.

Because of the way the FDA staff worded the question that the Advisory Committee voted on, the panel not only was in favor of approving biosimilar licensure but also recommended that license for six of the seven diverse indications that Remicade currently has: treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease, and adult ulcerative colitis. The panel did not vote on licensing the biosimilar for treatment of pediatric ulcerative colitis because that specific indication for Remicade remains on patent for a few more years.

The broad range of indications for which the Committee recommended approval was notable because the formulation of biosimilar infliximab under review, manufactured by Celltrion and known in the United States as CT-P13, had been clinically studied only in patients with rheumatoid arthritis or ankylosing spondylitis. The other four recommended indications represented extrapolations, based on the totality of biosimilar evidence presented at the meeting by both Celltrion staffers and consultants as well as analyses presented by FDA staff members.

The overall thrust of the extrapolation issue was that if biosimilarity to Remicade was proven by a range of preclinical and clinical testing, and if safety and efficacy similar to Remicade was shown in trials that enrolled only patients with rheumatoid arthritis or ankylosing spondylitis, then the safety and efficacy previously proven for Remicade for the other indications could be reasonably extrapolated to apply to CT-P13 also, even though CT-P13 was never tested on patients with those conditions. This turned out to often be the key issue that panel members grappled with as they decided whether to vote in favor of the question the FDA asked them to address.

“Many of us are uncomfortable with this new pathway” of extrapolation, said panel member Dr. Beth L. Jonas, a rheumatologist at the University of North Carolina at Chapel Hill.

“I feel we’re taking a risk” with the extrapolations, said Dr. Mary E. Maloney, professor of medicine and chief of dermatology at the University of Massachusetts in Worcester. “We have a responsibility to take a risk to provide biosimilars to patients and to reduce their cost” for needed treatments, she said during the Committee’s discussion of their votes.

“Biosimilar is a new concept, but it’s the future of how we will look at drugs,” explained panel member Dr. Wilma Bergfeld, professor of dermatology at the Cleveland Clinic.

CT-P13 is currently marketed in many other countries worldwide under the brand names Remsima or Inflectra.

The FDA’s staff was clearly behind this application. After summarizing the agency’s internal analysis of the data submitted by Celltrion, Dr. Nikolay Nikolov, clinical team leader for the FDA’s Division of Pulmonary, Allergy and Rheumatology Products, concluded that “the totality of evidence provided by the applicant supports a conclusion that CT-P13 is biosimilar to U.S.-licensed Remicade,” and that “scientific justification for extrapolating the clinical data supports a finding of biosimilarity for all indications for which U.S.-licensed Remicade is licensed.” The FDA’s position makes it seem very likely that the agency will accept the Advisory Committee’s vote and grant CT-P13 license for U.S. marketing in the near future.

CT-P13 also received support during the public comment period of the Committee’s deliberations. At that time, Dr. Gideon P. Smith, a dermatologist at Massachusetts General Hospital in Boston spoke on behalf of the American Academy of Dermatology Association. “Biologics are some of the most important recent developments in treating plaque psoriasis, but cost is an important issue. We hope that biosimilars will decrease the cost of this treatment,” Dr. Smith said. “Infliximab is a complex molecule with a complex production process. We are concerned about the safety and efficacy of treatment. The AADA supports approval based on reducing cost and improving patient access. However, we strongly recommend caution through long-term postmarketing surveillance and using registry data to identify issues of immunogenicity, efficacy, and safety that were not seen in the clinical trials.”

The drug also received support from Dr. Angus B. Worthing, who represented the American College of Rheumatology. “Biosimilars may be the only tool to keep prices of biologics within reason,” said Dr. Worthing, a rheumatologist in Washington. But he also stressed that “extrapolation should be done with caution and not routinely granted.”

CT-P13 has the potential to make a fairly widely used biologic significantly more affordable. In countries where it has come onto the market, it’s been priced at roughly 30% below the prevailing cost of Remicade prior to this competition.

“Infliximab is an extremely important tool in our armamentarium for treatment of both ulcerative colitis and Crohn’s disease,” commented Dr. Stephen B. Hanauer, professor of gastroenterology and hepatology at Northwestern University in Chicago. “Biologic therapies account for an increasing proportion of health care costs for chronic diseases such as inflammatory bowel disease and reducing these costs will be important as increasing numbers of patients are benefiting from long-term biologic therapies. Having reviewed the extensive preclinical and clinical data with CT-P13, I am comfortable with potential substitution or switching as long as physicians are aware of the change and can track any potential reactions to the administered product,” he said in an interview.

“Infliximab is currently used by U.S. rheumatologists to treat certain patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. It is not the most-widely used tumor necrosis factor inhibitor, which is adalimumab, but it is often used. After FDA approval, biosimilar infliximab is anticipated to be priced lower than Remicade and that would likely increase use of infliximab for rheumatologic conditions,” said Dr. Jonathan Kay, a rheumatologist and professor of medicine at the University of Massachusetts in Worcester. “The clinical experience with CT-P13 in trials and in routine use in other countries show no significant loss of efficacy or any other major problem when changing patients from Remicade to CT-P13. All the data suggest that CT-P13 is highly similar to the reference product. It’s almost akin to comparing one lot of Remicade to another lot of Remicade. I personally would not have a problem initiating a patient on CT-P13 if infliximab was the appropriate drug to use,” Dr. Kay said in an interview.

Dr. Hanauer has been a consultant to Celltrion. Dr. Kay has been a consultant to several drug companies.

[email protected]

On Twitter @mitchelzoler

Bloom syndrome, also called congenital telangiectatic erythema and stunted growth, was first described by David Bloom in 1954.¹ It is a rare autosomal-recessive disorder (Online Mendelian Inheritance in Man 210900) characterized by specific clinical manifestations including photosensitivity, telangiectatic facial erythema, proportionate growth deficiency, hypogonadism, immunodeficiency, and a tendency to develop various malignancies.² Linkage analysis revealed that the Bloom syndrome gene locus resides on chromosome arm 15q26.1,³ and the BLM gene in this region has been identified as being responsible for the development of Bloom syndrome.^4,5 We report the case of a 12-year-old Chinese girl with Bloom syndrome and detected BLM gene. The evaluation was approved by the Institutional Ethical Review Boards of Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China).

Case Report

We evaluated a Bloom syndrome family, which consisted of the patient and her parents. The patient was a 12-year-old Chinese girl who was apparently healthy until 3 months of age when her parents noticed an erythematous eruption with blisters on the face. Exacerbation after exposure to sunlight is usual, which results in the eruption becoming prominent in summer and fainter in winter.² Gradually, the patient’s skin lesions became more progressive, extending to the forehead, nose, and ears, with oozing, crusting, atrophy, and telangiectases developing on the face despite treatment. In the last 3 years, no blisters were present on the patient’s face because of her efforts to avoid sun exposure. She had no history of recurrent infections.

On physical examination, the patient was generally healthy with normal intelligence and short stature. She weighed 26 kg and was approximately 122-cm tall. Telangiectatic erythema and slight scaling were noted on the face, which simulated lupus erythematosus (Figures 1A and 1B). She had additional abnormalities including alopecia areata (Figure 1C), eyebrow hair loss, flat nose, reticular pigmentation on the forehead and trunk, and finger swelling. The distal phalanges on all 10 fingers became short and sharpened and the fingernails became wider than they were long (Figure 1D). Laboratory investigations, including a complete blood cell count, liver and kidney function tests, stool examination, serum complement, and albumin and globulin levels, were within reference range.

After informed consent was obtained, a mutation analysis of the BLM gene was performed in the patient and her parents. We used a genomic DNA purification kit to extract genomic DNA from peripheral blood according to the manufacturer’s protocol. Genomic DNA was used to amplify the exons of the BLM gene with intron flanking sequences by polymerase chain reaction with the primer described elsewhere.⁶ After the amplification, the polymerase chain reaction products were purified and the BLM gene was sequenced. Sequence comparisons and analysis were performed using Phred/Phrap/Consed version 12.0.

