Man spraying pesticide

in his garden

Researchers have linked residential pesticide exposure to childhood cancers, but the estimated risks vary according to the cancer type, the type of pesticide, and where it is applied.

The investigators conducted a meta-analysis of published studies and found that childhood exposure to indoor pesticides was associated with a

significantly increased risk of all the cancers analyzed, as well as leukemia and lymphoma individually.

Overall, exposure to outdoor pesticides was not associated with an increased risk of childhood cancers. However, herbicide exposure was linked to an increased risk of leukemia and all cancers combined.

Mei Chen, PhD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and colleagues conducted this meta-analysis and reported the results in Pediatrics.

The team searched for observational studies published in PubMed before February 2014 and ultimately included 16 studies in their analysis.

They assessed exposure to indoor pesticides and indoor insecticides (a subgroup of indoor pesticides), as well as exposure to outdoor pesticides, which included outdoor insecticides, herbicides, and fungicides.

The cancer types analyzed were leukemia, lymphoma, brain tumors, neuroblastoma, Wilms tumor, and soft tissue sarcoma.

Indoor pesticides

When the investigators analyzed all cancer types together, they found a significantly increased risk of childhood cancers associated with exposure to indoor pesticides (odds ratio [OR]=1.40).

Likewise, there was a significantly increased risk for leukemia (OR=1.48), acute leukemia (OR=1.59), lymphoma (OR=1.43), and all hematopoietic malignancies (leukemias and lymphomas, OR=1.47).

But the increased risk of childhood brain tumors was not statistically significant, and the other cancers were not analyzed separately.

Exposure to indoor insecticides was associated with a significant increase in the risk of leukemia (OR=1.47), acute leukemia (OR=1.59), lymphoma (OR=1.43), and all hematopoietic malignancies (OR=1.46).

Outdoor pesticides

There was no significant association between exposure to outdoor pesticides or outdoor insecticides and any of the cancer types. And there were not enough studies on fungicides to assess the risk of cancers associated with their use.

However, there was a significant association between exposure to herbicide and all childhood cancers (OR=1.35) as well as leukemia (OR=1.26).

The investigators said these results suggest cancer risks are related to the type of pesticides used and where they are applied.

And although additional research is needed to confirm the association between pesticide exposure and childhood cancers, steps should be taken to limit exposure to pesticides during childhood.

Man spraying pesticide

in his garden

Researchers have linked residential pesticide exposure to childhood cancers, but the estimated risks vary according to the cancer type, the type of pesticide, and where it is applied.

The investigators conducted a meta-analysis of published studies and found that childhood exposure to indoor pesticides was associated with a

significantly increased risk of all the cancers analyzed, as well as leukemia and lymphoma individually.

Overall, exposure to outdoor pesticides was not associated with an increased risk of childhood cancers. However, herbicide exposure was linked to an increased risk of leukemia and all cancers combined.

Mei Chen, PhD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and colleagues conducted this meta-analysis and reported the results in Pediatrics.

The team searched for observational studies published in PubMed before February 2014 and ultimately included 16 studies in their analysis.

They assessed exposure to indoor pesticides and indoor insecticides (a subgroup of indoor pesticides), as well as exposure to outdoor pesticides, which included outdoor insecticides, herbicides, and fungicides.

The cancer types analyzed were leukemia, lymphoma, brain tumors, neuroblastoma, Wilms tumor, and soft tissue sarcoma.

Indoor pesticides

When the investigators analyzed all cancer types together, they found a significantly increased risk of childhood cancers associated with exposure to indoor pesticides (odds ratio [OR]=1.40).

Likewise, there was a significantly increased risk for leukemia (OR=1.48), acute leukemia (OR=1.59), lymphoma (OR=1.43), and all hematopoietic malignancies (leukemias and lymphomas, OR=1.47).

But the increased risk of childhood brain tumors was not statistically significant, and the other cancers were not analyzed separately.

Exposure to indoor insecticides was associated with a significant increase in the risk of leukemia (OR=1.47), acute leukemia (OR=1.59), lymphoma (OR=1.43), and all hematopoietic malignancies (OR=1.46).

Outdoor pesticides

There was no significant association between exposure to outdoor pesticides or outdoor insecticides and any of the cancer types. And there were not enough studies on fungicides to assess the risk of cancers associated with their use.

However, there was a significant association between exposure to herbicide and all childhood cancers (OR=1.35) as well as leukemia (OR=1.26).

The investigators said these results suggest cancer risks are related to the type of pesticides used and where they are applied.

And although additional research is needed to confirm the association between pesticide exposure and childhood cancers, steps should be taken to limit exposure to pesticides during childhood.

Man spraying pesticide

in his garden

Researchers have linked residential pesticide exposure to childhood cancers, but the estimated risks vary according to the cancer type, the type of pesticide, and where it is applied.

The investigators conducted a meta-analysis of published studies and found that childhood exposure to indoor pesticides was associated with a

significantly increased risk of all the cancers analyzed, as well as leukemia and lymphoma individually.

Overall, exposure to outdoor pesticides was not associated with an increased risk of childhood cancers. However, herbicide exposure was linked to an increased risk of leukemia and all cancers combined.

Mei Chen, PhD, of the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and colleagues conducted this meta-analysis and reported the results in Pediatrics.

The team searched for observational studies published in PubMed before February 2014 and ultimately included 16 studies in their analysis.

They assessed exposure to indoor pesticides and indoor insecticides (a subgroup of indoor pesticides), as well as exposure to outdoor pesticides, which included outdoor insecticides, herbicides, and fungicides.

The cancer types analyzed were leukemia, lymphoma, brain tumors, neuroblastoma, Wilms tumor, and soft tissue sarcoma.

Indoor pesticides

When the investigators analyzed all cancer types together, they found a significantly increased risk of childhood cancers associated with exposure to indoor pesticides (odds ratio [OR]=1.40).

Likewise, there was a significantly increased risk for leukemia (OR=1.48), acute leukemia (OR=1.59), lymphoma (OR=1.43), and all hematopoietic malignancies (leukemias and lymphomas, OR=1.47).

But the increased risk of childhood brain tumors was not statistically significant, and the other cancers were not analyzed separately.

Exposure to indoor insecticides was associated with a significant increase in the risk of leukemia (OR=1.47), acute leukemia (OR=1.59), lymphoma (OR=1.43), and all hematopoietic malignancies (OR=1.46).

Outdoor pesticides

There was no significant association between exposure to outdoor pesticides or outdoor insecticides and any of the cancer types. And there were not enough studies on fungicides to assess the risk of cancers associated with their use.

However, there was a significant association between exposure to herbicide and all childhood cancers (OR=1.35) as well as leukemia (OR=1.26).

The investigators said these results suggest cancer risks are related to the type of pesticides used and where they are applied.

And although additional research is needed to confirm the association between pesticide exposure and childhood cancers, steps should be taken to limit exposure to pesticides during childhood.

Platelet-membrane-coated

nanoparticles binding to the

lining of a damaged artery

Image courtesy of the

Zhang Research Group

Nanoparticles disguised as human platelets can provide targeted drug delivery, according to research published in Nature.

The nanoparticles are made of a biodegradable polymer coated with human platelet membranes.

This coating allows the nanoparticles to circulate in the bloodstream without being attacked by the immune system and to preferentially bind to damaged blood vessels and certain pathogens.

Murine experiments showed that these platelet-mimicking nanoparticles can deliver drugs to targeted sites, thereby increasing the therapeutic effect.

“Because of their targeting ability, platelet-mimicking nanoparticles can directly provide a much higher dose of medication specifically to diseased areas without saturating the entire body with drugs,” said study author Liangfang Zhang, PhD, of the University of California San Diego.

Creating the platelet mimics

To make the nanoparticles, Dr Zhang and his colleagues first separated platelets from whole blood samples using a centrifuge. The platelets were then processed to isolate the membranes from the platelets.

Next, the platelet membranes were broken up into much smaller pieces and fused to the surface of the nanoparticle cores. The resulting platelet-membrane-coated nanoparticles were approximately 100 nanometers in diameter.

This cloaking technology is based on a strategy Dr Zhang’s group had developed to cloak nanoparticles in red blood cell membranes. The researchers previously demonstrated that nanoparticles disguised as red blood cells are capable of removing toxins from the bloodstream.

With the current work, the researchers were able to produce platelet mimics that contain the complete set of surface receptors, antigens, and proteins naturally present on platelet membranes.

“Our technique takes advantage of the unique natural properties of human platelet membranes, which have a natural preference to bind to certain tissues and organisms in the body,” Dr Zhang said.

This targeting ability, which red blood cell membranes do not have, makes platelet membranes extremely useful for targeted drug delivery, according to the researchers.

Platelet mimics at work

The researchers packed the platelet-mimicking nanoparticles with docetaxel, a drug used to prevent scar tissue formation in the lining of damaged blood vessels, and administered them to rats afflicted with injured arteries.

The docetaxel-containing nanoparticles collected at the damaged sites of arteries and healed them.

The researchers then injected nanoparticles containing one-sixth the clinical dose of the antibiotic vancomycin into a group of mice systemically infected with methicillin-resistant Staphylococcus aureus bacteria.

Bacterial counts in the organs of these mice were up to 1000 times lower than in mice treated with the clinical dose of vancomycin alone.

“Our platelet-mimicking nanoparticles can increase the therapeutic efficacy of antibiotics because they can focus treatment on the bacteria locally without spreading drugs to healthy tissues and organs throughout the rest of the body,” Dr Zhang said. “We hope to develop platelet-mimicking nanoparticles into new treatments for systemic bacterial infections and cardiovascular disease.”

Dr Zhang noted that this drug delivery technique could potentially be used in other diseases as well, including cancers.

Platelet-membrane-coated

nanoparticles binding to the

lining of a damaged artery

Image courtesy of the

Zhang Research Group

Nanoparticles disguised as human platelets can provide targeted drug delivery, according to research published in Nature.

The nanoparticles are made of a biodegradable polymer coated with human platelet membranes.

This coating allows the nanoparticles to circulate in the bloodstream without being attacked by the immune system and to preferentially bind to damaged blood vessels and certain pathogens.

Murine experiments showed that these platelet-mimicking nanoparticles can deliver drugs to targeted sites, thereby increasing the therapeutic effect.

