Researchers in the lab

Credit: NIH

A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.

The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.

Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.

The researchers reported these discoveries in Cancer Cell.

Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.

The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin^-CD34⁺CD38^-CD90⁺CD45RA^- cells—that appeared to have all the properties of cancer stem cells.

These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.

“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”

Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.

But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.

“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.

Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.

“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”

Researchers in the lab

Credit: NIH

A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.

The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.

Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.

The researchers reported these discoveries in Cancer Cell.

Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.

The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin^-CD34⁺CD38^-CD90⁺CD45RA^- cells—that appeared to have all the properties of cancer stem cells.

These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.

“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”

Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.

But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.

“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.

Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.

“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”

Researchers in the lab

Credit: NIH

A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.

The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.

Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.

The researchers reported these discoveries in Cancer Cell.

Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.

The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin^-CD34⁺CD38^-CD90⁺CD45RA^- cells—that appeared to have all the properties of cancer stem cells.

These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.

“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”

Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.

But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.

“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.

Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.

“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Doctor and patient

Credit: CDC

Results of a proof-of-principle study suggest virotherapy can be effective against multiple myeloma (MM).

The study included 2 MM patients who each received a single dose of a measles virus engineered to target myeloma plasma cells (MV-NIS).

Both patients responded to the treatment, with initial reductions in M protein and complete resolution of bone marrow plasmacytosis. One of the patients achieved a complete remission that lasted 9 months.

The patients did experience adverse effects associated with MV-NIS, but all were resolved with appropriate treatment.

“This is the first study to establish the feasibility of systemic oncolytic virotherapy for disseminated cancer,” said Stephen Russell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.

“These patients were not responsive to other therapies and had experienced several recurrences of their disease.”

Dr Russell and his colleagues described this research in Mayo Clinic Proceedings.

Patient characteristics, treatment

The researchers explained that the 2 patients described in this report were the first to receive MV-NIS at the highest possible dose. They both received the virus at a dose of 10¹¹ TCID₅₀, infused into a superficial arm vein in 100 mL of normal saline over 60 minutes.

Both patients had limited previous exposure to measles (and therefore fewer antibodies to the virus) and essentially no remaining treatment options.

The first patient was a 49-year-old woman with heavily pretreated, light chain MM. Her last relapse was 9 months after her second autologous stem cell transplant, while she was not receiving therapy.

The second patient was a 65-year-old woman with relapsing IgA k MM that was refractory to all approved antimyeloma drugs. Her disease had progressed while she was receiving carfilzomib, pomalidomide, and dexamethasone therapy.

Adverse events

Patient 1 experienced a number of adverse effects related to MV-NIS, including a severe headache during treatment that required clinicians to temporarily stop her infusion.

This was followed by fever, tachycardia, hypotension, severe nausea and vomiting, and a superficial venous thrombosis extending from the wrist to the upper humerus. But all of these events responded to treatment.

Patient 2 also experienced adverse effects related to MV-NIS, including fever, tachycardia, hypotension, and headache. She responded to treatment for these events, and her recurring fever resolved spontaneously after a few hours.

Treatment response

Both patients’ disease responded to MV-NIS. They experienced initial reductions in M protein and complete resolution of bone marrow plasmacytosis at 6 weeks after treatment.

Patient 1 achieved a complete remission that lasted 9 months. A scan at 6 weeks showed the patient had experienced substantial improvement in all 5 of her previously identified lesions.

Although patient 2 initially responded to treatment, her plasmacytomas were progressing at the 6-week mark, and her free light chain level was increasing. Her 6-week scan revealed increased size and FDG uptake in most soft tissue lesions, although a few lesions did show varying degrees of improvement.

Doctor and patient

Credit: CDC

Results of a proof-of-principle study suggest virotherapy can be effective against multiple myeloma (MM).

The study included 2 MM patients who each received a single dose of a measles virus engineered to target myeloma plasma cells (MV-NIS).

Both patients responded to the treatment, with initial reductions in M protein and complete resolution of bone marrow plasmacytosis. One of the patients achieved a complete remission that lasted 9 months.

The patients did experience adverse effects associated with MV-NIS, but all were resolved with appropriate treatment.

“This is the first study to establish the feasibility of systemic oncolytic virotherapy for disseminated cancer,” said Stephen Russell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.

“These patients were not responsive to other therapies and had experienced several recurrences of their disease.”

Dr Russell and his colleagues described this research in Mayo Clinic Proceedings.

Patient characteristics, treatment

The researchers explained that the 2 patients described in this report were the first to receive MV-NIS at the highest possible dose. They both received the virus at a dose of 10¹¹ TCID₅₀, infused into a superficial arm vein in 100 mL of normal saline over 60 minutes.

Both patients had limited previous exposure to measles (and therefore fewer antibodies to the virus) and essentially no remaining treatment options.

The first patient was a 49-year-old woman with heavily pretreated, light chain MM. Her last relapse was 9 months after her second autologous stem cell transplant, while she was not receiving therapy.

The second patient was a 65-year-old woman with relapsing IgA k MM that was refractory to all approved antimyeloma drugs. Her disease had progressed while she was receiving carfilzomib, pomalidomide, and dexamethasone therapy.

Adverse events

Patient 1 experienced a number of adverse effects related to MV-NIS, including a severe headache during treatment that required clinicians to temporarily stop her infusion.

This was followed by fever, tachycardia, hypotension, severe nausea and vomiting, and a superficial venous thrombosis extending from the wrist to the upper humerus. But all of these events responded to treatment.

Patient 2 also experienced adverse effects related to MV-NIS, including fever, tachycardia, hypotension, and headache. She responded to treatment for these events, and her recurring fever resolved spontaneously after a few hours.

Treatment response

Both patients’ disease responded to MV-NIS. They experienced initial reductions in M protein and complete resolution of bone marrow plasmacytosis at 6 weeks after treatment.

Patient 1 achieved a complete remission that lasted 9 months. A scan at 6 weeks showed the patient had experienced substantial improvement in all 5 of her previously identified lesions.

Although patient 2 initially responded to treatment, her plasmacytomas were progressing at the 6-week mark, and her free light chain level was increasing. Her 6-week scan revealed increased size and FDG uptake in most soft tissue lesions, although a few lesions did show varying degrees of improvement.

Doctor and patient

Credit: CDC

Results of a proof-of-principle study suggest virotherapy can be effective against multiple myeloma (MM).

The study included 2 MM patients who each received a single dose of a measles virus engineered to target myeloma plasma cells (MV-NIS).

Both patients responded to the treatment, with initial reductions in M protein and complete resolution of bone marrow plasmacytosis. One of the patients achieved a complete remission that lasted 9 months.

The patients did experience adverse effects associated with MV-NIS, but all were resolved with appropriate treatment.