The patient was found to carry changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A (Figure 2).

Comment

Patients with Bloom syndrome have a characteristic clinical appearance that typically includes photosensitivity, telangiectatic facial erythema, and growth deficiency. Telangiectatic erythema of the face develops during infancy or early childhood as red macules or plaques and may simulate lupus erythematosus. The lesions are described as a butterfly rash affecting the bridge of the nose and cheeks but also may involve the margins of the eyelids, forehead, ears, and sometimes the dorsa of the hands and forearms. Moderate and proportionate growth deficiencies develop both in utero and postnatally. Patients with Bloom syndrome characteristically have narrow, slender, distinct facial features with micrognathism and a relatively prominent nose. They usually may have mild microcephaly, meaning the head is longer and narrower than normal.^2,7-10

German and Takebe¹¹ reported 14 Japanese patients with Bloom syndrome. The phenotype differs somewhat from most cases recognized elsewhere in that dolichocephaly was a less constant feature, the facial skin was less prominent, and life-threatening infections were less common. Our patient had typical telangiectatic facial erythema without microcephaly, dolichocephaly, or any infections. She also had some uncommon manifestations such as alopecia areata, eyebrow hair loss, flat nose, reticular pigmentation, and short sharpened distal phalanges with fingernails that were wider than they were long. Although she had no recurrent infections and laboratory tests were within reference range, the alopecia areata and eyebrow hair loss may be associated with an abnormal immune response. The reasons for the short sharpened distal phalanges and the fingernail findings are unclear. The presence of reticular pigmentation also is unclear but may be associated with photosensitivity. Since the BLM gene was discovered to be the disease-causing gene of Bloom syndrome in 1995,^4,5 approximately 70 mutations were reported. The BLM gene encodes for the Bloom syndrome protein, a DNA helicase of the highly conserved RecQ subfamily of helicases, a group of nuclear proteins important in the maintenance of genomic stability.¹²

Mutation analysis of the BLM gene in our patient showed changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene, which altered proline residue with leucine residue at 868 and valine residue with isoleucine residue at 1321, respectively. According to GenBank,^13,14 c.2603C>T and c.3961G>A are single nucleotide polymorphisms of the BLM gene. The genotypic distribution of International HapMap Project¹⁵ showed that C=602/602 and T=0/602 on c.2603 in 301 unrelated Chinese patients and G=585/602 and A=17/602 on c.3961 in 301 unrelated Chinese patients. Because of the low prevalence of genotypes c.2603T and c.3961A in China, the relationship between clinical features and c.2603C>T and c.3961G>A of the BLM gene in our patient requires further study.

In conclusion, we report a patient with Bloom syndrome with uncommon clinical manifestations. Our findings indicate that c.2603C>T and c.3961G>A of the BLM gene may be the pathogenic nature for Bloom syndrome in China.

Acknowledgments

The authors would like to thank the patient and her family for their participation in the study. The authors also thank Li Qi, BA, Beijing, China, for his contribution to the review of the data in the literature.

Bloom syndrome, also called congenital telangiectatic erythema and stunted growth, was first described by David Bloom in 1954.¹ It is a rare autosomal-recessive disorder (Online Mendelian Inheritance in Man 210900) characterized by specific clinical manifestations including photosensitivity, telangiectatic facial erythema, proportionate growth deficiency, hypogonadism, immunodeficiency, and a tendency to develop various malignancies.² Linkage analysis revealed that the Bloom syndrome gene locus resides on chromosome arm 15q26.1,³ and the BLM gene in this region has been identified as being responsible for the development of Bloom syndrome.^4,5 We report the case of a 12-year-old Chinese girl with Bloom syndrome and detected BLM gene. The evaluation was approved by the Institutional Ethical Review Boards of Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China).

Case Report

We evaluated a Bloom syndrome family, which consisted of the patient and her parents. The patient was a 12-year-old Chinese girl who was apparently healthy until 3 months of age when her parents noticed an erythematous eruption with blisters on the face. Exacerbation after exposure to sunlight is usual, which results in the eruption becoming prominent in summer and fainter in winter.² Gradually, the patient’s skin lesions became more progressive, extending to the forehead, nose, and ears, with oozing, crusting, atrophy, and telangiectases developing on the face despite treatment. In the last 3 years, no blisters were present on the patient’s face because of her efforts to avoid sun exposure. She had no history of recurrent infections.

On physical examination, the patient was generally healthy with normal intelligence and short stature. She weighed 26 kg and was approximately 122-cm tall. Telangiectatic erythema and slight scaling were noted on the face, which simulated lupus erythematosus (Figures 1A and 1B). She had additional abnormalities including alopecia areata (Figure 1C), eyebrow hair loss, flat nose, reticular pigmentation on the forehead and trunk, and finger swelling. The distal phalanges on all 10 fingers became short and sharpened and the fingernails became wider than they were long (Figure 1D). Laboratory investigations, including a complete blood cell count, liver and kidney function tests, stool examination, serum complement, and albumin and globulin levels, were within reference range.

After informed consent was obtained, a mutation analysis of the BLM gene was performed in the patient and her parents. We used a genomic DNA purification kit to extract genomic DNA from peripheral blood according to the manufacturer’s protocol. Genomic DNA was used to amplify the exons of the BLM gene with intron flanking sequences by polymerase chain reaction with the primer described elsewhere.⁶ After the amplification, the polymerase chain reaction products were purified and the BLM gene was sequenced. Sequence comparisons and analysis were performed using Phred/Phrap/Consed version 12.0.

The patient was found to carry changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A (Figure 2).

Comment

Patients with Bloom syndrome have a characteristic clinical appearance that typically includes photosensitivity, telangiectatic facial erythema, and growth deficiency. Telangiectatic erythema of the face develops during infancy or early childhood as red macules or plaques and may simulate lupus erythematosus. The lesions are described as a butterfly rash affecting the bridge of the nose and cheeks but also may involve the margins of the eyelids, forehead, ears, and sometimes the dorsa of the hands and forearms. Moderate and proportionate growth deficiencies develop both in utero and postnatally. Patients with Bloom syndrome characteristically have narrow, slender, distinct facial features with micrognathism and a relatively prominent nose. They usually may have mild microcephaly, meaning the head is longer and narrower than normal.^2,7-10

German and Takebe¹¹ reported 14 Japanese patients with Bloom syndrome. The phenotype differs somewhat from most cases recognized elsewhere in that dolichocephaly was a less constant feature, the facial skin was less prominent, and life-threatening infections were less common. Our patient had typical telangiectatic facial erythema without microcephaly, dolichocephaly, or any infections. She also had some uncommon manifestations such as alopecia areata, eyebrow hair loss, flat nose, reticular pigmentation, and short sharpened distal phalanges with fingernails that were wider than they were long. Although she had no recurrent infections and laboratory tests were within reference range, the alopecia areata and eyebrow hair loss may be associated with an abnormal immune response. The reasons for the short sharpened distal phalanges and the fingernail findings are unclear. The presence of reticular pigmentation also is unclear but may be associated with photosensitivity. Since the BLM gene was discovered to be the disease-causing gene of Bloom syndrome in 1995,^4,5 approximately 70 mutations were reported. The BLM gene encodes for the Bloom syndrome protein, a DNA helicase of the highly conserved RecQ subfamily of helicases, a group of nuclear proteins important in the maintenance of genomic stability.¹²

Mutation analysis of the BLM gene in our patient showed changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene, which altered proline residue with leucine residue at 868 and valine residue with isoleucine residue at 1321, respectively. According to GenBank,^13,14 c.2603C>T and c.3961G>A are single nucleotide polymorphisms of the BLM gene. The genotypic distribution of International HapMap Project¹⁵ showed that C=602/602 and T=0/602 on c.2603 in 301 unrelated Chinese patients and G=585/602 and A=17/602 on c.3961 in 301 unrelated Chinese patients. Because of the low prevalence of genotypes c.2603T and c.3961A in China, the relationship between clinical features and c.2603C>T and c.3961G>A of the BLM gene in our patient requires further study.