“Because of their targeting ability, platelet-mimicking nanoparticles can directly provide a much higher dose of medication specifically to diseased areas without saturating the entire body with drugs,” said study author Liangfang Zhang, PhD, of the University of California San Diego.

Creating the platelet mimics

To make the nanoparticles, Dr Zhang and his colleagues first separated platelets from whole blood samples using a centrifuge. The platelets were then processed to isolate the membranes from the platelets.

Next, the platelet membranes were broken up into much smaller pieces and fused to the surface of the nanoparticle cores. The resulting platelet-membrane-coated nanoparticles were approximately 100 nanometers in diameter.

This cloaking technology is based on a strategy Dr Zhang’s group had developed to cloak nanoparticles in red blood cell membranes. The researchers previously demonstrated that nanoparticles disguised as red blood cells are capable of removing toxins from the bloodstream.

With the current work, the researchers were able to produce platelet mimics that contain the complete set of surface receptors, antigens, and proteins naturally present on platelet membranes.

“Our technique takes advantage of the unique natural properties of human platelet membranes, which have a natural preference to bind to certain tissues and organisms in the body,” Dr Zhang said.

This targeting ability, which red blood cell membranes do not have, makes platelet membranes extremely useful for targeted drug delivery, according to the researchers.

Platelet mimics at work

The researchers packed the platelet-mimicking nanoparticles with docetaxel, a drug used to prevent scar tissue formation in the lining of damaged blood vessels, and administered them to rats afflicted with injured arteries.

The docetaxel-containing nanoparticles collected at the damaged sites of arteries and healed them.

The researchers then injected nanoparticles containing one-sixth the clinical dose of the antibiotic vancomycin into a group of mice systemically infected with methicillin-resistant Staphylococcus aureus bacteria.

Bacterial counts in the organs of these mice were up to 1000 times lower than in mice treated with the clinical dose of vancomycin alone.

“Our platelet-mimicking nanoparticles can increase the therapeutic efficacy of antibiotics because they can focus treatment on the bacteria locally without spreading drugs to healthy tissues and organs throughout the rest of the body,” Dr Zhang said. “We hope to develop platelet-mimicking nanoparticles into new treatments for systemic bacterial infections and cardiovascular disease.”

Dr Zhang noted that this drug delivery technique could potentially be used in other diseases as well, including cancers.

Platelet-membrane-coated

nanoparticles binding to the

lining of a damaged artery

Image courtesy of the

Zhang Research Group

Nanoparticles disguised as human platelets can provide targeted drug delivery, according to research published in Nature.

The nanoparticles are made of a biodegradable polymer coated with human platelet membranes.

This coating allows the nanoparticles to circulate in the bloodstream without being attacked by the immune system and to preferentially bind to damaged blood vessels and certain pathogens.

Murine experiments showed that these platelet-mimicking nanoparticles can deliver drugs to targeted sites, thereby increasing the therapeutic effect.

“Because of their targeting ability, platelet-mimicking nanoparticles can directly provide a much higher dose of medication specifically to diseased areas without saturating the entire body with drugs,” said study author Liangfang Zhang, PhD, of the University of California San Diego.

Creating the platelet mimics

To make the nanoparticles, Dr Zhang and his colleagues first separated platelets from whole blood samples using a centrifuge. The platelets were then processed to isolate the membranes from the platelets.

Next, the platelet membranes were broken up into much smaller pieces and fused to the surface of the nanoparticle cores. The resulting platelet-membrane-coated nanoparticles were approximately 100 nanometers in diameter.

This cloaking technology is based on a strategy Dr Zhang’s group had developed to cloak nanoparticles in red blood cell membranes. The researchers previously demonstrated that nanoparticles disguised as red blood cells are capable of removing toxins from the bloodstream.

With the current work, the researchers were able to produce platelet mimics that contain the complete set of surface receptors, antigens, and proteins naturally present on platelet membranes.

“Our technique takes advantage of the unique natural properties of human platelet membranes, which have a natural preference to bind to certain tissues and organisms in the body,” Dr Zhang said.

This targeting ability, which red blood cell membranes do not have, makes platelet membranes extremely useful for targeted drug delivery, according to the researchers.

Platelet mimics at work

The researchers packed the platelet-mimicking nanoparticles with docetaxel, a drug used to prevent scar tissue formation in the lining of damaged blood vessels, and administered them to rats afflicted with injured arteries.

The docetaxel-containing nanoparticles collected at the damaged sites of arteries and healed them.

The researchers then injected nanoparticles containing one-sixth the clinical dose of the antibiotic vancomycin into a group of mice systemically infected with methicillin-resistant Staphylococcus aureus bacteria.

Bacterial counts in the organs of these mice were up to 1000 times lower than in mice treated with the clinical dose of vancomycin alone.

“Our platelet-mimicking nanoparticles can increase the therapeutic efficacy of antibiotics because they can focus treatment on the bacteria locally without spreading drugs to healthy tissues and organs throughout the rest of the body,” Dr Zhang said. “We hope to develop platelet-mimicking nanoparticles into new treatments for systemic bacterial infections and cardiovascular disease.”

Dr Zhang noted that this drug delivery technique could potentially be used in other diseases as well, including cancers.

Early mortality after autologous hematopoietic stem cell transplantation (ASCT) for light-chain amyloidosis has declined dramatically in recent years, and 5-year survival is now deemed “excellent” at 77%, according to a report published online Sept. 14 in Journal of Clinical Oncology.

Light-chain amyloidosis results in deposition of insoluble amyloid fibers in many tissues, particularly the heart and kidneys, and can lead to organ failure and death. While medical therapies target the plasma cell clone that is the source of the amyloid, treatments have minimal effect on amyloid that has already accumulated in tissues. Alternatively, ASCT can produce durable hematologic responses and has resulted in improved function of affected organs, based on several single-center studies.

However, the only large, prospective randomized clinical trial to compare ASCT and medical therapy was done in 2007. That study showed autotransplantation carried a high (24%) early mortality, which contributed heavily to inferior overall survival, said Dr. Anita D’Souza of the division of hematology and oncology, Medical College of Wisconsin, Milwaukee, and her associates.

Since that study, supportive care during the peritransplantation period has greatly improved. Large U.S. transplant centers now report that early mortality is less than 5%.

©Nephron/Wikimedia Commons/CC BY-SA 3.0

To assess time trends in autotransplantation mortality, Dr. D’Souza and her associates analyzed data from the Center for International Blood & Marrow Transplant Research, a registry that collects transplant data from 320 centers worldwide and captures information concerning most U.S. procedures. They focused on 1,536 North American patients with light-chain amyloidosis who underwent ASCT during three successive 5-year periods: 1995-2000, 2001-2006, and 2007-2012. The median follow-up was 56 months.

Over time, 30-day mortality declined from 11% to 5% to 3%, respectively; and 100-day mortality declined from 20% to 11% to 5%. One-year overall survival rose from 75% to 85% to 90%, and 5-year overall survival improved from 55% to 61% to 77%.

Even among patients with renal amyloidosis, 3-year overall survival improved over time from 78% during the earliest study period to 89% during the most recent time period. However, mortality did not improve significantly over time among patients with cardiac involvement, which continues to be the single most-important variable associated with poor outcomes, the researchers said (J Clin Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4015]).

A transplant center’s experience with this procedure proved to be of crucial importance to early patient mortality. Centers that performed a low volume of ASCT for light-chain amyloidosis, defined as fewer than four transplants per year, had a 30-day mortality of 5% and a 100-day mortality of 7%, while centers that performed more than four procedures per year had significantly lower mortalities of 1% and 3%, respectively. There were no significant differences between low- and high-volume centers regarding patient, organ, or medication factors, which “led us to believe that high-volume centers do not necessarily select fitter patients for transplantation. Rather, they may be more experienced in supporting and treating these patients in the early posttransplantation period,” Dr. D’Souza and her associates said.

These “reassuring” findings, together with the recent development of novel plasma-cell–targeting agents such as bortezomib, suggest that it is time to consider performing a more current multicenter prospective study comparing autotransplantation against medical therapy, they added.

Early mortality after autologous hematopoietic stem cell transplantation (ASCT) for light-chain amyloidosis has declined dramatically in recent years, and 5-year survival is now deemed “excellent” at 77%, according to a report published online Sept. 14 in Journal of Clinical Oncology.

Light-chain amyloidosis results in deposition of insoluble amyloid fibers in many tissues, particularly the heart and kidneys, and can lead to organ failure and death. While medical therapies target the plasma cell clone that is the source of the amyloid, treatments have minimal effect on amyloid that has already accumulated in tissues. Alternatively, ASCT can produce durable hematologic responses and has resulted in improved function of affected organs, based on several single-center studies.

However, the only large, prospective randomized clinical trial to compare ASCT and medical therapy was done in 2007. That study showed autotransplantation carried a high (24%) early mortality, which contributed heavily to inferior overall survival, said Dr. Anita D’Souza of the division of hematology and oncology, Medical College of Wisconsin, Milwaukee, and her associates.

Since that study, supportive care during the peritransplantation period has greatly improved. Large U.S. transplant centers now report that early mortality is less than 5%.

©Nephron/Wikimedia Commons/CC BY-SA 3.0

To assess time trends in autotransplantation mortality, Dr. D’Souza and her associates analyzed data from the Center for International Blood & Marrow Transplant Research, a registry that collects transplant data from 320 centers worldwide and captures information concerning most U.S. procedures. They focused on 1,536 North American patients with light-chain amyloidosis who underwent ASCT during three successive 5-year periods: 1995-2000, 2001-2006, and 2007-2012. The median follow-up was 56 months.

Over time, 30-day mortality declined from 11% to 5% to 3%, respectively; and 100-day mortality declined from 20% to 11% to 5%. One-year overall survival rose from 75% to 85% to 90%, and 5-year overall survival improved from 55% to 61% to 77%.

Even among patients with renal amyloidosis, 3-year overall survival improved over time from 78% during the earliest study period to 89% during the most recent time period. However, mortality did not improve significantly over time among patients with cardiac involvement, which continues to be the single most-important variable associated with poor outcomes, the researchers said (J Clin Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4015]).