“This is the first study to establish the feasibility of systemic oncolytic virotherapy for disseminated cancer,” said Stephen Russell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.

“These patients were not responsive to other therapies and had experienced several recurrences of their disease.”

Dr Russell and his colleagues described this research in Mayo Clinic Proceedings.

Patient characteristics, treatment

The researchers explained that the 2 patients described in this report were the first to receive MV-NIS at the highest possible dose. They both received the virus at a dose of 10¹¹ TCID₅₀, infused into a superficial arm vein in 100 mL of normal saline over 60 minutes.

Both patients had limited previous exposure to measles (and therefore fewer antibodies to the virus) and essentially no remaining treatment options.

The first patient was a 49-year-old woman with heavily pretreated, light chain MM. Her last relapse was 9 months after her second autologous stem cell transplant, while she was not receiving therapy.

The second patient was a 65-year-old woman with relapsing IgA k MM that was refractory to all approved antimyeloma drugs. Her disease had progressed while she was receiving carfilzomib, pomalidomide, and dexamethasone therapy.

Adverse events

Patient 1 experienced a number of adverse effects related to MV-NIS, including a severe headache during treatment that required clinicians to temporarily stop her infusion.

This was followed by fever, tachycardia, hypotension, severe nausea and vomiting, and a superficial venous thrombosis extending from the wrist to the upper humerus. But all of these events responded to treatment.

Patient 2 also experienced adverse effects related to MV-NIS, including fever, tachycardia, hypotension, and headache. She responded to treatment for these events, and her recurring fever resolved spontaneously after a few hours.

Treatment response

Both patients’ disease responded to MV-NIS. They experienced initial reductions in M protein and complete resolution of bone marrow plasmacytosis at 6 weeks after treatment.

Patient 1 achieved a complete remission that lasted 9 months. A scan at 6 weeks showed the patient had experienced substantial improvement in all 5 of her previously identified lesions.

Although patient 2 initially responded to treatment, her plasmacytomas were progressing at the 6-week mark, and her free light chain level was increasing. Her 6-week scan revealed increased size and FDG uptake in most soft tissue lesions, although a few lesions did show varying degrees of improvement.

Benjamin Yellen, PhD

Credit: Duke University

Using components similar to those that control electrons in microchips, engineers have designed a device that can sort, store, and retrieve individual cells for study.

The team hopes this chip-like device could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes.

Benjamin Yellen, PhD, of Duke University in Durham, North Carolina, and his colleagues described the device in Nature Communications.

The team created the device by printing thin electromagnetic components, like those found on microchips, onto a slide. These patterns create magnetic tracks and elements like switches, transistors, and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin, liquid film.

Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much the way electrons are controlled on computer chips.

The engineers showed that a grid of 9 compartments—3 across by 3 down—allows the magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied, and retrieved.

“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” Dr Yellen said. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

As an example, Dr Yellen pointed to cells affected by cancers. Most afflicted cells are active and can be targeted by therapeutics. But a few rare cells remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission.

With the new technology, Dr Yellen and his colleagues hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them, and analyze their genetic activity.

“Our technology can offer new tools to improve our basic understanding of cancer metastasis at the single-cell level, how cancer cells respond to chemical and physical stimuli, and to test new concepts for gene delivery and metabolite transfer during cell division and growth,” said study author CheolGi Kim, PhD, of the Daegu Gyeongbuk Institute of Science and Technology in the Republic of Korea.

The researchers now plan to demonstrate a larger grid of 8-by-8 or 16-by-16 compartments with cells, and then to scale it up to hundreds of thousands of compartments.

“Our idea is a simple one,” Dr Kim said. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialization.”

“There’s another technique paper we need to do as a follow-up before we get to actual biological applications,” Dr Yellen added. “But they’re on their way.”

Benjamin Yellen, PhD

Credit: Duke University

Using components similar to those that control electrons in microchips, engineers have designed a device that can sort, store, and retrieve individual cells for study.

The team hopes this chip-like device could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes.

Benjamin Yellen, PhD, of Duke University in Durham, North Carolina, and his colleagues described the device in Nature Communications.

The team created the device by printing thin electromagnetic components, like those found on microchips, onto a slide. These patterns create magnetic tracks and elements like switches, transistors, and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin, liquid film.

Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much the way electrons are controlled on computer chips.

The engineers showed that a grid of 9 compartments—3 across by 3 down—allows the magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied, and retrieved.

“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” Dr Yellen said. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

As an example, Dr Yellen pointed to cells affected by cancers. Most afflicted cells are active and can be targeted by therapeutics. But a few rare cells remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission.

With the new technology, Dr Yellen and his colleagues hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them, and analyze their genetic activity.

“Our technology can offer new tools to improve our basic understanding of cancer metastasis at the single-cell level, how cancer cells respond to chemical and physical stimuli, and to test new concepts for gene delivery and metabolite transfer during cell division and growth,” said study author CheolGi Kim, PhD, of the Daegu Gyeongbuk Institute of Science and Technology in the Republic of Korea.

The researchers now plan to demonstrate a larger grid of 8-by-8 or 16-by-16 compartments with cells, and then to scale it up to hundreds of thousands of compartments.

“Our idea is a simple one,” Dr Kim said. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialization.”

“There’s another technique paper we need to do as a follow-up before we get to actual biological applications,” Dr Yellen added. “But they’re on their way.”

Benjamin Yellen, PhD

Credit: Duke University

Using components similar to those that control electrons in microchips, engineers have designed a device that can sort, store, and retrieve individual cells for study.

The team hopes this chip-like device could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes.

Benjamin Yellen, PhD, of Duke University in Durham, North Carolina, and his colleagues described the device in Nature Communications.

The team created the device by printing thin electromagnetic components, like those found on microchips, onto a slide. These patterns create magnetic tracks and elements like switches, transistors, and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin, liquid film.

Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much the way electrons are controlled on computer chips.

The engineers showed that a grid of 9 compartments—3 across by 3 down—allows the magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied, and retrieved.

“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” Dr Yellen said. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

As an example, Dr Yellen pointed to cells affected by cancers. Most afflicted cells are active and can be targeted by therapeutics. But a few rare cells remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission.

With the new technology, Dr Yellen and his colleagues hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them, and analyze their genetic activity.

“Our technology can offer new tools to improve our basic understanding of cancer metastasis at the single-cell level, how cancer cells respond to chemical and physical stimuli, and to test new concepts for gene delivery and metabolite transfer during cell division and growth,” said study author CheolGi Kim, PhD, of the Daegu Gyeongbuk Institute of Science and Technology in the Republic of Korea.

The researchers now plan to demonstrate a larger grid of 8-by-8 or 16-by-16 compartments with cells, and then to scale it up to hundreds of thousands of compartments.