In conclusion, we report a patient with Bloom syndrome with uncommon clinical manifestations. Our findings indicate that c.2603C>T and c.3961G>A of the BLM gene may be the pathogenic nature for Bloom syndrome in China.

Acknowledgments

The authors would like to thank the patient and her family for their participation in the study. The authors also thank Li Qi, BA, Beijing, China, for his contribution to the review of the data in the literature.

Bloom syndrome, also called congenital telangiectatic erythema and stunted growth, was first described by David Bloom in 1954.¹ It is a rare autosomal-recessive disorder (Online Mendelian Inheritance in Man 210900) characterized by specific clinical manifestations including photosensitivity, telangiectatic facial erythema, proportionate growth deficiency, hypogonadism, immunodeficiency, and a tendency to develop various malignancies.² Linkage analysis revealed that the Bloom syndrome gene locus resides on chromosome arm 15q26.1,³ and the BLM gene in this region has been identified as being responsible for the development of Bloom syndrome.^4,5 We report the case of a 12-year-old Chinese girl with Bloom syndrome and detected BLM gene. The evaluation was approved by the Institutional Ethical Review Boards of Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China).

Case Report

We evaluated a Bloom syndrome family, which consisted of the patient and her parents. The patient was a 12-year-old Chinese girl who was apparently healthy until 3 months of age when her parents noticed an erythematous eruption with blisters on the face. Exacerbation after exposure to sunlight is usual, which results in the eruption becoming prominent in summer and fainter in winter.² Gradually, the patient’s skin lesions became more progressive, extending to the forehead, nose, and ears, with oozing, crusting, atrophy, and telangiectases developing on the face despite treatment. In the last 3 years, no blisters were present on the patient’s face because of her efforts to avoid sun exposure. She had no history of recurrent infections.

On physical examination, the patient was generally healthy with normal intelligence and short stature. She weighed 26 kg and was approximately 122-cm tall. Telangiectatic erythema and slight scaling were noted on the face, which simulated lupus erythematosus (Figures 1A and 1B). She had additional abnormalities including alopecia areata (Figure 1C), eyebrow hair loss, flat nose, reticular pigmentation on the forehead and trunk, and finger swelling. The distal phalanges on all 10 fingers became short and sharpened and the fingernails became wider than they were long (Figure 1D). Laboratory investigations, including a complete blood cell count, liver and kidney function tests, stool examination, serum complement, and albumin and globulin levels, were within reference range.

After informed consent was obtained, a mutation analysis of the BLM gene was performed in the patient and her parents. We used a genomic DNA purification kit to extract genomic DNA from peripheral blood according to the manufacturer’s protocol. Genomic DNA was used to amplify the exons of the BLM gene with intron flanking sequences by polymerase chain reaction with the primer described elsewhere.⁶ After the amplification, the polymerase chain reaction products were purified and the BLM gene was sequenced. Sequence comparisons and analysis were performed using Phred/Phrap/Consed version 12.0.

The patient was found to carry changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene. The patient’s father was found to carry c.2603C>T and her mother carried c.3961G>A (Figure 2).

Comment

Patients with Bloom syndrome have a characteristic clinical appearance that typically includes photosensitivity, telangiectatic facial erythema, and growth deficiency. Telangiectatic erythema of the face develops during infancy or early childhood as red macules or plaques and may simulate lupus erythematosus. The lesions are described as a butterfly rash affecting the bridge of the nose and cheeks but also may involve the margins of the eyelids, forehead, ears, and sometimes the dorsa of the hands and forearms. Moderate and proportionate growth deficiencies develop both in utero and postnatally. Patients with Bloom syndrome characteristically have narrow, slender, distinct facial features with micrognathism and a relatively prominent nose. They usually may have mild microcephaly, meaning the head is longer and narrower than normal.^2,7-10

German and Takebe¹¹ reported 14 Japanese patients with Bloom syndrome. The phenotype differs somewhat from most cases recognized elsewhere in that dolichocephaly was a less constant feature, the facial skin was less prominent, and life-threatening infections were less common. Our patient had typical telangiectatic facial erythema without microcephaly, dolichocephaly, or any infections. She also had some uncommon manifestations such as alopecia areata, eyebrow hair loss, flat nose, reticular pigmentation, and short sharpened distal phalanges with fingernails that were wider than they were long. Although she had no recurrent infections and laboratory tests were within reference range, the alopecia areata and eyebrow hair loss may be associated with an abnormal immune response. The reasons for the short sharpened distal phalanges and the fingernail findings are unclear. The presence of reticular pigmentation also is unclear but may be associated with photosensitivity. Since the BLM gene was discovered to be the disease-causing gene of Bloom syndrome in 1995,^4,5 approximately 70 mutations were reported. The BLM gene encodes for the Bloom syndrome protein, a DNA helicase of the highly conserved RecQ subfamily of helicases, a group of nuclear proteins important in the maintenance of genomic stability.¹²

Mutation analysis of the BLM gene in our patient showed changes in 2 heterozygous nucleotide sites, including c.2603C>T in exon 13 and c.3961G>A in exon 21 of the BLM gene, which altered proline residue with leucine residue at 868 and valine residue with isoleucine residue at 1321, respectively. According to GenBank,^13,14 c.2603C>T and c.3961G>A are single nucleotide polymorphisms of the BLM gene. The genotypic distribution of International HapMap Project¹⁵ showed that C=602/602 and T=0/602 on c.2603 in 301 unrelated Chinese patients and G=585/602 and A=17/602 on c.3961 in 301 unrelated Chinese patients. Because of the low prevalence of genotypes c.2603T and c.3961A in China, the relationship between clinical features and c.2603C>T and c.3961G>A of the BLM gene in our patient requires further study.

In conclusion, we report a patient with Bloom syndrome with uncommon clinical manifestations. Our findings indicate that c.2603C>T and c.3961G>A of the BLM gene may be the pathogenic nature for Bloom syndrome in China.

Acknowledgments

The authors would like to thank the patient and her family for their participation in the study. The authors also thank Li Qi, BA, Beijing, China, for his contribution to the review of the data in the literature.

It is now common for patients to arrive in a physician office and never see the physician. Instead, patients are seen by so-called physician extenders. As our population ages, the need for medical care continues to grow beyond the capacity of the 900,000 US physicians that provide required services, particularly in the first level (primary care). The response to the physician shortage has entailed a variety of strategies. There has been a major immigration of foreign physicians, particularly from India; US medical schools have been encouraged to increase enrollment; and new medical schools have been inaugurated. Physicians have been pushed to adopt electronic medical records to permit increased throughput of patients in office practices. These multiple approaches have had an effect, though sometimes the results are undesirable. For example, complicated computer programs often detract from the physician-patient relationship.

One of the early solutions offered to deal with the doctor shortage in primary care was the concept of physician extenders (PEs), also called mid-level practitioners, who are professionals trained to take on a number of the simpler tasks performed by physicians. There are 2 basic classes of PEs: nurse practitioners and physician assistants. Nurse practitioners are originally trained to perform nursing but then undertake a course of study including scientific courses and clinical exposure to various parts of medicine. Physician assistants receive similar training. The duration of training for PEs usually is 18 to 24 months, whereas physicians attend medical school for 4 years. Unlike physicians, mid-level practitioners do not enter physician postgraduate residency training programs, which last many years.