A transplant center’s experience with this procedure proved to be of crucial importance to early patient mortality. Centers that performed a low volume of ASCT for light-chain amyloidosis, defined as fewer than four transplants per year, had a 30-day mortality of 5% and a 100-day mortality of 7%, while centers that performed more than four procedures per year had significantly lower mortalities of 1% and 3%, respectively. There were no significant differences between low- and high-volume centers regarding patient, organ, or medication factors, which “led us to believe that high-volume centers do not necessarily select fitter patients for transplantation. Rather, they may be more experienced in supporting and treating these patients in the early posttransplantation period,” Dr. D’Souza and her associates said.

These “reassuring” findings, together with the recent development of novel plasma-cell–targeting agents such as bortezomib, suggest that it is time to consider performing a more current multicenter prospective study comparing autotransplantation against medical therapy, they added.

Early mortality after autologous hematopoietic stem cell transplantation (ASCT) for light-chain amyloidosis has declined dramatically in recent years, and 5-year survival is now deemed “excellent” at 77%, according to a report published online Sept. 14 in Journal of Clinical Oncology.

Light-chain amyloidosis results in deposition of insoluble amyloid fibers in many tissues, particularly the heart and kidneys, and can lead to organ failure and death. While medical therapies target the plasma cell clone that is the source of the amyloid, treatments have minimal effect on amyloid that has already accumulated in tissues. Alternatively, ASCT can produce durable hematologic responses and has resulted in improved function of affected organs, based on several single-center studies.

However, the only large, prospective randomized clinical trial to compare ASCT and medical therapy was done in 2007. That study showed autotransplantation carried a high (24%) early mortality, which contributed heavily to inferior overall survival, said Dr. Anita D’Souza of the division of hematology and oncology, Medical College of Wisconsin, Milwaukee, and her associates.

Since that study, supportive care during the peritransplantation period has greatly improved. Large U.S. transplant centers now report that early mortality is less than 5%.

©Nephron/Wikimedia Commons/CC BY-SA 3.0

To assess time trends in autotransplantation mortality, Dr. D’Souza and her associates analyzed data from the Center for International Blood & Marrow Transplant Research, a registry that collects transplant data from 320 centers worldwide and captures information concerning most U.S. procedures. They focused on 1,536 North American patients with light-chain amyloidosis who underwent ASCT during three successive 5-year periods: 1995-2000, 2001-2006, and 2007-2012. The median follow-up was 56 months.

Over time, 30-day mortality declined from 11% to 5% to 3%, respectively; and 100-day mortality declined from 20% to 11% to 5%. One-year overall survival rose from 75% to 85% to 90%, and 5-year overall survival improved from 55% to 61% to 77%.

Even among patients with renal amyloidosis, 3-year overall survival improved over time from 78% during the earliest study period to 89% during the most recent time period. However, mortality did not improve significantly over time among patients with cardiac involvement, which continues to be the single most-important variable associated with poor outcomes, the researchers said (J Clin Oncol. 2015 Sep 14 [doi:10.1200/JCO.2015.62.4015]).

A transplant center’s experience with this procedure proved to be of crucial importance to early patient mortality. Centers that performed a low volume of ASCT for light-chain amyloidosis, defined as fewer than four transplants per year, had a 30-day mortality of 5% and a 100-day mortality of 7%, while centers that performed more than four procedures per year had significantly lower mortalities of 1% and 3%, respectively. There were no significant differences between low- and high-volume centers regarding patient, organ, or medication factors, which “led us to believe that high-volume centers do not necessarily select fitter patients for transplantation. Rather, they may be more experienced in supporting and treating these patients in the early posttransplantation period,” Dr. D’Souza and her associates said.

These “reassuring” findings, together with the recent development of novel plasma-cell–targeting agents such as bortezomib, suggest that it is time to consider performing a more current multicenter prospective study comparing autotransplantation against medical therapy, they added.

VANCOUVER – Evidence-based therapy for nail psoriasis is in a sorry state because of a lack of consensus on a reliable nail psoriasis scoring system for use in clinical trials, according to a coauthor of the Cochrane systematic review of interventions for nail psoriasis.

“The last 12 randomized clinical trials used 21 ways of scoring the results of treatment, so comparing the studies means comparing apples to oranges. Which is the most effective treatment? What should we advise our patients? We don’t know. Comparison is impossible,” Dr. Marcel C. Pasch said at the World Congress of Dermatology.

Bruce Jancin/Frontline Medical News

The Cochrane report (Cochrane Database Syst Rev. 2013 Jan 31;1:CD007633) deemed the evidence for topical therapies as “inconclusive and weak,” even though topicals are the treatment mainstay for this localized expression of psoriasis. Indeed, Dr. Pasch and his coauthors found that no topical therapy has been shown effective in improving nail psoriasis. The Cochrane group concluded that just five therapies rise to the standard of being evidence based in terms of efficacy: the tumor necrosis factor (TNF) inhibitors infliximab (Remicade) and golimumab (Simponi), superficial radiation therapy, Grenz rays, and electron beam therapy. All five are strikingly impractical for use in clinical practice.

“The findings are quite disappointing because nobody sends a patient with psoriasis to the radiotherapist, and while giving an anti-TNF biologic only for the nails will be effective, at least in my country it won’t be reimbursed,” wrote Dr. Pasch, a dermatologist at Radboud University Nijmegen (the Netherlands) Medical Centre.

The presence and severity of nail psoriasis is unrelated to the severity of cutaneous psoriasis. Moreover, nail psoriasis without cutaneous involvement occurs in 5%-10% of psoriasis patients.

Since publication of the Cochrane systematic review, 12 new randomized controlled trials of treatments for nail psoriasis have appeared. Six focused on biologics: the anti-TNF agents certolizumab (Cimzia), etanercept (Enbrel), and adalimumab (Humira); the anti–interleukin-12/23 agent ustekinumab (Stelara); and the interleukin-17A inhibitor secukiumab (Cosentyx). Dr. Pasch said in his opinion all five biologics were supported by convincing studies and now can be added to the short list of evidence-based nail psoriasis therapies.

Of the six recent studies of topical therapies, two provided persuasive evidence of efficacy, in his view: tacrolimus ointment and indigo naturalis extract in oil (Lindioil), a variant of a traditional Chinese medicine therapy, which at this time isn’t commercially available.

In contrast, studies of clobetasol nail lacquer, pulsed dye laser therapy, a nail lacquer based upon chitin from crab shells, and a study of calcitriol ointment versus betamethasone dipropionate ointment failed to be convincing either because of methodologic problems or lack of efficacy, he continued.

These 12 recent randomized clinical trials utilized 21 different nail psoriasis scoring systems.

“Which scoring system is best? The answer is, we don’t know,” Dr. Pasch said.

He and his coinvestigators compared eight different scoring systems in a prospective study and concluded that the Nijmegen–Nail Psoriasis Activity Index Tool (N-NAIL), which Dr. Pasch helped develop, best reflected the clinical severity of nail psoriasis (J Am Acad Dermatol. 2014 Jun;70[6]:1061-6).

However, he added that at present there is no validated scoring system for nail psoriasis. And creation of a single validated scoring system that researchers can agree on as the standard is a prerequisite for making major advances in the treatment of nail psoriasis, in Dr. Pasch’s view.

He is so convinced of this that he has created an organization whose goal is to achieve consensus on one reliable, validated nail psoriasis scoring system for use in clinical trials. At the World Congress of Dermatology, he invited stakeholders – including academic and community dermatologists, patient organizations, and the pharmaceutical industry – to join (www.nailinitiative.org).

Session chair Dr. Peter van de Kerkhof, chairman of dermatology at Radboud University, said he sees the NAPSI (Nail Psoriasis Severity Index) being used in lots of clinical trials in psoriasis. What’s wrong with building a consensus around NAPSI? he asked.

“The problem is not the NAPSI score,” Dr. Pasch replied. “The problem is that in each trial a modified NAPSI score is used, but they are all modified in different ways. We have the single-hand NAPSI, the eight-finger NAPSI, the 10-finger NAPSI, the target NAPSI. The NAPSI doesn’t exist anymore.”

He reported receiving research grants from Pfizer and Janssen-Cilag.

[email protected]

VANCOUVER – Evidence-based therapy for nail psoriasis is in a sorry state because of a lack of consensus on a reliable nail psoriasis scoring system for use in clinical trials, according to a coauthor of the Cochrane systematic review of interventions for nail psoriasis.

“The last 12 randomized clinical trials used 21 ways of scoring the results of treatment, so comparing the studies means comparing apples to oranges. Which is the most effective treatment? What should we advise our patients? We don’t know. Comparison is impossible,” Dr. Marcel C. Pasch said at the World Congress of Dermatology.

Bruce Jancin/Frontline Medical News

The Cochrane report (Cochrane Database Syst Rev. 2013 Jan 31;1:CD007633) deemed the evidence for topical therapies as “inconclusive and weak,” even though topicals are the treatment mainstay for this localized expression of psoriasis. Indeed, Dr. Pasch and his coauthors found that no topical therapy has been shown effective in improving nail psoriasis. The Cochrane group concluded that just five therapies rise to the standard of being evidence based in terms of efficacy: the tumor necrosis factor (TNF) inhibitors infliximab (Remicade) and golimumab (Simponi), superficial radiation therapy, Grenz rays, and electron beam therapy. All five are strikingly impractical for use in clinical practice.

“The findings are quite disappointing because nobody sends a patient with psoriasis to the radiotherapist, and while giving an anti-TNF biologic only for the nails will be effective, at least in my country it won’t be reimbursed,” wrote Dr. Pasch, a dermatologist at Radboud University Nijmegen (the Netherlands) Medical Centre.

The presence and severity of nail psoriasis is unrelated to the severity of cutaneous psoriasis. Moreover, nail psoriasis without cutaneous involvement occurs in 5%-10% of psoriasis patients.

Since publication of the Cochrane systematic review, 12 new randomized controlled trials of treatments for nail psoriasis have appeared. Six focused on biologics: the anti-TNF agents certolizumab (Cimzia), etanercept (Enbrel), and adalimumab (Humira); the anti–interleukin-12/23 agent ustekinumab (Stelara); and the interleukin-17A inhibitor secukiumab (Cosentyx). Dr. Pasch said in his opinion all five biologics were supported by convincing studies and now can be added to the short list of evidence-based nail psoriasis therapies.

Of the six recent studies of topical therapies, two provided persuasive evidence of efficacy, in his view: tacrolimus ointment and indigo naturalis extract in oil (Lindioil), a variant of a traditional Chinese medicine therapy, which at this time isn’t commercially available.