“Our idea is a simple one,” Dr Kim said. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialization.”

“There’s another technique paper we need to do as a follow-up before we get to actual biological applications,” Dr Yellen added. “But they’re on their way.”

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Lately, I've been busy wading through a heavily publicized study that was published this month in the Lancet. In their paper, "Antipsychotics, mood stabilisers and risk of violent crime," Dr. Seena Fazel and his associates linked Swedish national registers to compare rates of violent crime among 82,647 male and female psychiatric patients to assess the effect of medication on this outcome.

The study made quite a splash in the news, because the outcome was almost too good to be true. There was a 64% reduction in violent crime among patients who had been prescribed any antipsychotic or mood stabilizer, compared with those taking other psychotropics. The reduction in violence for those taking neuroleptics and mood stabilizers was 45% and 24%, respectively. Selective serotonin reuptake inhibitors (SSRIs) had no apparent effect on crime (Lancet 2014 [doi:10.1016/S0140-6736(14)60379-2]).
Given our American anxiety over spree shooters and other high-profile crimes allegedly committed by untreated psychiatric patients, this study clearly deserves some scrutiny to thoroughly understand the findings, limitations, and other factors that could limit generalizability to the United States.

The authors compared mental health treatment registries with the national criminal history database. They looked at the rate and types of crimes committed by psychiatric patients when they were in and out of treatment. The "in-treatment" time interval was defined as the time between two or more prescriptions, as long as the prescriptions were no more than 4 months apart. Individuals who had only been given one script [prescription] were excluded. The outcome measure was any criminal conviction. The conviction outcome was based upon the date the offense took place, not the date of conviction. Individuals were excluded if the offense date was unknown.

A within-individual analysis showed significant reduction in all crimes, including violent crime, drug-related crime, and less severe crimes, during times when patients were prescribed medication, compared with medication-free intervals. When medicated, the rate of violent crime did not differ between patients with and without a history of violent offenses when diagnosis was not considered. When the analysis was limited to people with schizophrenia, bipolar disorder, or other psychotic disorders, the prescription of neuroleptics significantly reduced violent crime for both men and women.

For bipolar disorder, mood stabilizing medication reduced violent crime for men but not for women. The SSRI-medicated group was used as a control, to account for the general effect of contact with the mental health system and non-medication interventions related to this, and there was no effect on violent crime with this class of medication.

Now on to the limitations. Medication adherence was not assessed and could not be verified apart from patients given depot neuroleptics. The overall rate of violent crime was low, as would be expected. Only 6% of men and 1% of the women committed a violent crime. The numbers were so low that the study could not statistically assess the impact of violent crime history among patients diagnosed with psychosis. This is a small but crucial finding that did not make the traditional media coverage of this study.

Also, only 40% of those patients taking antipsychotics and mood stabilizers had a diagnosis of schizophrenia, other psychosis, or bipolar disorder, suggesting that, in Sweden, these medications might be prescribed for other indications such as characterologic low frustration tolerance or irritability. The analysis did not look at impact on violent crime by personality disorder diagnosis.

The authors acknowledged that their research could not prove a causal link between psychiatric illness and violence, another important conclusion that was not mentioned in traditional media coverage. In Sweden, mental illness cannot be used to prevent or mitigate a criminal conviction, so any connection between psychiatric symptoms and crime in this population can't be determined. The study also did not consider which subjects, if any, were taking medication or in treatment under court-mandated conditions.

As legislators and advocacy groups push to strengthen involuntary treatment laws, there is a risk that "bottom line" media coverage of research like this may inappropriately sway public opinion. Psychiatrists should be prepared to respond to proposed policies based on inaccurate interpretation of research.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson's employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Lately, I've been busy wading through a heavily publicized study that was published this month in the Lancet. In their paper, "Antipsychotics, mood stabilisers and risk of violent crime," Dr. Seena Fazel and his associates linked Swedish national registers to compare rates of violent crime among 82,647 male and female psychiatric patients to assess the effect of medication on this outcome.

The study made quite a splash in the news, because the outcome was almost too good to be true. There was a 64% reduction in violent crime among patients who had been prescribed any antipsychotic or mood stabilizer, compared with those taking other psychotropics. The reduction in violence for those taking neuroleptics and mood stabilizers was 45% and 24%, respectively. Selective serotonin reuptake inhibitors (SSRIs) had no apparent effect on crime (Lancet 2014 [doi:10.1016/S0140-6736(14)60379-2]).
Given our American anxiety over spree shooters and other high-profile crimes allegedly committed by untreated psychiatric patients, this study clearly deserves some scrutiny to thoroughly understand the findings, limitations, and other factors that could limit generalizability to the United States.

The authors compared mental health treatment registries with the national criminal history database. They looked at the rate and types of crimes committed by psychiatric patients when they were in and out of treatment. The "in-treatment" time interval was defined as the time between two or more prescriptions, as long as the prescriptions were no more than 4 months apart. Individuals who had only been given one script [prescription] were excluded. The outcome measure was any criminal conviction. The conviction outcome was based upon the date the offense took place, not the date of conviction. Individuals were excluded if the offense date was unknown.

A within-individual analysis showed significant reduction in all crimes, including violent crime, drug-related crime, and less severe crimes, during times when patients were prescribed medication, compared with medication-free intervals. When medicated, the rate of violent crime did not differ between patients with and without a history of violent offenses when diagnosis was not considered. When the analysis was limited to people with schizophrenia, bipolar disorder, or other psychotic disorders, the prescription of neuroleptics significantly reduced violent crime for both men and women.

For bipolar disorder, mood stabilizing medication reduced violent crime for men but not for women. The SSRI-medicated group was used as a control, to account for the general effect of contact with the mental health system and non-medication interventions related to this, and there was no effect on violent crime with this class of medication.

Now on to the limitations. Medication adherence was not assessed and could not be verified apart from patients given depot neuroleptics. The overall rate of violent crime was low, as would be expected. Only 6% of men and 1% of the women committed a violent crime. The numbers were so low that the study could not statistically assess the impact of violent crime history among patients diagnosed with psychosis. This is a small but crucial finding that did not make the traditional media coverage of this study.

Also, only 40% of those patients taking antipsychotics and mood stabilizers had a diagnosis of schizophrenia, other psychosis, or bipolar disorder, suggesting that, in Sweden, these medications might be prescribed for other indications such as characterologic low frustration tolerance or irritability. The analysis did not look at impact on violent crime by personality disorder diagnosis.

The authors acknowledged that their research could not prove a causal link between psychiatric illness and violence, another important conclusion that was not mentioned in traditional media coverage. In Sweden, mental illness cannot be used to prevent or mitigate a criminal conviction, so any connection between psychiatric symptoms and crime in this population can't be determined. The study also did not consider which subjects, if any, were taking medication or in treatment under court-mandated conditions.