The original concept was that PEs would work side by side with physicians who would supervise the care provided by the PEs. This team concept was designed to free physicians from the more mundane aspects of medical care and allow them to focus on the more challenging diagnostic and therapeutic issues presented by individual patients. In an era in which the burden of documentation has become increasingly onerous, the assistance of paraprofessionals can spare physicians the entry of redundant details in electronic databases that do not contribute to patient welfare.

However, research suggests that the concept of mid-level providers undertaking first-level care side by side with physicians has diverged from the original goal. An article by Coldiron and Ratnarathorn (JAMA Dermatol. 2014;150:1153-1159) studied Medicare billing data. The authors discovered that a variety of activities, many with higher reimbursement than primary care, were billed directly by PEs without apparent physician involvement, including a large number of complex invasive procedures, more than half in dermatology. Their article focused on dermatologic procedures, such as the destruction of skin cancers and advanced surgical repairs, but they listed many other procedures that are typically in the domain of highly trained physicians, including radiologic interpretations such as mammography and joint injections such as spinal injections. The data they presented were substantiated by publications in the medical literature suggesting that mid-level providers at certain hospitals even perform heart catheterizations and gastrointestinal endoscopies.

There have been no apologies for the unsupervised conduct of physician activities by nonphysicians. On the contrary, many PEs claim to be as well trained and proficient as medical doctors. Coldiron and Ratnarathorn argued otherwise. They pointed out that physicians receive an average of 10,000 hours of training compared to 2000 hours for mid-level practitioners, and they raised concerns about misdiagnoses, complications, and unnecessary procedures performed by PEs without supervision. In an editorial, Jalian and Avram (JAMA Dermatol. 2014;150:1149-1151) pointed out that a disproportionate number of cases of lawsuits for laser-induced injuries are related to performance by nonphysicians.

The pressures to allow nonphysicians to practice medicine independently are increasing. There is a shortage of physicians, especially in states such as Massachusetts that have substantial governmental limitation of physician reimbursement. In Massachusetts, regulations encourage mid-level practitioners to practice without physician supervision and even call themselves “doctors.” Furthermore, hospitals have faced residency funding cuts by Medicare and have had regulatory limitation of work hours by medical doctors in residency training. As a result, many institutions have turned to PEs to perform procedures that are typically performed by medical doctors.

Perhaps the greatest pressure favoring use of nonphysicians is financial. Mid-level practitioners receive lower salaries, typically 45% less, than medical doctors. In an era in which lowering costs has supplanted the goal of offering the best medical care possible, the attraction of replacement of a physician by a professional with less training becomes irresistible. It also is of concern that many physicians ignore the requirement to supervise the work of mid-level practitioners to maximize profit. Physicians often hire a mid-level provider rather than finding another physician to partner in their practice. Patients referred to a dermatologist often are seen by a PE and never even see the physician.

The concept of PEs working in a team with physicians remains an excellent approach to remedying the shortage of medical doctors, but we need to return to the original plan. Physician extenders should perform primary care rather than complex and lucrative subspecialties. There must be adequate supervision and definitely participation by physicians in rendering care.

All of the authors in the articles cited argue for greater regulation of unsupervised PEs to prevent performance of procedures where they lack expertise. Although the regulatory approach is sensible, it is more important to ensure that patients choose who gives them their medical care. They should not be obligated to see mid-level practitioners if they want to see a medical doctor. Above all, patients must be informed of the qualifications of those who provide their medical care. They should not be blindsided when they arrive for an appointment with their physician and find themselves shunted to a PE. We must not allow financial considerations to override the integrity of the medical care process.

What do you think is the optimal and safest role for PEs in a dermatology practice?

We want to know your views! Tell us what you think.

It is now common for patients to arrive in a physician office and never see the physician. Instead, patients are seen by so-called physician extenders. As our population ages, the need for medical care continues to grow beyond the capacity of the 900,000 US physicians that provide required services, particularly in the first level (primary care). The response to the physician shortage has entailed a variety of strategies. There has been a major immigration of foreign physicians, particularly from India; US medical schools have been encouraged to increase enrollment; and new medical schools have been inaugurated. Physicians have been pushed to adopt electronic medical records to permit increased throughput of patients in office practices. These multiple approaches have had an effect, though sometimes the results are undesirable. For example, complicated computer programs often detract from the physician-patient relationship.

One of the early solutions offered to deal with the doctor shortage in primary care was the concept of physician extenders (PEs), also called mid-level practitioners, who are professionals trained to take on a number of the simpler tasks performed by physicians. There are 2 basic classes of PEs: nurse practitioners and physician assistants. Nurse practitioners are originally trained to perform nursing but then undertake a course of study including scientific courses and clinical exposure to various parts of medicine. Physician assistants receive similar training. The duration of training for PEs usually is 18 to 24 months, whereas physicians attend medical school for 4 years. Unlike physicians, mid-level practitioners do not enter physician postgraduate residency training programs, which last many years.

The original concept was that PEs would work side by side with physicians who would supervise the care provided by the PEs. This team concept was designed to free physicians from the more mundane aspects of medical care and allow them to focus on the more challenging diagnostic and therapeutic issues presented by individual patients. In an era in which the burden of documentation has become increasingly onerous, the assistance of paraprofessionals can spare physicians the entry of redundant details in electronic databases that do not contribute to patient welfare.

However, research suggests that the concept of mid-level providers undertaking first-level care side by side with physicians has diverged from the original goal. An article by Coldiron and Ratnarathorn (JAMA Dermatol. 2014;150:1153-1159) studied Medicare billing data. The authors discovered that a variety of activities, many with higher reimbursement than primary care, were billed directly by PEs without apparent physician involvement, including a large number of complex invasive procedures, more than half in dermatology. Their article focused on dermatologic procedures, such as the destruction of skin cancers and advanced surgical repairs, but they listed many other procedures that are typically in the domain of highly trained physicians, including radiologic interpretations such as mammography and joint injections such as spinal injections. The data they presented were substantiated by publications in the medical literature suggesting that mid-level providers at certain hospitals even perform heart catheterizations and gastrointestinal endoscopies.

There have been no apologies for the unsupervised conduct of physician activities by nonphysicians. On the contrary, many PEs claim to be as well trained and proficient as medical doctors. Coldiron and Ratnarathorn argued otherwise. They pointed out that physicians receive an average of 10,000 hours of training compared to 2000 hours for mid-level practitioners, and they raised concerns about misdiagnoses, complications, and unnecessary procedures performed by PEs without supervision. In an editorial, Jalian and Avram (JAMA Dermatol. 2014;150:1149-1151) pointed out that a disproportionate number of cases of lawsuits for laser-induced injuries are related to performance by nonphysicians.

The pressures to allow nonphysicians to practice medicine independently are increasing. There is a shortage of physicians, especially in states such as Massachusetts that have substantial governmental limitation of physician reimbursement. In Massachusetts, regulations encourage mid-level practitioners to practice without physician supervision and even call themselves “doctors.” Furthermore, hospitals have faced residency funding cuts by Medicare and have had regulatory limitation of work hours by medical doctors in residency training. As a result, many institutions have turned to PEs to perform procedures that are typically performed by medical doctors.

Perhaps the greatest pressure favoring use of nonphysicians is financial. Mid-level practitioners receive lower salaries, typically 45% less, than medical doctors. In an era in which lowering costs has supplanted the goal of offering the best medical care possible, the attraction of replacement of a physician by a professional with less training becomes irresistible. It also is of concern that many physicians ignore the requirement to supervise the work of mid-level practitioners to maximize profit. Physicians often hire a mid-level provider rather than finding another physician to partner in their practice. Patients referred to a dermatologist often are seen by a PE and never even see the physician.

The concept of PEs working in a team with physicians remains an excellent approach to remedying the shortage of medical doctors, but we need to return to the original plan. Physician extenders should perform primary care rather than complex and lucrative subspecialties. There must be adequate supervision and definitely participation by physicians in rendering care.