In contrast, studies of clobetasol nail lacquer, pulsed dye laser therapy, a nail lacquer based upon chitin from crab shells, and a study of calcitriol ointment versus betamethasone dipropionate ointment failed to be convincing either because of methodologic problems or lack of efficacy, he continued.

These 12 recent randomized clinical trials utilized 21 different nail psoriasis scoring systems.

“Which scoring system is best? The answer is, we don’t know,” Dr. Pasch said.

He and his coinvestigators compared eight different scoring systems in a prospective study and concluded that the Nijmegen–Nail Psoriasis Activity Index Tool (N-NAIL), which Dr. Pasch helped develop, best reflected the clinical severity of nail psoriasis (J Am Acad Dermatol. 2014 Jun;70[6]:1061-6).

However, he added that at present there is no validated scoring system for nail psoriasis. And creation of a single validated scoring system that researchers can agree on as the standard is a prerequisite for making major advances in the treatment of nail psoriasis, in Dr. Pasch’s view.

He is so convinced of this that he has created an organization whose goal is to achieve consensus on one reliable, validated nail psoriasis scoring system for use in clinical trials. At the World Congress of Dermatology, he invited stakeholders – including academic and community dermatologists, patient organizations, and the pharmaceutical industry – to join (www.nailinitiative.org).

Session chair Dr. Peter van de Kerkhof, chairman of dermatology at Radboud University, said he sees the NAPSI (Nail Psoriasis Severity Index) being used in lots of clinical trials in psoriasis. What’s wrong with building a consensus around NAPSI? he asked.

“The problem is not the NAPSI score,” Dr. Pasch replied. “The problem is that in each trial a modified NAPSI score is used, but they are all modified in different ways. We have the single-hand NAPSI, the eight-finger NAPSI, the 10-finger NAPSI, the target NAPSI. The NAPSI doesn’t exist anymore.”

He reported receiving research grants from Pfizer and Janssen-Cilag.

[email protected]

VANCOUVER – Evidence-based therapy for nail psoriasis is in a sorry state because of a lack of consensus on a reliable nail psoriasis scoring system for use in clinical trials, according to a coauthor of the Cochrane systematic review of interventions for nail psoriasis.

“The last 12 randomized clinical trials used 21 ways of scoring the results of treatment, so comparing the studies means comparing apples to oranges. Which is the most effective treatment? What should we advise our patients? We don’t know. Comparison is impossible,” Dr. Marcel C. Pasch said at the World Congress of Dermatology.

Bruce Jancin/Frontline Medical News

The Cochrane report (Cochrane Database Syst Rev. 2013 Jan 31;1:CD007633) deemed the evidence for topical therapies as “inconclusive and weak,” even though topicals are the treatment mainstay for this localized expression of psoriasis. Indeed, Dr. Pasch and his coauthors found that no topical therapy has been shown effective in improving nail psoriasis. The Cochrane group concluded that just five therapies rise to the standard of being evidence based in terms of efficacy: the tumor necrosis factor (TNF) inhibitors infliximab (Remicade) and golimumab (Simponi), superficial radiation therapy, Grenz rays, and electron beam therapy. All five are strikingly impractical for use in clinical practice.

“The findings are quite disappointing because nobody sends a patient with psoriasis to the radiotherapist, and while giving an anti-TNF biologic only for the nails will be effective, at least in my country it won’t be reimbursed,” wrote Dr. Pasch, a dermatologist at Radboud University Nijmegen (the Netherlands) Medical Centre.

The presence and severity of nail psoriasis is unrelated to the severity of cutaneous psoriasis. Moreover, nail psoriasis without cutaneous involvement occurs in 5%-10% of psoriasis patients.

Since publication of the Cochrane systematic review, 12 new randomized controlled trials of treatments for nail psoriasis have appeared. Six focused on biologics: the anti-TNF agents certolizumab (Cimzia), etanercept (Enbrel), and adalimumab (Humira); the anti–interleukin-12/23 agent ustekinumab (Stelara); and the interleukin-17A inhibitor secukiumab (Cosentyx). Dr. Pasch said in his opinion all five biologics were supported by convincing studies and now can be added to the short list of evidence-based nail psoriasis therapies.

Of the six recent studies of topical therapies, two provided persuasive evidence of efficacy, in his view: tacrolimus ointment and indigo naturalis extract in oil (Lindioil), a variant of a traditional Chinese medicine therapy, which at this time isn’t commercially available.

In contrast, studies of clobetasol nail lacquer, pulsed dye laser therapy, a nail lacquer based upon chitin from crab shells, and a study of calcitriol ointment versus betamethasone dipropionate ointment failed to be convincing either because of methodologic problems or lack of efficacy, he continued.

These 12 recent randomized clinical trials utilized 21 different nail psoriasis scoring systems.

“Which scoring system is best? The answer is, we don’t know,” Dr. Pasch said.

He and his coinvestigators compared eight different scoring systems in a prospective study and concluded that the Nijmegen–Nail Psoriasis Activity Index Tool (N-NAIL), which Dr. Pasch helped develop, best reflected the clinical severity of nail psoriasis (J Am Acad Dermatol. 2014 Jun;70[6]:1061-6).

However, he added that at present there is no validated scoring system for nail psoriasis. And creation of a single validated scoring system that researchers can agree on as the standard is a prerequisite for making major advances in the treatment of nail psoriasis, in Dr. Pasch’s view.

He is so convinced of this that he has created an organization whose goal is to achieve consensus on one reliable, validated nail psoriasis scoring system for use in clinical trials. At the World Congress of Dermatology, he invited stakeholders – including academic and community dermatologists, patient organizations, and the pharmaceutical industry – to join (www.nailinitiative.org).

Session chair Dr. Peter van de Kerkhof, chairman of dermatology at Radboud University, said he sees the NAPSI (Nail Psoriasis Severity Index) being used in lots of clinical trials in psoriasis. What’s wrong with building a consensus around NAPSI? he asked.

“The problem is not the NAPSI score,” Dr. Pasch replied. “The problem is that in each trial a modified NAPSI score is used, but they are all modified in different ways. We have the single-hand NAPSI, the eight-finger NAPSI, the 10-finger NAPSI, the target NAPSI. The NAPSI doesn’t exist anymore.”

He reported receiving research grants from Pfizer and Janssen-Cilag.

[email protected]

Photo by Octapharma

The US Food and Drug Administration (FDA) has approved the recombinant factor VIII product simoctocog alfa (Nuwiq) for adults and children with hemophilia A.

The approval includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is already approved for use in the European Union, Argentina, Australia, and Canada.

In the US, simoctocog alfa is being developed by Octapharma USA, a subsidiary of Octapharma AG.

According to Octapharma USA, simoctocog alfa should be available in the US by early 2016. The company plans to offer hemophilia A patients educational and support services in connection with the product.

Trials of simoctocog alfa

Simoctocog alfa has been evaluated for safety in 5 prospective trials and for efficacy in 3 prospective studies.

A total of 135 previously treated patients with severe hemophilia A have received simoctocog alfa across all the studies. This includes 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11.

The patients were treated with a total of 16,134 infusions over 15,950 exposure days.

In a study of adults, the overall prophylactic efficacy of simoctocog alfa for spontaneous bleeds was rated “excellent” or “good” in 92% of patients. In a study of children, prophylactic efficacy for spontaneous bleeds was rated “excellent” or “good” in 97% of patients.

The mean annualized bleeding rates for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults.

For hemophilia A patients receiving simoctocog alfa prophylaxis compared to on-demand treatment, the annualized bleeding rates were reduced 96% for adults and 93% for children.

Treatment of breakthrough bleeds during simoctocog alfa prophylaxis was rated as “excellent” or “good” in 100% of bleeds (30/30) in adults and 82% of bleeds (89/108) in children.

For on-demand treatment with simoctocog alfa in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was considered “excellent” or “good” in 94% of bleeds (931/986).

The overall efficacy in surgical prophylaxis was rated “excellent” or “good” in 97% of procedures using simoctocog alfa (32/33).

For all the trials of simoctocog alfa, there were 7 adverse events reported. Each of these events occurred once, with a rate of 0.7% across all 135 patients. The events were paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

Non-neutralizing anti-factor VIII antibodies (without inhibitory activity as measured by the modified Bethesda assay) were reported in 4 patients (3%). Three of the 4 patients had pre-existing non-neutralizing antibodies prior to simoctocog alfa exposure.

For more details on simoctocog alfa, see the full prescribing information, available at www.octapharmausa.com.

Photo by Octapharma

The US Food and Drug Administration (FDA) has approved the recombinant factor VIII product simoctocog alfa (Nuwiq) for adults and children with hemophilia A.

The approval includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is already approved for use in the European Union, Argentina, Australia, and Canada.

In the US, simoctocog alfa is being developed by Octapharma USA, a subsidiary of Octapharma AG.

According to Octapharma USA, simoctocog alfa should be available in the US by early 2016. The company plans to offer hemophilia A patients educational and support services in connection with the product.

Trials of simoctocog alfa

Simoctocog alfa has been evaluated for safety in 5 prospective trials and for efficacy in 3 prospective studies.

A total of 135 previously treated patients with severe hemophilia A have received simoctocog alfa across all the studies. This includes 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11.

The patients were treated with a total of 16,134 infusions over 15,950 exposure days.

In a study of adults, the overall prophylactic efficacy of simoctocog alfa for spontaneous bleeds was rated “excellent” or “good” in 92% of patients. In a study of children, prophylactic efficacy for spontaneous bleeds was rated “excellent” or “good” in 97% of patients.

The mean annualized bleeding rates for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults.

For hemophilia A patients receiving simoctocog alfa prophylaxis compared to on-demand treatment, the annualized bleeding rates were reduced 96% for adults and 93% for children.

Treatment of breakthrough bleeds during simoctocog alfa prophylaxis was rated as “excellent” or “good” in 100% of bleeds (30/30) in adults and 82% of bleeds (89/108) in children.

For on-demand treatment with simoctocog alfa in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was considered “excellent” or “good” in 94% of bleeds (931/986).

The overall efficacy in surgical prophylaxis was rated “excellent” or “good” in 97% of procedures using simoctocog alfa (32/33).