As legislators and advocacy groups push to strengthen involuntary treatment laws, there is a risk that "bottom line" media coverage of research like this may inappropriately sway public opinion. Psychiatrists should be prepared to respond to proposed policies based on inaccurate interpretation of research.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson's employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Lately, I've been busy wading through a heavily publicized study that was published this month in the Lancet. In their paper, "Antipsychotics, mood stabilisers and risk of violent crime," Dr. Seena Fazel and his associates linked Swedish national registers to compare rates of violent crime among 82,647 male and female psychiatric patients to assess the effect of medication on this outcome.

The study made quite a splash in the news, because the outcome was almost too good to be true. There was a 64% reduction in violent crime among patients who had been prescribed any antipsychotic or mood stabilizer, compared with those taking other psychotropics. The reduction in violence for those taking neuroleptics and mood stabilizers was 45% and 24%, respectively. Selective serotonin reuptake inhibitors (SSRIs) had no apparent effect on crime (Lancet 2014 [doi:10.1016/S0140-6736(14)60379-2]).
Given our American anxiety over spree shooters and other high-profile crimes allegedly committed by untreated psychiatric patients, this study clearly deserves some scrutiny to thoroughly understand the findings, limitations, and other factors that could limit generalizability to the United States.

The authors compared mental health treatment registries with the national criminal history database. They looked at the rate and types of crimes committed by psychiatric patients when they were in and out of treatment. The "in-treatment" time interval was defined as the time between two or more prescriptions, as long as the prescriptions were no more than 4 months apart. Individuals who had only been given one script [prescription] were excluded. The outcome measure was any criminal conviction. The conviction outcome was based upon the date the offense took place, not the date of conviction. Individuals were excluded if the offense date was unknown.

A within-individual analysis showed significant reduction in all crimes, including violent crime, drug-related crime, and less severe crimes, during times when patients were prescribed medication, compared with medication-free intervals. When medicated, the rate of violent crime did not differ between patients with and without a history of violent offenses when diagnosis was not considered. When the analysis was limited to people with schizophrenia, bipolar disorder, or other psychotic disorders, the prescription of neuroleptics significantly reduced violent crime for both men and women.

For bipolar disorder, mood stabilizing medication reduced violent crime for men but not for women. The SSRI-medicated group was used as a control, to account for the general effect of contact with the mental health system and non-medication interventions related to this, and there was no effect on violent crime with this class of medication.

Now on to the limitations. Medication adherence was not assessed and could not be verified apart from patients given depot neuroleptics. The overall rate of violent crime was low, as would be expected. Only 6% of men and 1% of the women committed a violent crime. The numbers were so low that the study could not statistically assess the impact of violent crime history among patients diagnosed with psychosis. This is a small but crucial finding that did not make the traditional media coverage of this study.

Also, only 40% of those patients taking antipsychotics and mood stabilizers had a diagnosis of schizophrenia, other psychosis, or bipolar disorder, suggesting that, in Sweden, these medications might be prescribed for other indications such as characterologic low frustration tolerance or irritability. The analysis did not look at impact on violent crime by personality disorder diagnosis.

The authors acknowledged that their research could not prove a causal link between psychiatric illness and violence, another important conclusion that was not mentioned in traditional media coverage. In Sweden, mental illness cannot be used to prevent or mitigate a criminal conviction, so any connection between psychiatric symptoms and crime in this population can't be determined. The study also did not consider which subjects, if any, were taking medication or in treatment under court-mandated conditions.

As legislators and advocacy groups push to strengthen involuntary treatment laws, there is a risk that "bottom line" media coverage of research like this may inappropriately sway public opinion. Psychiatrists should be prepared to respond to proposed policies based on inaccurate interpretation of research.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson's employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

If you have patients who express interest in cosmetic procedures, and especially if you are a cosmetic dermatologist or a plastic surgeon, you might want to familiarize yourself with RealSelf.com. Founded in 2006, RealSelf is an online community for learning and sharing information about cosmetic surgery, dermatology, dentistry, and other elective treatments. In 2013, the site had 36 million unique visitors, and it is expected to grow.

Why might RealSelf be relevant for you? Simply put, it’s another channel to market you and your practice. It works by allowing physicians to answer users’ questions about cosmetic procedures ranging from rhinoplasty and liposuction to tattoo removal and Botox. Over time, your participation can lead to new consultations at your practice.

To ensure credibility, physicians must be board-certified in order to join RealSelf’s physician community. There is an element of game mechanics: The more active the physician, the more exposure his or her profile and practice receives. Similarly, paid subscriptions lead to more exposure than free subscriptions (more on this later.) Although this model does not appeal to some physicians, many of them do like the platform, and see it as a way to build a reputation as an expert and to market their practices.

Unlike doctor review sites that focus on the physician, RealSelf focuses on the procedure. For each procedure, users will find actual patient reviews and before and after photos, as well as Q&A’s with board-certified physicians. Users will also find licensed physicians in their area as well as the average cost for the procedure. RealSelf believes that patients value transparency, and including prices creates transparency.

Since most patients genuinely want to help other patients make informed medical decisions, the reviews tend to be thoughtful and thorough, and many of them contain multiple before-and-after photos. As a physician perusing the patient reviews, you’ll start to notice that most of them are reasonable. For example, customer satisfaction with laser treatment for melasma was 51%, whereas satisfaction for laser treatment for rosacea was 80%.

Patients and prospective patients are flocking to the site because it allows them to share their experiences, interact with other patients, and gain access to physician experts in the field. Many patients have difficulty making decisions about cosmetic procedures; RealSelf aims to alleviate their fears and help them "make confident health and beauty decisions." If a prospective patient wants to see a video of tattoo removal or Botox injections, he or she can. If a patient wants to ask physicians their opinions, he or she can. According to RealSelf, physicians have answered over 500,000 questions on the site.

Of course, all this isn’t free for physicians. RealSelf is a business. They have a tiered membership – free, pro, and spotlight. To obtain free membership, you simply visit the site and follow the prompts to "claim your profile." Once your profile is completed, you will have access to a "doctor advisor" who can help you "optimize your visibility on the site." Both "pro" and "spotlight" offer additional benefits, such as integrating patient reviews on your practice website, promotions on Facebook and Twitter, extended directory listings, and exposure in your local area. RealSelf does not discuss costs of membership until you have claimed your profile.

Only you can determine if RealSelf is beneficial to you and your practice. If, for example, you’re not looking for new patients, then you might find it unnecessary. But at the very least, you’ll know what RealSelf is the next time a fellow cosmetic physician brings it up at a conference. And it’s never a bad idea to be familiar with current social technologies that may affect your livelihood.