All of the authors in the articles cited argue for greater regulation of unsupervised PEs to prevent performance of procedures where they lack expertise. Although the regulatory approach is sensible, it is more important to ensure that patients choose who gives them their medical care. They should not be obligated to see mid-level practitioners if they want to see a medical doctor. Above all, patients must be informed of the qualifications of those who provide their medical care. They should not be blindsided when they arrive for an appointment with their physician and find themselves shunted to a PE. We must not allow financial considerations to override the integrity of the medical care process.

What do you think is the optimal and safest role for PEs in a dermatology practice?

We want to know your views! Tell us what you think.

It is now common for patients to arrive in a physician office and never see the physician. Instead, patients are seen by so-called physician extenders. As our population ages, the need for medical care continues to grow beyond the capacity of the 900,000 US physicians that provide required services, particularly in the first level (primary care). The response to the physician shortage has entailed a variety of strategies. There has been a major immigration of foreign physicians, particularly from India; US medical schools have been encouraged to increase enrollment; and new medical schools have been inaugurated. Physicians have been pushed to adopt electronic medical records to permit increased throughput of patients in office practices. These multiple approaches have had an effect, though sometimes the results are undesirable. For example, complicated computer programs often detract from the physician-patient relationship.

One of the early solutions offered to deal with the doctor shortage in primary care was the concept of physician extenders (PEs), also called mid-level practitioners, who are professionals trained to take on a number of the simpler tasks performed by physicians. There are 2 basic classes of PEs: nurse practitioners and physician assistants. Nurse practitioners are originally trained to perform nursing but then undertake a course of study including scientific courses and clinical exposure to various parts of medicine. Physician assistants receive similar training. The duration of training for PEs usually is 18 to 24 months, whereas physicians attend medical school for 4 years. Unlike physicians, mid-level practitioners do not enter physician postgraduate residency training programs, which last many years.

The original concept was that PEs would work side by side with physicians who would supervise the care provided by the PEs. This team concept was designed to free physicians from the more mundane aspects of medical care and allow them to focus on the more challenging diagnostic and therapeutic issues presented by individual patients. In an era in which the burden of documentation has become increasingly onerous, the assistance of paraprofessionals can spare physicians the entry of redundant details in electronic databases that do not contribute to patient welfare.

However, research suggests that the concept of mid-level providers undertaking first-level care side by side with physicians has diverged from the original goal. An article by Coldiron and Ratnarathorn (JAMA Dermatol. 2014;150:1153-1159) studied Medicare billing data. The authors discovered that a variety of activities, many with higher reimbursement than primary care, were billed directly by PEs without apparent physician involvement, including a large number of complex invasive procedures, more than half in dermatology. Their article focused on dermatologic procedures, such as the destruction of skin cancers and advanced surgical repairs, but they listed many other procedures that are typically in the domain of highly trained physicians, including radiologic interpretations such as mammography and joint injections such as spinal injections. The data they presented were substantiated by publications in the medical literature suggesting that mid-level providers at certain hospitals even perform heart catheterizations and gastrointestinal endoscopies.

There have been no apologies for the unsupervised conduct of physician activities by nonphysicians. On the contrary, many PEs claim to be as well trained and proficient as medical doctors. Coldiron and Ratnarathorn argued otherwise. They pointed out that physicians receive an average of 10,000 hours of training compared to 2000 hours for mid-level practitioners, and they raised concerns about misdiagnoses, complications, and unnecessary procedures performed by PEs without supervision. In an editorial, Jalian and Avram (JAMA Dermatol. 2014;150:1149-1151) pointed out that a disproportionate number of cases of lawsuits for laser-induced injuries are related to performance by nonphysicians.

The pressures to allow nonphysicians to practice medicine independently are increasing. There is a shortage of physicians, especially in states such as Massachusetts that have substantial governmental limitation of physician reimbursement. In Massachusetts, regulations encourage mid-level practitioners to practice without physician supervision and even call themselves “doctors.” Furthermore, hospitals have faced residency funding cuts by Medicare and have had regulatory limitation of work hours by medical doctors in residency training. As a result, many institutions have turned to PEs to perform procedures that are typically performed by medical doctors.

Perhaps the greatest pressure favoring use of nonphysicians is financial. Mid-level practitioners receive lower salaries, typically 45% less, than medical doctors. In an era in which lowering costs has supplanted the goal of offering the best medical care possible, the attraction of replacement of a physician by a professional with less training becomes irresistible. It also is of concern that many physicians ignore the requirement to supervise the work of mid-level practitioners to maximize profit. Physicians often hire a mid-level provider rather than finding another physician to partner in their practice. Patients referred to a dermatologist often are seen by a PE and never even see the physician.

The concept of PEs working in a team with physicians remains an excellent approach to remedying the shortage of medical doctors, but we need to return to the original plan. Physician extenders should perform primary care rather than complex and lucrative subspecialties. There must be adequate supervision and definitely participation by physicians in rendering care.

All of the authors in the articles cited argue for greater regulation of unsupervised PEs to prevent performance of procedures where they lack expertise. Although the regulatory approach is sensible, it is more important to ensure that patients choose who gives them their medical care. They should not be obligated to see mid-level practitioners if they want to see a medical doctor. Above all, patients must be informed of the qualifications of those who provide their medical care. They should not be blindsided when they arrive for an appointment with their physician and find themselves shunted to a PE. We must not allow financial considerations to override the integrity of the medical care process.

What do you think is the optimal and safest role for PEs in a dermatology practice?

We want to know your views! Tell us what you think.

I’ve previously written about how my secretary took 8 weeks off for maternity leave. Well, she’s back now, and brought a new staff member with her.

I know several doctors who are horrified that I let her bring the baby to work every day. They tell me it’s unprofessional, a distraction, inconvenient, etc.

Me? I think it’s great.

I have no problem with her being here. If anything, she adds an upbeat vibe to the office. Seeing an adorable newborn up front cheers all comers. She’s quickly become the most popular person here. Nowadays, when I call someone back from the lobby, they jokingly protest and say, but “I’m looking at the baby!” At this point, we’ve even had people coming by just to see her, once word spread there was a baby at my office.

Is it unprofessional? Maybe by someone else’s standards, but not mine. At this stage of life, she’s certainly not in the way. She’s (generally) quiet, sweet, and smiley. Besides, having her here spares my secretary the expense of child care and makes her happy. If keeping your staff happy isn’t part of being professional, I don’t know what is.

Is she a distraction? Perhaps, but not in a bad way. Maybe I take a few seconds here and there to wave at her or help my secretary with something, but nothing that compromises patient care.

Courtesy Dr. Allan M. Block

Is it inconvenient to have her here? Nope. We have an extra exam room, so it’s easy for my secretary to have a quiet, private place to feed and change her every few hours. If the phones go to voice mail for a few minutes, or I have to keep an ear out for the front door opening, I don’t mind.

She and I both have young families. When we were looking for a new office 3 years ago, one of our requirements was what we called “the sick kid room.” An extra space where, if a kid couldn’t go to school, we wouldn’t be stuck trying to figure out what to do. They’ve always been welcome here, and always will be.

Having kids on site isn’t perfect for every practice. Certainly, a pediatrics office (with a lot more sick kids going in and out) wouldn’t be ideal. But at my place the young lady has brightened things up for all and makes the day more fun.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’ve previously written about how my secretary took 8 weeks off for maternity leave. Well, she’s back now, and brought a new staff member with her.

I know several doctors who are horrified that I let her bring the baby to work every day. They tell me it’s unprofessional, a distraction, inconvenient, etc.

Me? I think it’s great.