For all the trials of simoctocog alfa, there were 7 adverse events reported. Each of these events occurred once, with a rate of 0.7% across all 135 patients. The events were paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

Non-neutralizing anti-factor VIII antibodies (without inhibitory activity as measured by the modified Bethesda assay) were reported in 4 patients (3%). Three of the 4 patients had pre-existing non-neutralizing antibodies prior to simoctocog alfa exposure.

For more details on simoctocog alfa, see the full prescribing information, available at www.octapharmausa.com.

Photo by Octapharma

The US Food and Drug Administration (FDA) has approved the recombinant factor VIII product simoctocog alfa (Nuwiq) for adults and children with hemophilia A.

The approval includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is already approved for use in the European Union, Argentina, Australia, and Canada.

In the US, simoctocog alfa is being developed by Octapharma USA, a subsidiary of Octapharma AG.

According to Octapharma USA, simoctocog alfa should be available in the US by early 2016. The company plans to offer hemophilia A patients educational and support services in connection with the product.

Trials of simoctocog alfa

Simoctocog alfa has been evaluated for safety in 5 prospective trials and for efficacy in 3 prospective studies.

A total of 135 previously treated patients with severe hemophilia A have received simoctocog alfa across all the studies. This includes 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11.

The patients were treated with a total of 16,134 infusions over 15,950 exposure days.

In a study of adults, the overall prophylactic efficacy of simoctocog alfa for spontaneous bleeds was rated “excellent” or “good” in 92% of patients. In a study of children, prophylactic efficacy for spontaneous bleeds was rated “excellent” or “good” in 97% of patients.

The mean annualized bleeding rates for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults.

For hemophilia A patients receiving simoctocog alfa prophylaxis compared to on-demand treatment, the annualized bleeding rates were reduced 96% for adults and 93% for children.

Treatment of breakthrough bleeds during simoctocog alfa prophylaxis was rated as “excellent” or “good” in 100% of bleeds (30/30) in adults and 82% of bleeds (89/108) in children.

For on-demand treatment with simoctocog alfa in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was considered “excellent” or “good” in 94% of bleeds (931/986).

The overall efficacy in surgical prophylaxis was rated “excellent” or “good” in 97% of procedures using simoctocog alfa (32/33).

For all the trials of simoctocog alfa, there were 7 adverse events reported. Each of these events occurred once, with a rate of 0.7% across all 135 patients. The events were paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

Non-neutralizing anti-factor VIII antibodies (without inhibitory activity as measured by the modified Bethesda assay) were reported in 4 patients (3%). Three of the 4 patients had pre-existing non-neutralizing antibodies prior to simoctocog alfa exposure.

For more details on simoctocog alfa, see the full prescribing information, available at www.octapharmausa.com.

Dermatologists have become accustomed to reading about the associations of dermatologic disease with extracutaneous comorbidities (psoriasis certainly takes the lead). One may see the headline “Study finds increased risk for melanoma in female acne patients” and say “Sure, why not?” However, before we all jump on the association bandwagon, let’s better appreciate this finding.

A study published online January 8 in Cancer by Zhang et al followed 99,128 female nurses in the Nurses’ Health Study II cohort for 20 years. This cohort has been utilized for numerous prospective studies over the year. Even after adjusting for known risk factors, investigators discovered that women with a history of severe cystic teenage acne had a hazard ratio of 1.44 for melanoma. The authors replicated the association with an independent melanoma case-control study of 930 cases and 1026 controls, finding an odds ratio of 1.27. They also found that individuals with teenage acne were more likely to have nevi (52.7% vs 50.1% in the cohort study; 55.2% vs 45.1% in the control study).

These data points ultimately led the team to conclude that acne may serve as an independent risk factor for melanoma, attributing androgens in female acne as a possible and plausible explanation due to their known effect on telomere elongation; melanocytes with longer telomere lengths have more opportunity to develop mutations, which could lead to malignant transformation, as the extended length ultimately delays initiation of cellular senescence. The longer these cells are “awake,” more moles can form, which means more room for trouble.

What’s the issue?

The size of this cohort certainly gives credibility to the data and statistics presented. Although the study is powered very well by the numbers, it is a unique cohort because all participants were nurses, narrowing down the demographics to some degree given general patterns, behaviors, and backgrounds when it comes to this group, an issue that has been previously raised with using this cohort. That said, more research is certainly warranted to elucidate the proposed mechanism and further clarify the association.

From a purely clinical standpoint, this paper is powerful ammo that can be used in our war against skin cancer. This very large cohort probably does not follow the American Academy of Dermatology guidelines for sun protection, skin cancer prevention, and surveillance. It could be a nice tidbit for patients at the end of your spiel on acne and then work in the photoprotection discussion, something we haven’t been the best at according to a recent study published in JAMA Dermatology (JAMA Dermatol. 2014;150:51-55)! Would it be such a bad thing if this paper helped us encourage all women with moderate to severe acne to undertake more effective sun-safe behaviors and to visit their dermatologist every year for total-body skin examinations?

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

Dermatologists have become accustomed to reading about the associations of dermatologic disease with extracutaneous comorbidities (psoriasis certainly takes the lead). One may see the headline “Study finds increased risk for melanoma in female acne patients” and say “Sure, why not?” However, before we all jump on the association bandwagon, let’s better appreciate this finding.

A study published online January 8 in Cancer by Zhang et al followed 99,128 female nurses in the Nurses’ Health Study II cohort for 20 years. This cohort has been utilized for numerous prospective studies over the year. Even after adjusting for known risk factors, investigators discovered that women with a history of severe cystic teenage acne had a hazard ratio of 1.44 for melanoma. The authors replicated the association with an independent melanoma case-control study of 930 cases and 1026 controls, finding an odds ratio of 1.27. They also found that individuals with teenage acne were more likely to have nevi (52.7% vs 50.1% in the cohort study; 55.2% vs 45.1% in the control study).

These data points ultimately led the team to conclude that acne may serve as an independent risk factor for melanoma, attributing androgens in female acne as a possible and plausible explanation due to their known effect on telomere elongation; melanocytes with longer telomere lengths have more opportunity to develop mutations, which could lead to malignant transformation, as the extended length ultimately delays initiation of cellular senescence. The longer these cells are “awake,” more moles can form, which means more room for trouble.

What’s the issue?

The size of this cohort certainly gives credibility to the data and statistics presented. Although the study is powered very well by the numbers, it is a unique cohort because all participants were nurses, narrowing down the demographics to some degree given general patterns, behaviors, and backgrounds when it comes to this group, an issue that has been previously raised with using this cohort. That said, more research is certainly warranted to elucidate the proposed mechanism and further clarify the association.

From a purely clinical standpoint, this paper is powerful ammo that can be used in our war against skin cancer. This very large cohort probably does not follow the American Academy of Dermatology guidelines for sun protection, skin cancer prevention, and surveillance. It could be a nice tidbit for patients at the end of your spiel on acne and then work in the photoprotection discussion, something we haven’t been the best at according to a recent study published in JAMA Dermatology (JAMA Dermatol. 2014;150:51-55)! Would it be such a bad thing if this paper helped us encourage all women with moderate to severe acne to undertake more effective sun-safe behaviors and to visit their dermatologist every year for total-body skin examinations?

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

Dermatologists have become accustomed to reading about the associations of dermatologic disease with extracutaneous comorbidities (psoriasis certainly takes the lead). One may see the headline “Study finds increased risk for melanoma in female acne patients” and say “Sure, why not?” However, before we all jump on the association bandwagon, let’s better appreciate this finding.

A study published online January 8 in Cancer by Zhang et al followed 99,128 female nurses in the Nurses’ Health Study II cohort for 20 years. This cohort has been utilized for numerous prospective studies over the year. Even after adjusting for known risk factors, investigators discovered that women with a history of severe cystic teenage acne had a hazard ratio of 1.44 for melanoma. The authors replicated the association with an independent melanoma case-control study of 930 cases and 1026 controls, finding an odds ratio of 1.27. They also found that individuals with teenage acne were more likely to have nevi (52.7% vs 50.1% in the cohort study; 55.2% vs 45.1% in the control study).

These data points ultimately led the team to conclude that acne may serve as an independent risk factor for melanoma, attributing androgens in female acne as a possible and plausible explanation due to their known effect on telomere elongation; melanocytes with longer telomere lengths have more opportunity to develop mutations, which could lead to malignant transformation, as the extended length ultimately delays initiation of cellular senescence. The longer these cells are “awake,” more moles can form, which means more room for trouble.

What’s the issue?

The size of this cohort certainly gives credibility to the data and statistics presented. Although the study is powered very well by the numbers, it is a unique cohort because all participants were nurses, narrowing down the demographics to some degree given general patterns, behaviors, and backgrounds when it comes to this group, an issue that has been previously raised with using this cohort. That said, more research is certainly warranted to elucidate the proposed mechanism and further clarify the association.

From a purely clinical standpoint, this paper is powerful ammo that can be used in our war against skin cancer. This very large cohort probably does not follow the American Academy of Dermatology guidelines for sun protection, skin cancer prevention, and surveillance. It could be a nice tidbit for patients at the end of your spiel on acne and then work in the photoprotection discussion, something we haven’t been the best at according to a recent study published in JAMA Dermatology (JAMA Dermatol. 2014;150:51-55)! Would it be such a bad thing if this paper helped us encourage all women with moderate to severe acne to undertake more effective sun-safe behaviors and to visit their dermatologist every year for total-body skin examinations?

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

NEW YORK - Coating on endovascular devices is associated with embolization and microvascular occlusion leading to purpura or livedo racemosa, according to a new report.

Dr. Alina Bridges, of the Department of Dermatology at Mayo Clinic in Rochester, Minnesota, said by email that the study was conducted "to make clinicians and pathologists aware of this underrecognized phenomenon of iatrogenic hydrophilic polymer gel embolization that can involve the skin and present with purpura."

The phenomenon "has distinctive microscopic morphology and potential for internal organ involvement," she added.

Endovascular devices commonly are coated with hydrophilic polymer gels to improve maneuverability and prevent vasospasm. However, there are reports of the coating embolizing, resulting

in severe reactions such as stroke, pulmonary infarction, and death.

Dr. Bridges and colleagues presented a case study of eight patients with livedo racemosa and purpura after an endovascular procedure. The patients had punch biopsies obtained with hematoxylin-eosin-stained sections.