If you’ve used RealSelf, let us know what you think. For more information, visit RealSelf.com.

Disclaimer: I have no financial interest in RealSelf and am not an active member.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

If you have patients who express interest in cosmetic procedures, and especially if you are a cosmetic dermatologist or a plastic surgeon, you might want to familiarize yourself with RealSelf.com. Founded in 2006, RealSelf is an online community for learning and sharing information about cosmetic surgery, dermatology, dentistry, and other elective treatments. In 2013, the site had 36 million unique visitors, and it is expected to grow.

Why might RealSelf be relevant for you? Simply put, it’s another channel to market you and your practice. It works by allowing physicians to answer users’ questions about cosmetic procedures ranging from rhinoplasty and liposuction to tattoo removal and Botox. Over time, your participation can lead to new consultations at your practice.

To ensure credibility, physicians must be board-certified in order to join RealSelf’s physician community. There is an element of game mechanics: The more active the physician, the more exposure his or her profile and practice receives. Similarly, paid subscriptions lead to more exposure than free subscriptions (more on this later.) Although this model does not appeal to some physicians, many of them do like the platform, and see it as a way to build a reputation as an expert and to market their practices.

Unlike doctor review sites that focus on the physician, RealSelf focuses on the procedure. For each procedure, users will find actual patient reviews and before and after photos, as well as Q&A’s with board-certified physicians. Users will also find licensed physicians in their area as well as the average cost for the procedure. RealSelf believes that patients value transparency, and including prices creates transparency.

Since most patients genuinely want to help other patients make informed medical decisions, the reviews tend to be thoughtful and thorough, and many of them contain multiple before-and-after photos. As a physician perusing the patient reviews, you’ll start to notice that most of them are reasonable. For example, customer satisfaction with laser treatment for melasma was 51%, whereas satisfaction for laser treatment for rosacea was 80%.

Patients and prospective patients are flocking to the site because it allows them to share their experiences, interact with other patients, and gain access to physician experts in the field. Many patients have difficulty making decisions about cosmetic procedures; RealSelf aims to alleviate their fears and help them "make confident health and beauty decisions." If a prospective patient wants to see a video of tattoo removal or Botox injections, he or she can. If a patient wants to ask physicians their opinions, he or she can. According to RealSelf, physicians have answered over 500,000 questions on the site.

Of course, all this isn’t free for physicians. RealSelf is a business. They have a tiered membership – free, pro, and spotlight. To obtain free membership, you simply visit the site and follow the prompts to "claim your profile." Once your profile is completed, you will have access to a "doctor advisor" who can help you "optimize your visibility on the site." Both "pro" and "spotlight" offer additional benefits, such as integrating patient reviews on your practice website, promotions on Facebook and Twitter, extended directory listings, and exposure in your local area. RealSelf does not discuss costs of membership until you have claimed your profile.

Only you can determine if RealSelf is beneficial to you and your practice. If, for example, you’re not looking for new patients, then you might find it unnecessary. But at the very least, you’ll know what RealSelf is the next time a fellow cosmetic physician brings it up at a conference. And it’s never a bad idea to be familiar with current social technologies that may affect your livelihood.

If you’ve used RealSelf, let us know what you think. For more information, visit RealSelf.com.

Disclaimer: I have no financial interest in RealSelf and am not an active member.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

If you have patients who express interest in cosmetic procedures, and especially if you are a cosmetic dermatologist or a plastic surgeon, you might want to familiarize yourself with RealSelf.com. Founded in 2006, RealSelf is an online community for learning and sharing information about cosmetic surgery, dermatology, dentistry, and other elective treatments. In 2013, the site had 36 million unique visitors, and it is expected to grow.

Why might RealSelf be relevant for you? Simply put, it’s another channel to market you and your practice. It works by allowing physicians to answer users’ questions about cosmetic procedures ranging from rhinoplasty and liposuction to tattoo removal and Botox. Over time, your participation can lead to new consultations at your practice.

To ensure credibility, physicians must be board-certified in order to join RealSelf’s physician community. There is an element of game mechanics: The more active the physician, the more exposure his or her profile and practice receives. Similarly, paid subscriptions lead to more exposure than free subscriptions (more on this later.) Although this model does not appeal to some physicians, many of them do like the platform, and see it as a way to build a reputation as an expert and to market their practices.

Unlike doctor review sites that focus on the physician, RealSelf focuses on the procedure. For each procedure, users will find actual patient reviews and before and after photos, as well as Q&A’s with board-certified physicians. Users will also find licensed physicians in their area as well as the average cost for the procedure. RealSelf believes that patients value transparency, and including prices creates transparency.

Since most patients genuinely want to help other patients make informed medical decisions, the reviews tend to be thoughtful and thorough, and many of them contain multiple before-and-after photos. As a physician perusing the patient reviews, you’ll start to notice that most of them are reasonable. For example, customer satisfaction with laser treatment for melasma was 51%, whereas satisfaction for laser treatment for rosacea was 80%.

Patients and prospective patients are flocking to the site because it allows them to share their experiences, interact with other patients, and gain access to physician experts in the field. Many patients have difficulty making decisions about cosmetic procedures; RealSelf aims to alleviate their fears and help them "make confident health and beauty decisions." If a prospective patient wants to see a video of tattoo removal or Botox injections, he or she can. If a patient wants to ask physicians their opinions, he or she can. According to RealSelf, physicians have answered over 500,000 questions on the site.

Of course, all this isn’t free for physicians. RealSelf is a business. They have a tiered membership – free, pro, and spotlight. To obtain free membership, you simply visit the site and follow the prompts to "claim your profile." Once your profile is completed, you will have access to a "doctor advisor" who can help you "optimize your visibility on the site." Both "pro" and "spotlight" offer additional benefits, such as integrating patient reviews on your practice website, promotions on Facebook and Twitter, extended directory listings, and exposure in your local area. RealSelf does not discuss costs of membership until you have claimed your profile.

Only you can determine if RealSelf is beneficial to you and your practice. If, for example, you’re not looking for new patients, then you might find it unnecessary. But at the very least, you’ll know what RealSelf is the next time a fellow cosmetic physician brings it up at a conference. And it’s never a bad idea to be familiar with current social technologies that may affect your livelihood.

If you’ve used RealSelf, let us know what you think. For more information, visit RealSelf.com.

Disclaimer: I have no financial interest in RealSelf and am not an active member.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

Benzoyl peroxide (BPO) has been used for more than 45 years for the treatment of acne, and has recently been enjoying renewed popularity, thanks to its performance in recent studies of both prescription and over-the-counter formulations (J. Drugs Dermatol. 2013;12:180-5). In fact, BPO is one of the two most common ingredients in OTC acne products (Semin. Cutan. Med. Surg. 2008;27:170-6). The prescription form is used alone or in combination with tretinoin, adapalene, or clindamycin. BPO, originally sourced from the coal tar component chlorhydroxyquinoline, is now typically prepared by treating hydrogen peroxide with benzoyl chloride (Dermatol. Clin. 2009;27:17-24). Because it can generate reactive oxygen species and commonly leads to skin irritation, its use is somewhat limited.