I have no problem with her being here. If anything, she adds an upbeat vibe to the office. Seeing an adorable newborn up front cheers all comers. She’s quickly become the most popular person here. Nowadays, when I call someone back from the lobby, they jokingly protest and say, but “I’m looking at the baby!” At this point, we’ve even had people coming by just to see her, once word spread there was a baby at my office.

Is it unprofessional? Maybe by someone else’s standards, but not mine. At this stage of life, she’s certainly not in the way. She’s (generally) quiet, sweet, and smiley. Besides, having her here spares my secretary the expense of child care and makes her happy. If keeping your staff happy isn’t part of being professional, I don’t know what is.

Is she a distraction? Perhaps, but not in a bad way. Maybe I take a few seconds here and there to wave at her or help my secretary with something, but nothing that compromises patient care.

Courtesy Dr. Allan M. Block

Is it inconvenient to have her here? Nope. We have an extra exam room, so it’s easy for my secretary to have a quiet, private place to feed and change her every few hours. If the phones go to voice mail for a few minutes, or I have to keep an ear out for the front door opening, I don’t mind.

She and I both have young families. When we were looking for a new office 3 years ago, one of our requirements was what we called “the sick kid room.” An extra space where, if a kid couldn’t go to school, we wouldn’t be stuck trying to figure out what to do. They’ve always been welcome here, and always will be.

Having kids on site isn’t perfect for every practice. Certainly, a pediatrics office (with a lot more sick kids going in and out) wouldn’t be ideal. But at my place the young lady has brightened things up for all and makes the day more fun.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’ve previously written about how my secretary took 8 weeks off for maternity leave. Well, she’s back now, and brought a new staff member with her.

I know several doctors who are horrified that I let her bring the baby to work every day. They tell me it’s unprofessional, a distraction, inconvenient, etc.

Me? I think it’s great.

I have no problem with her being here. If anything, she adds an upbeat vibe to the office. Seeing an adorable newborn up front cheers all comers. She’s quickly become the most popular person here. Nowadays, when I call someone back from the lobby, they jokingly protest and say, but “I’m looking at the baby!” At this point, we’ve even had people coming by just to see her, once word spread there was a baby at my office.

Is it unprofessional? Maybe by someone else’s standards, but not mine. At this stage of life, she’s certainly not in the way. She’s (generally) quiet, sweet, and smiley. Besides, having her here spares my secretary the expense of child care and makes her happy. If keeping your staff happy isn’t part of being professional, I don’t know what is.

Is she a distraction? Perhaps, but not in a bad way. Maybe I take a few seconds here and there to wave at her or help my secretary with something, but nothing that compromises patient care.

Courtesy Dr. Allan M. Block

Is it inconvenient to have her here? Nope. We have an extra exam room, so it’s easy for my secretary to have a quiet, private place to feed and change her every few hours. If the phones go to voice mail for a few minutes, or I have to keep an ear out for the front door opening, I don’t mind.

She and I both have young families. When we were looking for a new office 3 years ago, one of our requirements was what we called “the sick kid room.” An extra space where, if a kid couldn’t go to school, we wouldn’t be stuck trying to figure out what to do. They’ve always been welcome here, and always will be.

Having kids on site isn’t perfect for every practice. Certainly, a pediatrics office (with a lot more sick kids going in and out) wouldn’t be ideal. But at my place the young lady has brightened things up for all and makes the day more fun.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Defibrotide improved survival at 100 days after hematopoietic stem cell transplantation (HSCT) in patients with hepatic veno-occlusive disease, based on an open-label trial that compared trial participants with historical controls.

Of the 102 patients in the defibrotide group, 39 were alive 100 days after HSCT (38.2%), compared with 8 of 32 (25.0%) in the historical control group. The propensity-adjusted, between-group difference was 23.0% (95.1% confidence interval, 5.2%-40.8%; P = .0109). At 180 days post-HSCT, the difference in survival between the groups was not significant (Blood. 2016 Feb 3. doi: 10.1182/blood-2015-10-676924).

Patrice Wendling/Frontline Medical News

Defibrotide has Fast Track designation from the FDA and the new drug application is currently under Priority Review with a decision expected by March 31, 2016. A potentially fatal complication of HSCT, hepatic veno-occlusive disease is characterized by hepatomegaly, jaundice, rapid weight gain, fluid retention, and ascites. There are no approved therapies.

“In this context, defibrotide provides a promising treatment option for patients with a high unmet medical need,” wrote Dr. Paul G. Richardson of Dana-Farber Cancer Institute in Boston and his colleagues.

At day 100 post-HSCT, complete response was seen in 25.5% of the defibrotide group and in 12.5% of the historical control group. The propensity-adjusted, between-group difference was 19% (95.1% CI, 3.5-34.6%; P = .0160). The complete response was durable in 22 of the 26 patients. In the control group, complete response was limited in two patients, impossible to assess in one patient, and durable in one patient.

The multicenter, open-label, phase III trial prospectively enrolled 102 patients with hepatic veno-occlusive disease from 2006 to 2008. Defibrotide was administered intravenously at 25 mg/kg/day in 4 divided doses for a minimum of 21 days. Treatment continued beyond 21 days until resolution of veno-occlusive disease or until the patient was discharged from the hospital.

To identify the historical controls, 6,867 medical charts of HSCT patients hospitalized from 1995 to 2007 were reviewed, and 32 historical control patients were selected. Most (21 of 32) were diagnosed with during 2000-2006, and 11 were diagnosed before 2000. The historical controls were selected by an independent medical review committee, and met the same entry criteria as the defibrotide group.

Because recruiting for the defibrotide group and screening for historical controls occurred at the same institutions during similar time periods, patient management and supportive care were likely similar for the two groups. Propensity scores were included in the analysis to adjust for prognostic factors that were unbalanced between treatment and control groups, including ventilator and dialysis dependency at study entry, age greater or less than 16 years, prior HSCT (0 vs. 1), and allogeneic or autologous transplant.

Hypotension was the most common adverse event reported in the defibrotide and control groups (39% and 50%, respectively), followed by diarrhea (23.5% and 37.5%, respectively). The defibrotide and control groups had similar incidences of common hemorrhagic adverse events (64% and 75%, respectively). Fatal adverse events occurred in 64% of the defibrotide group and 69% of the control group, and fatal hemorrhagic events occurred in 14.7% of the defibrotide group and 6.3% of the control group.

Approved by the European Union, defibrotide is a single-stranded, deoxyribonucleic acid derivative that stabilizes damaged endothelial cells and prevents further endothelial cell damage.

Dr. Richardson reported consulting or advisory roles with Gentium/Jazz Pharmaceuticals, the maker of defibrotide.

Defibrotide improved survival at 100 days after hematopoietic stem cell transplantation (HSCT) in patients with hepatic veno-occlusive disease, based on an open-label trial that compared trial participants with historical controls.

Of the 102 patients in the defibrotide group, 39 were alive 100 days after HSCT (38.2%), compared with 8 of 32 (25.0%) in the historical control group. The propensity-adjusted, between-group difference was 23.0% (95.1% confidence interval, 5.2%-40.8%; P = .0109). At 180 days post-HSCT, the difference in survival between the groups was not significant (Blood. 2016 Feb 3. doi: 10.1182/blood-2015-10-676924).

Patrice Wendling/Frontline Medical News

Defibrotide has Fast Track designation from the FDA and the new drug application is currently under Priority Review with a decision expected by March 31, 2016. A potentially fatal complication of HSCT, hepatic veno-occlusive disease is characterized by hepatomegaly, jaundice, rapid weight gain, fluid retention, and ascites. There are no approved therapies.

“In this context, defibrotide provides a promising treatment option for patients with a high unmet medical need,” wrote Dr. Paul G. Richardson of Dana-Farber Cancer Institute in Boston and his colleagues.