The study subjects were between 58 and 81 years old, most were men and most had previous endovascular procedures and multiple comorbidities, according to an article online August 11 in the Journal of the American Academy of Dermatology.

In all but one patient, the cutaneous lesions were unilateral and all but two were asymptomatic. Six patients presented with livedo racemosa and two with purpura.

All cases demonstrated pauci-inflammatory occlusion in the mid-dermal and small superficial vessels. Likewise, histopathologic evidence was consistent with previously reported cases of emboli secondary to hydrophilic gel polymer.

There was no evidence of embolic sequela to the organs in three patients. However, one patient died of unknown reasons and four patients experienced postoperative complications including spinal cord ischemia, acute kidney injury, and cerebral infarction. In all cases, the cutaneous manifestations resolved without intervention.

The authors say they suspect the incidence of this type of embolization is underrecognized, especially with the common use of hydrophilic polymer gel coatings.

"This report highlights the importance of awareness of this rare iatrogenic complication and the importance of investigating a patient's clinical history to determine if there had been recent exposure to an intravascular device with a hydrophilic coating," Dr. Bridges said.

"While the use of polymer-coated devices offers several advantages, clinicians must be aware of their potential complications, including stroke, myocardial and pulmonary infarction, gangrene, and/or death," she said.

The authors reported no funding or conflicts of interest.

NEW YORK - Coating on endovascular devices is associated with embolization and microvascular occlusion leading to purpura or livedo racemosa, according to a new report.

Dr. Alina Bridges, of the Department of Dermatology at Mayo Clinic in Rochester, Minnesota, said by email that the study was conducted "to make clinicians and pathologists aware of this underrecognized phenomenon of iatrogenic hydrophilic polymer gel embolization that can involve the skin and present with purpura."

The phenomenon "has distinctive microscopic morphology and potential for internal organ involvement," she added.

Endovascular devices commonly are coated with hydrophilic polymer gels to improve maneuverability and prevent vasospasm. However, there are reports of the coating embolizing, resulting

in severe reactions such as stroke, pulmonary infarction, and death.

Dr. Bridges and colleagues presented a case study of eight patients with livedo racemosa and purpura after an endovascular procedure. The patients had punch biopsies obtained with hematoxylin-eosin-stained sections.

The study subjects were between 58 and 81 years old, most were men and most had previous endovascular procedures and multiple comorbidities, according to an article online August 11 in the Journal of the American Academy of Dermatology.

In all but one patient, the cutaneous lesions were unilateral and all but two were asymptomatic. Six patients presented with livedo racemosa and two with purpura.

All cases demonstrated pauci-inflammatory occlusion in the mid-dermal and small superficial vessels. Likewise, histopathologic evidence was consistent with previously reported cases of emboli secondary to hydrophilic gel polymer.

There was no evidence of embolic sequela to the organs in three patients. However, one patient died of unknown reasons and four patients experienced postoperative complications including spinal cord ischemia, acute kidney injury, and cerebral infarction. In all cases, the cutaneous manifestations resolved without intervention.

The authors say they suspect the incidence of this type of embolization is underrecognized, especially with the common use of hydrophilic polymer gel coatings.

"This report highlights the importance of awareness of this rare iatrogenic complication and the importance of investigating a patient's clinical history to determine if there had been recent exposure to an intravascular device with a hydrophilic coating," Dr. Bridges said.

"While the use of polymer-coated devices offers several advantages, clinicians must be aware of their potential complications, including stroke, myocardial and pulmonary infarction, gangrene, and/or death," she said.

The authors reported no funding or conflicts of interest.

NEW YORK - Coating on endovascular devices is associated with embolization and microvascular occlusion leading to purpura or livedo racemosa, according to a new report.

Dr. Alina Bridges, of the Department of Dermatology at Mayo Clinic in Rochester, Minnesota, said by email that the study was conducted "to make clinicians and pathologists aware of this underrecognized phenomenon of iatrogenic hydrophilic polymer gel embolization that can involve the skin and present with purpura."

The phenomenon "has distinctive microscopic morphology and potential for internal organ involvement," she added.

Endovascular devices commonly are coated with hydrophilic polymer gels to improve maneuverability and prevent vasospasm. However, there are reports of the coating embolizing, resulting

in severe reactions such as stroke, pulmonary infarction, and death.

Dr. Bridges and colleagues presented a case study of eight patients with livedo racemosa and purpura after an endovascular procedure. The patients had punch biopsies obtained with hematoxylin-eosin-stained sections.

The study subjects were between 58 and 81 years old, most were men and most had previous endovascular procedures and multiple comorbidities, according to an article online August 11 in the Journal of the American Academy of Dermatology.

In all but one patient, the cutaneous lesions were unilateral and all but two were asymptomatic. Six patients presented with livedo racemosa and two with purpura.

All cases demonstrated pauci-inflammatory occlusion in the mid-dermal and small superficial vessels. Likewise, histopathologic evidence was consistent with previously reported cases of emboli secondary to hydrophilic gel polymer.

There was no evidence of embolic sequela to the organs in three patients. However, one patient died of unknown reasons and four patients experienced postoperative complications including spinal cord ischemia, acute kidney injury, and cerebral infarction. In all cases, the cutaneous manifestations resolved without intervention.

The authors say they suspect the incidence of this type of embolization is underrecognized, especially with the common use of hydrophilic polymer gel coatings.

"This report highlights the importance of awareness of this rare iatrogenic complication and the importance of investigating a patient's clinical history to determine if there had been recent exposure to an intravascular device with a hydrophilic coating," Dr. Bridges said.

"While the use of polymer-coated devices offers several advantages, clinicians must be aware of their potential complications, including stroke, myocardial and pulmonary infarction, gangrene, and/or death," she said.

The authors reported no funding or conflicts of interest.

Patients with actinic keratosis who used UPF 50 sunscreen containing DNA repair enzymes improved significantly more on two measures of malignant progression than did those who used sunscreen alone, according to research published in the Journal of Drugs in Dermatology.

At 6 months, improvements in field cancerization and levels of cyclobutane pyrimidine dimers were significantly greater (P less than .001) for the sunscreen-plus-enzymes group compared with sunscreen-only patients, wrote Dr. Mauro Carducci of Centro Ortopedico di Quadrante in Omegna, Italy, and his associates.

The study is the first of its type to directly compare the clinical effects of two such topicals, the investigators wrote. The findings set the stage for longer, larger trials that are powered to assess the risk of progression to squamous cell carcinoma, they added.

©Stockbyte/ thinkstockphotos.com

For the study, 28 patients with AK were randomly assigned to use SPF 50 sunscreen alone or a formula that contained 1% photolyase from Anacystis nidulans and 1% endonuclease from Micrococcus luteus. Patients applied 2 mg/cm² of sunscreen to treatment areas that contained 4-10 AKs. They were not allowed to use other topicals during the trial or for 2 weeks beforehand.

All of the patients were white and aged older than 65 years; three-quarters were men. The investigators used fluorescence diagnostics with methylaminolaevulinate to measure field cancerization, and analyzed skin biopsies to quantify CPD levels (J Drugs Dermatol. 2015;14[9]:986-90.).

Hyperkeratosis improved the same amount in both groups at month 6, according to the researchers. But field cancerizations dropped 29% from baseline in the sunscreen-plus-enzymes group, compared with a 10% decrease with sunscreen alone (P less than .0001). Likewise, CPD levels fell 61% from baseline in the sunscreen-plus-enzymes group compared with a 35% drop with sunscreen alone (P less than .0001).

Despite those significant differences, the study was not powered to detect differences in the risk of transformation to SCC, the researchers cautioned.

Biodue S.p.A. provided the methyl aminolevulinate used in the study. Dr. Enzo Emanuele, the study’s senior author, is a major shareholder of Living Research S.A.S., a privately held biomedical research organization that provided funding for the work. The other researchers reported no conflicts of interest.

Patients with actinic keratosis who used UPF 50 sunscreen containing DNA repair enzymes improved significantly more on two measures of malignant progression than did those who used sunscreen alone, according to research published in the Journal of Drugs in Dermatology.

At 6 months, improvements in field cancerization and levels of cyclobutane pyrimidine dimers were significantly greater (P less than .001) for the sunscreen-plus-enzymes group compared with sunscreen-only patients, wrote Dr. Mauro Carducci of Centro Ortopedico di Quadrante in Omegna, Italy, and his associates.

The study is the first of its type to directly compare the clinical effects of two such topicals, the investigators wrote. The findings set the stage for longer, larger trials that are powered to assess the risk of progression to squamous cell carcinoma, they added.

©Stockbyte/ thinkstockphotos.com

For the study, 28 patients with AK were randomly assigned to use SPF 50 sunscreen alone or a formula that contained 1% photolyase from Anacystis nidulans and 1% endonuclease from Micrococcus luteus. Patients applied 2 mg/cm² of sunscreen to treatment areas that contained 4-10 AKs. They were not allowed to use other topicals during the trial or for 2 weeks beforehand.

All of the patients were white and aged older than 65 years; three-quarters were men. The investigators used fluorescence diagnostics with methylaminolaevulinate to measure field cancerization, and analyzed skin biopsies to quantify CPD levels (J Drugs Dermatol. 2015;14[9]:986-90.).

Hyperkeratosis improved the same amount in both groups at month 6, according to the researchers. But field cancerizations dropped 29% from baseline in the sunscreen-plus-enzymes group, compared with a 10% decrease with sunscreen alone (P less than .0001). Likewise, CPD levels fell 61% from baseline in the sunscreen-plus-enzymes group compared with a 35% drop with sunscreen alone (P less than .0001).

Despite those significant differences, the study was not powered to detect differences in the risk of transformation to SCC, the researchers cautioned.

Biodue S.p.A. provided the methyl aminolevulinate used in the study. Dr. Enzo Emanuele, the study’s senior author, is a major shareholder of Living Research S.A.S., a privately held biomedical research organization that provided funding for the work. The other researchers reported no conflicts of interest.

Patients with actinic keratosis who used UPF 50 sunscreen containing DNA repair enzymes improved significantly more on two measures of malignant progression than did those who used sunscreen alone, according to research published in the Journal of Drugs in Dermatology.