Antibacterial uses

BPO imparts bactericidal activity by releasing highly reactive oxygen (free radicals) that can oxidize proteins in bacterial cell membranes. It also exhibits antibacterial action against Propionibacterium acnes and Corynebacterium acnes, the bacteria implicated in the pathophysiology of acne (Dermatol. Ther. 2012;25:6-11), as well as Staphylococcus capitis, S. epidermis, S. hominis, P. avidum, P. granulosum, and the yeast Pityrosporum ovale (J. Appl. Bacteriol. 1983;54:379-82).

Acne

Many studies over the years have shown that topically applied BPO effectively treats acne (Expert Opin. Pharmacother. 2009;10:2555-62). These ameliorative results, which include enhancing the benefits of other topical antimicrobials, are thought to arise because BPO, a highly lipophilic molecule, penetrates through the sebum and into the pilosebaceous unit, and exerts bactericidal, keratolytic, and anti-inflammatory activity (Skin Pharmacol. Physiol. 2006;19:283-9). BPO may contribute to the antiacne efficacy of other antimicrobials by preventing bacterial resistance and promoting penetration into the sebum, keratin, and polysaccharides to reach the target bacteria. Specifically, the oxidative activity of BPO helps eliminate the biofilm polysaccharides secreted by P. acnes, thus expediting the delivery of other agents to the bacteria (Int. J. Dermatol. 2006;45:872; Int. J. Dermatol. 2003;42:925-7).

Not surprisingly, several studies have shown that the antiacne efficacy of a combination of BPO with other antimicrobials, such as clindamycin, is greater than that of either agent used alone. Simpson et al. demonstrated that the use of clindamycin and BPO together led to a 61% decline in inflammatory lesions after 3 months, as compared with 39% and 35%, respectively, when the agents were used alone (J. Am. Acad. Dermatol. 1997;37:590-5). BPO is frequently paired with salicylic acid to treat acne (Clin. Exp. Dermatol. 2011;36:840-3).

Acne often improves more rapidly with BPO treatment than with retinoids and other acne therapies, and data suggest that the faster clearing of acne lesions and comedones is most likely because of its keratolytic activity (Dermatol. Clin. 2009;27:17-24; J. Dermatolog. Treat. 2003;14:166-71). However, the dryness and irritation associated with BPO usage may undermine patient compliance. Several studies have suggested that BPO is effective in cleanser formulations, which seem to reduce irritation (Clin. Exp. Dermatol. 2011;36:840-3).

Photocarcinogenicity

Reports that BPO predisposed mice to skin cancer, particularly when they were exposed to ultraviolet radiation, prompted the Food and Drug Administration to form an advisory committee in 1992 to review the safety of BPO. The committee called for additional photocarcinogenicity studies while suggesting that BPO products include animal safety data on the labels. BPO-containing acne products were kept on the market. In the ensuing two decades, newer safety studies have led the FDA to change the classification of BPO to category I, deeming the OTC topical treatment of acne to be generally recognized as safe and effective (GRASE) (Fed. Regist. 2010;75:9767-77).

Photoaging

When BPO breaks down into benzoic acid in the skin, benzoyloxy, a free radical, forms as an intermediate (Prog. Clin. Biol. Res. 1995;391:245). Benzoyloxy can decarboxylate into a phenyl radical. These free radicals produce oxidative stress, which may cause DNA strand breaks in keratinocytes or may harm proteins or lipids. In addition to becoming a free radical, BPO depletes membrane and cytosolic antioxidants (Toxicology 2001;165:225-34). No retrospective trials looking at the effects of long-term use of BP on photoaging have been performed, so the role of BPO in photoaging is not clear. One study in mice found that topical BP has some of the same effects on skin as UVB (J. Invest. Dermatol. 1999;112:933-38).

Other safety issues

Acne is not uncommon among pregnant women. Although safety studies of BPO use by pregnant women have not been performed, various authors suggest that only about 5% of topically applied BPO is absorbed systemically, implying that topical BPO can be safely used during pregnancy (Int. J. Dermatol. 2002;41:197-203; Can. Fam. Physician 2011;57:665-7; Drugs 2013;73:779-87; Dermatol. Ther. 2013;26:302-11).

In approximately 1% of patients, topical BPO causes contact or irritant dermatitis (Contact Dermatitis 1999;41:233; Contact Dermatitis 1996;34:68-9). The use of barrier repair moisturizers may reduce the incidence of irritation, though this has not been proven.

Usage considerations

BPO use for acne is linked to a reduction in antibiotic resistance (J. Drugs Dermatol. 2013;12:s73-6). Because BPO, a potent oxidizer, eliminates bacteria by generating reactive oxygen species in the sebaceous follicle, it is important to consider the chemical compatibility of BPO with other agents (J. Am. Acad. Dermatol. 1981;4:31-7). Martin et al. showed that BPO tends to degrade tretinoin to about 80% of initial content, an effect that is markedly enhanced by indoor light. However, even in the presence of light, adapalene is not degraded by BPO (Br. J. Dermatol. 1998;139 Suppl 52:8-11). But the order in which products are applied is important, given that BPO can inactivate other ingredients.

Studies have demonstrated that the use of BPO in body washes leads to greater efficacy when the product is left on for 5 minutes before rinsing (J. Drugs Dermatol. 2010;9:622-5; J. Clin. Aesthet. Dermatol. 2010;3:26-9). Notably, the efficacy of BPO in cleansing products is comparable to that observed in leave-on products, but BPO provokes less irritation than leave-on formulations (J. Drugs Dermatol. 2009;8:657-61; Skinmed. 2005;4:370).

Conclusion

BPO remains quite effective in acne therapy, and it is one of the few acne medications available both over the counter and by prescription in the United States. BPO helps prevent antibiotic resistance to erythromycin and clindamycin, which makes it an important ingredient in many acne skin care regimens. However, it is pro-oxidant, and clinicians and patients should take into account the risk of BPO contributing to skin aging because of the free radicals it produces.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Benzoyl peroxide (BPO) has been used for more than 45 years for the treatment of acne, and has recently been enjoying renewed popularity, thanks to its performance in recent studies of both prescription and over-the-counter formulations (J. Drugs Dermatol. 2013;12:180-5). In fact, BPO is one of the two most common ingredients in OTC acne products (Semin. Cutan. Med. Surg. 2008;27:170-6). The prescription form is used alone or in combination with tretinoin, adapalene, or clindamycin. BPO, originally sourced from the coal tar component chlorhydroxyquinoline, is now typically prepared by treating hydrogen peroxide with benzoyl chloride (Dermatol. Clin. 2009;27:17-24). Because it can generate reactive oxygen species and commonly leads to skin irritation, its use is somewhat limited.