At day 100 post-HSCT, complete response was seen in 25.5% of the defibrotide group and in 12.5% of the historical control group. The propensity-adjusted, between-group difference was 19% (95.1% CI, 3.5-34.6%; P = .0160). The complete response was durable in 22 of the 26 patients. In the control group, complete response was limited in two patients, impossible to assess in one patient, and durable in one patient.

The multicenter, open-label, phase III trial prospectively enrolled 102 patients with hepatic veno-occlusive disease from 2006 to 2008. Defibrotide was administered intravenously at 25 mg/kg/day in 4 divided doses for a minimum of 21 days. Treatment continued beyond 21 days until resolution of veno-occlusive disease or until the patient was discharged from the hospital.

To identify the historical controls, 6,867 medical charts of HSCT patients hospitalized from 1995 to 2007 were reviewed, and 32 historical control patients were selected. Most (21 of 32) were diagnosed with during 2000-2006, and 11 were diagnosed before 2000. The historical controls were selected by an independent medical review committee, and met the same entry criteria as the defibrotide group.

Because recruiting for the defibrotide group and screening for historical controls occurred at the same institutions during similar time periods, patient management and supportive care were likely similar for the two groups. Propensity scores were included in the analysis to adjust for prognostic factors that were unbalanced between treatment and control groups, including ventilator and dialysis dependency at study entry, age greater or less than 16 years, prior HSCT (0 vs. 1), and allogeneic or autologous transplant.

Hypotension was the most common adverse event reported in the defibrotide and control groups (39% and 50%, respectively), followed by diarrhea (23.5% and 37.5%, respectively). The defibrotide and control groups had similar incidences of common hemorrhagic adverse events (64% and 75%, respectively). Fatal adverse events occurred in 64% of the defibrotide group and 69% of the control group, and fatal hemorrhagic events occurred in 14.7% of the defibrotide group and 6.3% of the control group.

Approved by the European Union, defibrotide is a single-stranded, deoxyribonucleic acid derivative that stabilizes damaged endothelial cells and prevents further endothelial cell damage.

Dr. Richardson reported consulting or advisory roles with Gentium/Jazz Pharmaceuticals, the maker of defibrotide.

Defibrotide improved survival at 100 days after hematopoietic stem cell transplantation (HSCT) in patients with hepatic veno-occlusive disease, based on an open-label trial that compared trial participants with historical controls.

Of the 102 patients in the defibrotide group, 39 were alive 100 days after HSCT (38.2%), compared with 8 of 32 (25.0%) in the historical control group. The propensity-adjusted, between-group difference was 23.0% (95.1% confidence interval, 5.2%-40.8%; P = .0109). At 180 days post-HSCT, the difference in survival between the groups was not significant (Blood. 2016 Feb 3. doi: 10.1182/blood-2015-10-676924).

Patrice Wendling/Frontline Medical News

Defibrotide has Fast Track designation from the FDA and the new drug application is currently under Priority Review with a decision expected by March 31, 2016. A potentially fatal complication of HSCT, hepatic veno-occlusive disease is characterized by hepatomegaly, jaundice, rapid weight gain, fluid retention, and ascites. There are no approved therapies.

“In this context, defibrotide provides a promising treatment option for patients with a high unmet medical need,” wrote Dr. Paul G. Richardson of Dana-Farber Cancer Institute in Boston and his colleagues.

At day 100 post-HSCT, complete response was seen in 25.5% of the defibrotide group and in 12.5% of the historical control group. The propensity-adjusted, between-group difference was 19% (95.1% CI, 3.5-34.6%; P = .0160). The complete response was durable in 22 of the 26 patients. In the control group, complete response was limited in two patients, impossible to assess in one patient, and durable in one patient.

The multicenter, open-label, phase III trial prospectively enrolled 102 patients with hepatic veno-occlusive disease from 2006 to 2008. Defibrotide was administered intravenously at 25 mg/kg/day in 4 divided doses for a minimum of 21 days. Treatment continued beyond 21 days until resolution of veno-occlusive disease or until the patient was discharged from the hospital.

To identify the historical controls, 6,867 medical charts of HSCT patients hospitalized from 1995 to 2007 were reviewed, and 32 historical control patients were selected. Most (21 of 32) were diagnosed with during 2000-2006, and 11 were diagnosed before 2000. The historical controls were selected by an independent medical review committee, and met the same entry criteria as the defibrotide group.

Because recruiting for the defibrotide group and screening for historical controls occurred at the same institutions during similar time periods, patient management and supportive care were likely similar for the two groups. Propensity scores were included in the analysis to adjust for prognostic factors that were unbalanced between treatment and control groups, including ventilator and dialysis dependency at study entry, age greater or less than 16 years, prior HSCT (0 vs. 1), and allogeneic or autologous transplant.

Hypotension was the most common adverse event reported in the defibrotide and control groups (39% and 50%, respectively), followed by diarrhea (23.5% and 37.5%, respectively). The defibrotide and control groups had similar incidences of common hemorrhagic adverse events (64% and 75%, respectively). Fatal adverse events occurred in 64% of the defibrotide group and 69% of the control group, and fatal hemorrhagic events occurred in 14.7% of the defibrotide group and 6.3% of the control group.

Approved by the European Union, defibrotide is a single-stranded, deoxyribonucleic acid derivative that stabilizes damaged endothelial cells and prevents further endothelial cell damage.

Dr. Richardson reported consulting or advisory roles with Gentium/Jazz Pharmaceuticals, the maker of defibrotide.

SNOWMASS, COLO. – All four Food and Drug Administration–approved novel oral anticoagulants offer impressive safety advantages over the traditional strategy of low-molecular-weight heparin bridging to warfarin for treatment of acute venous thromboembolism, Dr. Patrick T. O’Gara observed at the Annual Cardiovascular Conference at Snowmass.

He highlighted a European analysis of six phase III clinical trials totaling more than 27,000 patients with venous thromboembolism (VTE) in which dabigatran (Pradaxa), rivaroxaban(Xarelto), apixaban (Eliquis), or edoxaban (Savaysa) was compared to the traditional strategy of unfractionated or low-molecular-weight heparin (LMWH) bridging to warfarin or another vitamin K antagonist. All four NOACs proved statistically noninferior to the traditional strategy in terms of efficacy as defined by prevention of recurrent VTE. Efficacy of NOACs and warfarin was similar regardless of body weight, chronic kidney disease, age, cancer, and pulmonary embolism versus deep venous thrombosis.

In terms of safety, it was no contest: The NOACs were collectively associated with a 39% lower risk of major bleeding, a 64% lower risk of fatal bleeding, and a 63% reduction in intracranial bleeding compared to LMWH/warfarin (Blood 2014 Sep 18;124[12]:1968-75).

“This is a big-ticket winner for the novel oral anticoagulants in the longer-term management of patients who have venous thromboembolic disease – not inferior to a strategy of low-molecular-weight heparin bridging to warfarin and much better with respect to serious consequences of a safety nature,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.

The pivotal trials for NOACs in VTE were generally structured statistically as noninferiority trials, with one exception: edoxaban has been shown to be superior to warfarin in a prespecified subgroup with submassive pulmonary embolism.

Further strengthening the case for routine use of NOACs in treating acute VTE is the emergence of fast-acting antidotes to the drugs in the event a patient develops a bleeding complication. Idarucizumab (Praxbind) received FDA approval last October as a reversal agent for dabigatran. Many experts think andexanet alpha will likely receive regulatory approval later this year as a universal antidote to all the factor Xa inhibitors, he noted.

It’s estimated that 70% of patients with pulmonary embolism can be classified as low risk and thus eligible for consideration for early hospital discharge and home treatment, provided their social situation is suitable. Pulmonary embolism patients are categorized as low risk if they are hemodynamically stable, don’t require supplemental oxygen, don’t show right ventricular dilatation on CT imaging in the emergency department, and lack serum biomarker evidence of right ventricular strain or injury.