At 6 months, improvements in field cancerization and levels of cyclobutane pyrimidine dimers were significantly greater (P less than .001) for the sunscreen-plus-enzymes group compared with sunscreen-only patients, wrote Dr. Mauro Carducci of Centro Ortopedico di Quadrante in Omegna, Italy, and his associates.

The study is the first of its type to directly compare the clinical effects of two such topicals, the investigators wrote. The findings set the stage for longer, larger trials that are powered to assess the risk of progression to squamous cell carcinoma, they added.

©Stockbyte/ thinkstockphotos.com

For the study, 28 patients with AK were randomly assigned to use SPF 50 sunscreen alone or a formula that contained 1% photolyase from Anacystis nidulans and 1% endonuclease from Micrococcus luteus. Patients applied 2 mg/cm² of sunscreen to treatment areas that contained 4-10 AKs. They were not allowed to use other topicals during the trial or for 2 weeks beforehand.

All of the patients were white and aged older than 65 years; three-quarters were men. The investigators used fluorescence diagnostics with methylaminolaevulinate to measure field cancerization, and analyzed skin biopsies to quantify CPD levels (J Drugs Dermatol. 2015;14[9]:986-90.).

Hyperkeratosis improved the same amount in both groups at month 6, according to the researchers. But field cancerizations dropped 29% from baseline in the sunscreen-plus-enzymes group, compared with a 10% decrease with sunscreen alone (P less than .0001). Likewise, CPD levels fell 61% from baseline in the sunscreen-plus-enzymes group compared with a 35% drop with sunscreen alone (P less than .0001).

Despite those significant differences, the study was not powered to detect differences in the risk of transformation to SCC, the researchers cautioned.

Biodue S.p.A. provided the methyl aminolevulinate used in the study. Dr. Enzo Emanuele, the study’s senior author, is a major shareholder of Living Research S.A.S., a privately held biomedical research organization that provided funding for the work. The other researchers reported no conflicts of interest.

Slide showing LSCs

Image by Robert Paulson

Two groups of researchers have reported results that help explain how leukemia resists treatment with BET inhibitors.

One group was able to grow and maintain leukemia stem cells (LSCs) in vitro, and their subsequent experiments showed how LSCs react to BET inhibition.

The other group found evidence to suggest that by measuring Wnt signaling markers, we might be able to predict which patients will respond to BET inhibition.

Both groups described their research in letters to Nature.

“[T]he risk of resistance developing is common in any cancer treatment,” said Mark Dawson, PhD, a researcher at Peter MacCallum Cancer Centre in East Melbourne, Victoria, Australia and an author of the LSC study.

“Knowing precisely how that happens in advance puts us one step ahead in outmaneuvering the disease. Being able to grow and maintain leukemia

stem cells in vitro also gives us unprecedented access and insight into how they work so we can find new and better ways to target and destroy them.”

In their study, Dr Dawson and his colleagues assessed BET inhibitor resistance in a model of acute myeloid leukemia.

The team transduced murine hematopoietic stem and progenitor cells with MLL–AF9 and treated the cells with the BET inhibitor I-BET or dimethylsulfoxide (vehicle). They then isolated individual blast colonies to generate 4 vehicle-treated and 5 I-BET-resistant cell lines.

The researchers found that resistance to I-BET also conferred resistance to the chemically distinct BET inhibitor JQ1 and to genetic knockdown of BET proteins.

Further investigation revealed that resistance to BET inhibitors emerges from LSCs, both ex vivo and in vivo. And that resistance is, in part, a result of increased Wnt/β-catenin signaling.

The researchers noted that not all LSCs are intrinsically resistant to BET inhibition, but a small proportion of them are either transcriptionally primed or display rapid transcriptional plasticity to survive the initial BET inhibitor challenge. The team said these cells then thrive and become the dominant population.

These findings are consistent with results of the other study, conducted by Johannes Zuber, MD, of the Research Institute of Molecular Pathology in Vienna, Austria, and his colleagues.

With this study, the researchers set out to determine why only certain leukemia subtypes are sensitive to BET inhibitors. Their experiments revealed that loss of the PRC2 complex, which is known to inactivate genes during normal development, can render leukemia cells resistant to BET inhibitors.

By further characterizing these resistant cells, the team found that MYC and other BRD4-regulated genes (which are turned off by BET inhibitors) were back on again. So the leukemia cells had found a way to activate these genes in the absence of BRD4.

The researchers then compared leukemia cells that had acquired resistance during BET inhibitor treatment to leukemia cells that were resistant in the first place.

In both cases, the cells used similar pathways to turn critical genes such as MYC back on and thereby escape the effects of BET inhibition. A pathway that proved particularly important was the Wnt signaling pathway, which is known to activate MYC in cancers.

To determine whether this knowledge could be used to predict which patients will respond to BET inhibitors, the researchers measured Wnt signaling markers in samples from leukemia patients.

The team found that cells with low Wnt activity were sensitive to BET inhibitors, while high Wnt activity was associated with resistance.

Specifically, the researchers quantified 9 Wnt-associated transcripts in sensitive and resistant samples. Three of these transcripts—TCF4, CCND2, and HOXB4—were significantly overexpressed in resistant samples.

So the team used these 3 transcripts to establish a “resistance index” that, they believe, may provide a first step toward developing a predictive biomarker.

The researchers said, collectively, their study reveals that leukemia cells can become resistant to BET inhibitors by rewiring the regulation of critical BRD4 target genes. This transcriptional plasticity highlights an emerging mode of drug resistance that is distinct from established resistance mechanisms such as mutations in binding pockets or drug elimination through efflux pumps.

Dr Zuber and his colleagues believe that a better understanding of these adaptation mechanisms will lead to combination therapies that will ultimately “outsmart” cancer cells.

“We now have learned that cancer cells can adapt to targeted therapies, but their repertoire of escape routes is quite limited,” Dr Zuber said. “A better understanding of the common escape routes will allow us to predict the next effective targeted therapy so that we are always one step ahead of the cancer cell.”

Slide showing LSCs

Image by Robert Paulson

Two groups of researchers have reported results that help explain how leukemia resists treatment with BET inhibitors.

One group was able to grow and maintain leukemia stem cells (LSCs) in vitro, and their subsequent experiments showed how LSCs react to BET inhibition.

The other group found evidence to suggest that by measuring Wnt signaling markers, we might be able to predict which patients will respond to BET inhibition.

Both groups described their research in letters to Nature.

“[T]he risk of resistance developing is common in any cancer treatment,” said Mark Dawson, PhD, a researcher at Peter MacCallum Cancer Centre in East Melbourne, Victoria, Australia and an author of the LSC study.

“Knowing precisely how that happens in advance puts us one step ahead in outmaneuvering the disease. Being able to grow and maintain leukemia

stem cells in vitro also gives us unprecedented access and insight into how they work so we can find new and better ways to target and destroy them.”

In their study, Dr Dawson and his colleagues assessed BET inhibitor resistance in a model of acute myeloid leukemia.

The team transduced murine hematopoietic stem and progenitor cells with MLL–AF9 and treated the cells with the BET inhibitor I-BET or dimethylsulfoxide (vehicle). They then isolated individual blast colonies to generate 4 vehicle-treated and 5 I-BET-resistant cell lines.

The researchers found that resistance to I-BET also conferred resistance to the chemically distinct BET inhibitor JQ1 and to genetic knockdown of BET proteins.

Further investigation revealed that resistance to BET inhibitors emerges from LSCs, both ex vivo and in vivo. And that resistance is, in part, a result of increased Wnt/β-catenin signaling.

The researchers noted that not all LSCs are intrinsically resistant to BET inhibition, but a small proportion of them are either transcriptionally primed or display rapid transcriptional plasticity to survive the initial BET inhibitor challenge. The team said these cells then thrive and become the dominant population.

These findings are consistent with results of the other study, conducted by Johannes Zuber, MD, of the Research Institute of Molecular Pathology in Vienna, Austria, and his colleagues.

With this study, the researchers set out to determine why only certain leukemia subtypes are sensitive to BET inhibitors. Their experiments revealed that loss of the PRC2 complex, which is known to inactivate genes during normal development, can render leukemia cells resistant to BET inhibitors.

By further characterizing these resistant cells, the team found that MYC and other BRD4-regulated genes (which are turned off by BET inhibitors) were back on again. So the leukemia cells had found a way to activate these genes in the absence of BRD4.

The researchers then compared leukemia cells that had acquired resistance during BET inhibitor treatment to leukemia cells that were resistant in the first place.

In both cases, the cells used similar pathways to turn critical genes such as MYC back on and thereby escape the effects of BET inhibition. A pathway that proved particularly important was the Wnt signaling pathway, which is known to activate MYC in cancers.

To determine whether this knowledge could be used to predict which patients will respond to BET inhibitors, the researchers measured Wnt signaling markers in samples from leukemia patients.

The team found that cells with low Wnt activity were sensitive to BET inhibitors, while high Wnt activity was associated with resistance.

Specifically, the researchers quantified 9 Wnt-associated transcripts in sensitive and resistant samples. Three of these transcripts—TCF4, CCND2, and HOXB4—were significantly overexpressed in resistant samples.

So the team used these 3 transcripts to establish a “resistance index” that, they believe, may provide a first step toward developing a predictive biomarker.

The researchers said, collectively, their study reveals that leukemia cells can become resistant to BET inhibitors by rewiring the regulation of critical BRD4 target genes. This transcriptional plasticity highlights an emerging mode of drug resistance that is distinct from established resistance mechanisms such as mutations in binding pockets or drug elimination through efflux pumps.

Dr Zuber and his colleagues believe that a better understanding of these adaptation mechanisms will lead to combination therapies that will ultimately “outsmart” cancer cells.

“We now have learned that cancer cells can adapt to targeted therapies, but their repertoire of escape routes is quite limited,” Dr Zuber said. “A better understanding of the common escape routes will allow us to predict the next effective targeted therapy so that we are always one step ahead of the cancer cell.”

Slide showing LSCs

Image by Robert Paulson

Two groups of researchers have reported results that help explain how leukemia resists treatment with BET inhibitors.

One group was able to grow and maintain leukemia stem cells (LSCs) in vitro, and their subsequent experiments showed how LSCs react to BET inhibition.

The other group found evidence to suggest that by measuring Wnt signaling markers, we might be able to predict which patients will respond to BET inhibition.

Both groups described their research in letters to Nature.