Antibacterial uses

BPO imparts bactericidal activity by releasing highly reactive oxygen (free radicals) that can oxidize proteins in bacterial cell membranes. It also exhibits antibacterial action against Propionibacterium acnes and Corynebacterium acnes, the bacteria implicated in the pathophysiology of acne (Dermatol. Ther. 2012;25:6-11), as well as Staphylococcus capitis, S. epidermis, S. hominis, P. avidum, P. granulosum, and the yeast Pityrosporum ovale (J. Appl. Bacteriol. 1983;54:379-82).

Acne

Many studies over the years have shown that topically applied BPO effectively treats acne (Expert Opin. Pharmacother. 2009;10:2555-62). These ameliorative results, which include enhancing the benefits of other topical antimicrobials, are thought to arise because BPO, a highly lipophilic molecule, penetrates through the sebum and into the pilosebaceous unit, and exerts bactericidal, keratolytic, and anti-inflammatory activity (Skin Pharmacol. Physiol. 2006;19:283-9). BPO may contribute to the antiacne efficacy of other antimicrobials by preventing bacterial resistance and promoting penetration into the sebum, keratin, and polysaccharides to reach the target bacteria. Specifically, the oxidative activity of BPO helps eliminate the biofilm polysaccharides secreted by P. acnes, thus expediting the delivery of other agents to the bacteria (Int. J. Dermatol. 2006;45:872; Int. J. Dermatol. 2003;42:925-7).

Not surprisingly, several studies have shown that the antiacne efficacy of a combination of BPO with other antimicrobials, such as clindamycin, is greater than that of either agent used alone. Simpson et al. demonstrated that the use of clindamycin and BPO together led to a 61% decline in inflammatory lesions after 3 months, as compared with 39% and 35%, respectively, when the agents were used alone (J. Am. Acad. Dermatol. 1997;37:590-5). BPO is frequently paired with salicylic acid to treat acne (Clin. Exp. Dermatol. 2011;36:840-3).

Acne often improves more rapidly with BPO treatment than with retinoids and other acne therapies, and data suggest that the faster clearing of acne lesions and comedones is most likely because of its keratolytic activity (Dermatol. Clin. 2009;27:17-24; J. Dermatolog. Treat. 2003;14:166-71). However, the dryness and irritation associated with BPO usage may undermine patient compliance. Several studies have suggested that BPO is effective in cleanser formulations, which seem to reduce irritation (Clin. Exp. Dermatol. 2011;36:840-3).

Photocarcinogenicity

Reports that BPO predisposed mice to skin cancer, particularly when they were exposed to ultraviolet radiation, prompted the Food and Drug Administration to form an advisory committee in 1992 to review the safety of BPO. The committee called for additional photocarcinogenicity studies while suggesting that BPO products include animal safety data on the labels. BPO-containing acne products were kept on the market. In the ensuing two decades, newer safety studies have led the FDA to change the classification of BPO to category I, deeming the OTC topical treatment of acne to be generally recognized as safe and effective (GRASE) (Fed. Regist. 2010;75:9767-77).

Photoaging

When BPO breaks down into benzoic acid in the skin, benzoyloxy, a free radical, forms as an intermediate (Prog. Clin. Biol. Res. 1995;391:245). Benzoyloxy can decarboxylate into a phenyl radical. These free radicals produce oxidative stress, which may cause DNA strand breaks in keratinocytes or may harm proteins or lipids. In addition to becoming a free radical, BPO depletes membrane and cytosolic antioxidants (Toxicology 2001;165:225-34). No retrospective trials looking at the effects of long-term use of BP on photoaging have been performed, so the role of BPO in photoaging is not clear. One study in mice found that topical BP has some of the same effects on skin as UVB (J. Invest. Dermatol. 1999;112:933-38).

Other safety issues

Acne is not uncommon among pregnant women. Although safety studies of BPO use by pregnant women have not been performed, various authors suggest that only about 5% of topically applied BPO is absorbed systemically, implying that topical BPO can be safely used during pregnancy (Int. J. Dermatol. 2002;41:197-203; Can. Fam. Physician 2011;57:665-7; Drugs 2013;73:779-87; Dermatol. Ther. 2013;26:302-11).

In approximately 1% of patients, topical BPO causes contact or irritant dermatitis (Contact Dermatitis 1999;41:233; Contact Dermatitis 1996;34:68-9). The use of barrier repair moisturizers may reduce the incidence of irritation, though this has not been proven.

Usage considerations

BPO use for acne is linked to a reduction in antibiotic resistance (J. Drugs Dermatol. 2013;12:s73-6). Because BPO, a potent oxidizer, eliminates bacteria by generating reactive oxygen species in the sebaceous follicle, it is important to consider the chemical compatibility of BPO with other agents (J. Am. Acad. Dermatol. 1981;4:31-7). Martin et al. showed that BPO tends to degrade tretinoin to about 80% of initial content, an effect that is markedly enhanced by indoor light. However, even in the presence of light, adapalene is not degraded by BPO (Br. J. Dermatol. 1998;139 Suppl 52:8-11). But the order in which products are applied is important, given that BPO can inactivate other ingredients.

Studies have demonstrated that the use of BPO in body washes leads to greater efficacy when the product is left on for 5 minutes before rinsing (J. Drugs Dermatol. 2010;9:622-5; J. Clin. Aesthet. Dermatol. 2010;3:26-9). Notably, the efficacy of BPO in cleansing products is comparable to that observed in leave-on products, but BPO provokes less irritation than leave-on formulations (J. Drugs Dermatol. 2009;8:657-61; Skinmed. 2005;4:370).

Conclusion

BPO remains quite effective in acne therapy, and it is one of the few acne medications available both over the counter and by prescription in the United States. BPO helps prevent antibiotic resistance to erythromycin and clindamycin, which makes it an important ingredient in many acne skin care regimens. However, it is pro-oxidant, and clinicians and patients should take into account the risk of BPO contributing to skin aging because of the free radicals it produces.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Benzoyl peroxide (BPO) has been used for more than 45 years for the treatment of acne, and has recently been enjoying renewed popularity, thanks to its performance in recent studies of both prescription and over-the-counter formulations (J. Drugs Dermatol. 2013;12:180-5). In fact, BPO is one of the two most common ingredients in OTC acne products (Semin. Cutan. Med. Surg. 2008;27:170-6). The prescription form is used alone or in combination with tretinoin, adapalene, or clindamycin. BPO, originally sourced from the coal tar component chlorhydroxyquinoline, is now typically prepared by treating hydrogen peroxide with benzoyl chloride (Dermatol. Clin. 2009;27:17-24). Because it can generate reactive oxygen species and commonly leads to skin irritation, its use is somewhat limited.