In making decisions about outpatient therapy for VTE, a point worth considering is that two NOACs, rivaroxaban and apixaban, possess the practical advantage of being single-agent therapy. That is, they don’t require a heparin bridge prior to their introduction, as established in the EINSTEIN trial for rivaroxaban and in the AMPLIFY study for apixaban. However, a loading dose is necessary. Rivaroxaban is given at 15 mg b.i.d. for 3 weeks before dropping down to 20 mg once daily. Apixaban has a loading dose of 10 mg b.i.d. for the first 7 days followed by 5 mg b.i.d. thereafter.

“You’ll note that you give a higher loading dose for these particular agents for events that occur on the venous side of the circulation compared with the management of patients who have nonvalvular atrial fibrillation,” Dr. O’Gara said.

In contrast, both dabigatran and edoxaban require either unfractionated or LMWH as bridge before switching to oral therapy.

Dr. O’Gara reported having no financial conflicts of interest regarding his presentation.

[email protected]

SNOWMASS, COLO. – All four Food and Drug Administration–approved novel oral anticoagulants offer impressive safety advantages over the traditional strategy of low-molecular-weight heparin bridging to warfarin for treatment of acute venous thromboembolism, Dr. Patrick T. O’Gara observed at the Annual Cardiovascular Conference at Snowmass.

He highlighted a European analysis of six phase III clinical trials totaling more than 27,000 patients with venous thromboembolism (VTE) in which dabigatran (Pradaxa), rivaroxaban(Xarelto), apixaban (Eliquis), or edoxaban (Savaysa) was compared to the traditional strategy of unfractionated or low-molecular-weight heparin (LMWH) bridging to warfarin or another vitamin K antagonist. All four NOACs proved statistically noninferior to the traditional strategy in terms of efficacy as defined by prevention of recurrent VTE. Efficacy of NOACs and warfarin was similar regardless of body weight, chronic kidney disease, age, cancer, and pulmonary embolism versus deep venous thrombosis.

In terms of safety, it was no contest: The NOACs were collectively associated with a 39% lower risk of major bleeding, a 64% lower risk of fatal bleeding, and a 63% reduction in intracranial bleeding compared to LMWH/warfarin (Blood 2014 Sep 18;124[12]:1968-75).

“This is a big-ticket winner for the novel oral anticoagulants in the longer-term management of patients who have venous thromboembolic disease – not inferior to a strategy of low-molecular-weight heparin bridging to warfarin and much better with respect to serious consequences of a safety nature,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.

The pivotal trials for NOACs in VTE were generally structured statistically as noninferiority trials, with one exception: edoxaban has been shown to be superior to warfarin in a prespecified subgroup with submassive pulmonary embolism.

Further strengthening the case for routine use of NOACs in treating acute VTE is the emergence of fast-acting antidotes to the drugs in the event a patient develops a bleeding complication. Idarucizumab (Praxbind) received FDA approval last October as a reversal agent for dabigatran. Many experts think andexanet alpha will likely receive regulatory approval later this year as a universal antidote to all the factor Xa inhibitors, he noted.

It’s estimated that 70% of patients with pulmonary embolism can be classified as low risk and thus eligible for consideration for early hospital discharge and home treatment, provided their social situation is suitable. Pulmonary embolism patients are categorized as low risk if they are hemodynamically stable, don’t require supplemental oxygen, don’t show right ventricular dilatation on CT imaging in the emergency department, and lack serum biomarker evidence of right ventricular strain or injury.

In making decisions about outpatient therapy for VTE, a point worth considering is that two NOACs, rivaroxaban and apixaban, possess the practical advantage of being single-agent therapy. That is, they don’t require a heparin bridge prior to their introduction, as established in the EINSTEIN trial for rivaroxaban and in the AMPLIFY study for apixaban. However, a loading dose is necessary. Rivaroxaban is given at 15 mg b.i.d. for 3 weeks before dropping down to 20 mg once daily. Apixaban has a loading dose of 10 mg b.i.d. for the first 7 days followed by 5 mg b.i.d. thereafter.

“You’ll note that you give a higher loading dose for these particular agents for events that occur on the venous side of the circulation compared with the management of patients who have nonvalvular atrial fibrillation,” Dr. O’Gara said.

In contrast, both dabigatran and edoxaban require either unfractionated or LMWH as bridge before switching to oral therapy.

Dr. O’Gara reported having no financial conflicts of interest regarding his presentation.

[email protected]

SNOWMASS, COLO. – All four Food and Drug Administration–approved novel oral anticoagulants offer impressive safety advantages over the traditional strategy of low-molecular-weight heparin bridging to warfarin for treatment of acute venous thromboembolism, Dr. Patrick T. O’Gara observed at the Annual Cardiovascular Conference at Snowmass.

He highlighted a European analysis of six phase III clinical trials totaling more than 27,000 patients with venous thromboembolism (VTE) in which dabigatran (Pradaxa), rivaroxaban(Xarelto), apixaban (Eliquis), or edoxaban (Savaysa) was compared to the traditional strategy of unfractionated or low-molecular-weight heparin (LMWH) bridging to warfarin or another vitamin K antagonist. All four NOACs proved statistically noninferior to the traditional strategy in terms of efficacy as defined by prevention of recurrent VTE. Efficacy of NOACs and warfarin was similar regardless of body weight, chronic kidney disease, age, cancer, and pulmonary embolism versus deep venous thrombosis.

In terms of safety, it was no contest: The NOACs were collectively associated with a 39% lower risk of major bleeding, a 64% lower risk of fatal bleeding, and a 63% reduction in intracranial bleeding compared to LMWH/warfarin (Blood 2014 Sep 18;124[12]:1968-75).

“This is a big-ticket winner for the novel oral anticoagulants in the longer-term management of patients who have venous thromboembolic disease – not inferior to a strategy of low-molecular-weight heparin bridging to warfarin and much better with respect to serious consequences of a safety nature,” said Dr. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, Boston.

The pivotal trials for NOACs in VTE were generally structured statistically as noninferiority trials, with one exception: edoxaban has been shown to be superior to warfarin in a prespecified subgroup with submassive pulmonary embolism.

Further strengthening the case for routine use of NOACs in treating acute VTE is the emergence of fast-acting antidotes to the drugs in the event a patient develops a bleeding complication. Idarucizumab (Praxbind) received FDA approval last October as a reversal agent for dabigatran. Many experts think andexanet alpha will likely receive regulatory approval later this year as a universal antidote to all the factor Xa inhibitors, he noted.

It’s estimated that 70% of patients with pulmonary embolism can be classified as low risk and thus eligible for consideration for early hospital discharge and home treatment, provided their social situation is suitable. Pulmonary embolism patients are categorized as low risk if they are hemodynamically stable, don’t require supplemental oxygen, don’t show right ventricular dilatation on CT imaging in the emergency department, and lack serum biomarker evidence of right ventricular strain or injury.

In making decisions about outpatient therapy for VTE, a point worth considering is that two NOACs, rivaroxaban and apixaban, possess the practical advantage of being single-agent therapy. That is, they don’t require a heparin bridge prior to their introduction, as established in the EINSTEIN trial for rivaroxaban and in the AMPLIFY study for apixaban. However, a loading dose is necessary. Rivaroxaban is given at 15 mg b.i.d. for 3 weeks before dropping down to 20 mg once daily. Apixaban has a loading dose of 10 mg b.i.d. for the first 7 days followed by 5 mg b.i.d. thereafter.

“You’ll note that you give a higher loading dose for these particular agents for events that occur on the venous side of the circulation compared with the management of patients who have nonvalvular atrial fibrillation,” Dr. O’Gara said.

In contrast, both dabigatran and edoxaban require either unfractionated or LMWH as bridge before switching to oral therapy.

Dr. O’Gara reported having no financial conflicts of interest regarding his presentation.

[email protected]