“[T]he risk of resistance developing is common in any cancer treatment,” said Mark Dawson, PhD, a researcher at Peter MacCallum Cancer Centre in East Melbourne, Victoria, Australia and an author of the LSC study.

“Knowing precisely how that happens in advance puts us one step ahead in outmaneuvering the disease. Being able to grow and maintain leukemia

stem cells in vitro also gives us unprecedented access and insight into how they work so we can find new and better ways to target and destroy them.”

In their study, Dr Dawson and his colleagues assessed BET inhibitor resistance in a model of acute myeloid leukemia.

The team transduced murine hematopoietic stem and progenitor cells with MLL–AF9 and treated the cells with the BET inhibitor I-BET or dimethylsulfoxide (vehicle). They then isolated individual blast colonies to generate 4 vehicle-treated and 5 I-BET-resistant cell lines.

The researchers found that resistance to I-BET also conferred resistance to the chemically distinct BET inhibitor JQ1 and to genetic knockdown of BET proteins.

Further investigation revealed that resistance to BET inhibitors emerges from LSCs, both ex vivo and in vivo. And that resistance is, in part, a result of increased Wnt/β-catenin signaling.

The researchers noted that not all LSCs are intrinsically resistant to BET inhibition, but a small proportion of them are either transcriptionally primed or display rapid transcriptional plasticity to survive the initial BET inhibitor challenge. The team said these cells then thrive and become the dominant population.

These findings are consistent with results of the other study, conducted by Johannes Zuber, MD, of the Research Institute of Molecular Pathology in Vienna, Austria, and his colleagues.

With this study, the researchers set out to determine why only certain leukemia subtypes are sensitive to BET inhibitors. Their experiments revealed that loss of the PRC2 complex, which is known to inactivate genes during normal development, can render leukemia cells resistant to BET inhibitors.

By further characterizing these resistant cells, the team found that MYC and other BRD4-regulated genes (which are turned off by BET inhibitors) were back on again. So the leukemia cells had found a way to activate these genes in the absence of BRD4.

The researchers then compared leukemia cells that had acquired resistance during BET inhibitor treatment to leukemia cells that were resistant in the first place.

In both cases, the cells used similar pathways to turn critical genes such as MYC back on and thereby escape the effects of BET inhibition. A pathway that proved particularly important was the Wnt signaling pathway, which is known to activate MYC in cancers.

To determine whether this knowledge could be used to predict which patients will respond to BET inhibitors, the researchers measured Wnt signaling markers in samples from leukemia patients.

The team found that cells with low Wnt activity were sensitive to BET inhibitors, while high Wnt activity was associated with resistance.

Specifically, the researchers quantified 9 Wnt-associated transcripts in sensitive and resistant samples. Three of these transcripts—TCF4, CCND2, and HOXB4—were significantly overexpressed in resistant samples.

So the team used these 3 transcripts to establish a “resistance index” that, they believe, may provide a first step toward developing a predictive biomarker.

The researchers said, collectively, their study reveals that leukemia cells can become resistant to BET inhibitors by rewiring the regulation of critical BRD4 target genes. This transcriptional plasticity highlights an emerging mode of drug resistance that is distinct from established resistance mechanisms such as mutations in binding pockets or drug elimination through efflux pumps.

Dr Zuber and his colleagues believe that a better understanding of these adaptation mechanisms will lead to combination therapies that will ultimately “outsmart” cancer cells.

“We now have learned that cancer cells can adapt to targeted therapies, but their repertoire of escape routes is quite limited,” Dr Zuber said. “A better understanding of the common escape routes will allow us to predict the next effective targeted therapy so that we are always one step ahead of the cancer cell.”

Withania somnifera

The active compound in a plant extract has shown promise for treating non-Hodgkin lymphomas (NHLs), according to researchers.

The compound, withaferin A, is a steroidal lactone isolated from the Ayruvedic medicinal plant Ashwagandha (Withania somnifera).

Withaferin A has previously exhibited activity against a range of solid tumor malignancies, but its effects in NHLs and other hematologic malignancies have not been well-studied.

So Subbarao Bondada, PhD, of the University of Kentucky in Lexington, and his colleagues tested withaferin A in NHLs and reported their results in Cancer Biology and Therapy.

Withaferin A exhibited activity in several human B-cell lymphoma cell lines—the diffuse large B-cell lymphoma (DLBCL) cell lines LY-3, LY-10, and SudHL-6; the Burkitt lymphoma cell lines Raji and Ramos; and the mantle cell lymphoma cell line MINO.

Ramos was the most sensitive to withaferin A, and the mantle cell lymphoma cell line JEKO was the most resistant. The researchers said they are still investigating this resistance.

Withaferin A also inhibited the growth of the murine immature B-cell lymphoma cell line BKS-2 and the germinal center lymphoma cell line A20-Luc/YFP.

Further investigation revealed that withaferin A induces cell-cycle arrest, prompts apoptosis, inhibits NF-kB nuclear translocation, and reduces the expression of pro-survival signals in B-cell lymphomas.

The researchers also found evidence to suggest that withaferin A inhibits the activity of Hsp90. Although Hsp90 levels were unaltered in withaferin-A-treated lymphoma cells, the team observed a “robust” increase in Hsp70 expression levels (which suggests a decrease in Hsp90 function).

Finally, the researchers tested withaferin A in mice injected with the murine DLBCL line A20-Luc. The treatment proved active against A20-Luc cells but did not affect other proliferating cells.

Mice treated with withaferin A had a significant reduction in tumor size, compared to placebo-treated mice, on days 10 and 13 (P<0.05).

Based on these results, the researchers concluded that withaferin A may hold promise for treating NHL, particularly DLBCL.

“It may be possible to develop orally administered versions of withaferin A that could be used in lymphoma patients with fewer side effects than current chemotherapy regimens,” Dr Bondada said.

He and his colleagues are now testing withaferin A in chronic lymphocytic leukemia.

Withania somnifera

The active compound in a plant extract has shown promise for treating non-Hodgkin lymphomas (NHLs), according to researchers.

The compound, withaferin A, is a steroidal lactone isolated from the Ayruvedic medicinal plant Ashwagandha (Withania somnifera).

Withaferin A has previously exhibited activity against a range of solid tumor malignancies, but its effects in NHLs and other hematologic malignancies have not been well-studied.

So Subbarao Bondada, PhD, of the University of Kentucky in Lexington, and his colleagues tested withaferin A in NHLs and reported their results in Cancer Biology and Therapy.

Withaferin A exhibited activity in several human B-cell lymphoma cell lines—the diffuse large B-cell lymphoma (DLBCL) cell lines LY-3, LY-10, and SudHL-6; the Burkitt lymphoma cell lines Raji and Ramos; and the mantle cell lymphoma cell line MINO.

Ramos was the most sensitive to withaferin A, and the mantle cell lymphoma cell line JEKO was the most resistant. The researchers said they are still investigating this resistance.

Withaferin A also inhibited the growth of the murine immature B-cell lymphoma cell line BKS-2 and the germinal center lymphoma cell line A20-Luc/YFP.

Further investigation revealed that withaferin A induces cell-cycle arrest, prompts apoptosis, inhibits NF-kB nuclear translocation, and reduces the expression of pro-survival signals in B-cell lymphomas.

The researchers also found evidence to suggest that withaferin A inhibits the activity of Hsp90. Although Hsp90 levels were unaltered in withaferin-A-treated lymphoma cells, the team observed a “robust” increase in Hsp70 expression levels (which suggests a decrease in Hsp90 function).

Finally, the researchers tested withaferin A in mice injected with the murine DLBCL line A20-Luc. The treatment proved active against A20-Luc cells but did not affect other proliferating cells.

Mice treated with withaferin A had a significant reduction in tumor size, compared to placebo-treated mice, on days 10 and 13 (P<0.05).

Based on these results, the researchers concluded that withaferin A may hold promise for treating NHL, particularly DLBCL.

“It may be possible to develop orally administered versions of withaferin A that could be used in lymphoma patients with fewer side effects than current chemotherapy regimens,” Dr Bondada said.

He and his colleagues are now testing withaferin A in chronic lymphocytic leukemia.

Withania somnifera

The active compound in a plant extract has shown promise for treating non-Hodgkin lymphomas (NHLs), according to researchers.

The compound, withaferin A, is a steroidal lactone isolated from the Ayruvedic medicinal plant Ashwagandha (Withania somnifera).

Withaferin A has previously exhibited activity against a range of solid tumor malignancies, but its effects in NHLs and other hematologic malignancies have not been well-studied.

So Subbarao Bondada, PhD, of the University of Kentucky in Lexington, and his colleagues tested withaferin A in NHLs and reported their results in Cancer Biology and Therapy.

Withaferin A exhibited activity in several human B-cell lymphoma cell lines—the diffuse large B-cell lymphoma (DLBCL) cell lines LY-3, LY-10, and SudHL-6; the Burkitt lymphoma cell lines Raji and Ramos; and the mantle cell lymphoma cell line MINO.

Ramos was the most sensitive to withaferin A, and the mantle cell lymphoma cell line JEKO was the most resistant. The researchers said they are still investigating this resistance.

Withaferin A also inhibited the growth of the murine immature B-cell lymphoma cell line BKS-2 and the germinal center lymphoma cell line A20-Luc/YFP.

Further investigation revealed that withaferin A induces cell-cycle arrest, prompts apoptosis, inhibits NF-kB nuclear translocation, and reduces the expression of pro-survival signals in B-cell lymphomas.

The researchers also found evidence to suggest that withaferin A inhibits the activity of Hsp90. Although Hsp90 levels were unaltered in withaferin-A-treated lymphoma cells, the team observed a “robust” increase in Hsp70 expression levels (which suggests a decrease in Hsp90 function).

Finally, the researchers tested withaferin A in mice injected with the murine DLBCL line A20-Luc. The treatment proved active against A20-Luc cells but did not affect other proliferating cells.

Mice treated with withaferin A had a significant reduction in tumor size, compared to placebo-treated mice, on days 10 and 13 (P<0.05).

Based on these results, the researchers concluded that withaferin A may hold promise for treating NHL, particularly DLBCL.

“It may be possible to develop orally administered versions of withaferin A that could be used in lymphoma patients with fewer side effects than current chemotherapy regimens,” Dr Bondada said.

He and his colleagues are now testing withaferin A in chronic lymphocytic leukemia.