Antibacterial uses

BPO imparts bactericidal activity by releasing highly reactive oxygen (free radicals) that can oxidize proteins in bacterial cell membranes. It also exhibits antibacterial action against Propionibacterium acnes and Corynebacterium acnes, the bacteria implicated in the pathophysiology of acne (Dermatol. Ther. 2012;25:6-11), as well as Staphylococcus capitis, S. epidermis, S. hominis, P. avidum, P. granulosum, and the yeast Pityrosporum ovale (J. Appl. Bacteriol. 1983;54:379-82).

Acne

Many studies over the years have shown that topically applied BPO effectively treats acne (Expert Opin. Pharmacother. 2009;10:2555-62). These ameliorative results, which include enhancing the benefits of other topical antimicrobials, are thought to arise because BPO, a highly lipophilic molecule, penetrates through the sebum and into the pilosebaceous unit, and exerts bactericidal, keratolytic, and anti-inflammatory activity (Skin Pharmacol. Physiol. 2006;19:283-9). BPO may contribute to the antiacne efficacy of other antimicrobials by preventing bacterial resistance and promoting penetration into the sebum, keratin, and polysaccharides to reach the target bacteria. Specifically, the oxidative activity of BPO helps eliminate the biofilm polysaccharides secreted by P. acnes, thus expediting the delivery of other agents to the bacteria (Int. J. Dermatol. 2006;45:872; Int. J. Dermatol. 2003;42:925-7).

Not surprisingly, several studies have shown that the antiacne efficacy of a combination of BPO with other antimicrobials, such as clindamycin, is greater than that of either agent used alone. Simpson et al. demonstrated that the use of clindamycin and BPO together led to a 61% decline in inflammatory lesions after 3 months, as compared with 39% and 35%, respectively, when the agents were used alone (J. Am. Acad. Dermatol. 1997;37:590-5). BPO is frequently paired with salicylic acid to treat acne (Clin. Exp. Dermatol. 2011;36:840-3).

Acne often improves more rapidly with BPO treatment than with retinoids and other acne therapies, and data suggest that the faster clearing of acne lesions and comedones is most likely because of its keratolytic activity (Dermatol. Clin. 2009;27:17-24; J. Dermatolog. Treat. 2003;14:166-71). However, the dryness and irritation associated with BPO usage may undermine patient compliance. Several studies have suggested that BPO is effective in cleanser formulations, which seem to reduce irritation (Clin. Exp. Dermatol. 2011;36:840-3).

Photocarcinogenicity

Reports that BPO predisposed mice to skin cancer, particularly when they were exposed to ultraviolet radiation, prompted the Food and Drug Administration to form an advisory committee in 1992 to review the safety of BPO. The committee called for additional photocarcinogenicity studies while suggesting that BPO products include animal safety data on the labels. BPO-containing acne products were kept on the market. In the ensuing two decades, newer safety studies have led the FDA to change the classification of BPO to category I, deeming the OTC topical treatment of acne to be generally recognized as safe and effective (GRASE) (Fed. Regist. 2010;75:9767-77).

Photoaging

When BPO breaks down into benzoic acid in the skin, benzoyloxy, a free radical, forms as an intermediate (Prog. Clin. Biol. Res. 1995;391:245). Benzoyloxy can decarboxylate into a phenyl radical. These free radicals produce oxidative stress, which may cause DNA strand breaks in keratinocytes or may harm proteins or lipids. In addition to becoming a free radical, BPO depletes membrane and cytosolic antioxidants (Toxicology 2001;165:225-34). No retrospective trials looking at the effects of long-term use of BP on photoaging have been performed, so the role of BPO in photoaging is not clear. One study in mice found that topical BP has some of the same effects on skin as UVB (J. Invest. Dermatol. 1999;112:933-38).

Other safety issues

Acne is not uncommon among pregnant women. Although safety studies of BPO use by pregnant women have not been performed, various authors suggest that only about 5% of topically applied BPO is absorbed systemically, implying that topical BPO can be safely used during pregnancy (Int. J. Dermatol. 2002;41:197-203; Can. Fam. Physician 2011;57:665-7; Drugs 2013;73:779-87; Dermatol. Ther. 2013;26:302-11).

In approximately 1% of patients, topical BPO causes contact or irritant dermatitis (Contact Dermatitis 1999;41:233; Contact Dermatitis 1996;34:68-9). The use of barrier repair moisturizers may reduce the incidence of irritation, though this has not been proven.

Usage considerations

BPO use for acne is linked to a reduction in antibiotic resistance (J. Drugs Dermatol. 2013;12:s73-6). Because BPO, a potent oxidizer, eliminates bacteria by generating reactive oxygen species in the sebaceous follicle, it is important to consider the chemical compatibility of BPO with other agents (J. Am. Acad. Dermatol. 1981;4:31-7). Martin et al. showed that BPO tends to degrade tretinoin to about 80% of initial content, an effect that is markedly enhanced by indoor light. However, even in the presence of light, adapalene is not degraded by BPO (Br. J. Dermatol. 1998;139 Suppl 52:8-11). But the order in which products are applied is important, given that BPO can inactivate other ingredients.

Studies have demonstrated that the use of BPO in body washes leads to greater efficacy when the product is left on for 5 minutes before rinsing (J. Drugs Dermatol. 2010;9:622-5; J. Clin. Aesthet. Dermatol. 2010;3:26-9). Notably, the efficacy of BPO in cleansing products is comparable to that observed in leave-on products, but BPO provokes less irritation than leave-on formulations (J. Drugs Dermatol. 2009;8:657-61; Skinmed. 2005;4:370).

Conclusion

BPO remains quite effective in acne therapy, and it is one of the few acne medications available both over the counter and by prescription in the United States. BPO helps prevent antibiotic resistance to erythromycin and clindamycin, which makes it an important ingredient in many acne skin care regimens. However, it is pro-oxidant, and clinicians and patients should take into account the risk of BPO contributing to skin aging because of the free radicals it produces.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

In Louisiana, opioid use lasted more than 6 months in 17% of nonsurgical workers’ compensation claims involving employees who received at least one prescription for pain medication, the Workers Compensation Research Institute reported.

In cases with more than 7 days of lost time, that was the highest rate seen among the 25 states in the study, with New York second at 12% and Pennsylvania and Texas tied for third at 11%. There were four states tied for the lowest rate, at 4%: Missouri, New Jersey, Indiana, and Wisconsin, according to the WCRI report.

Overall, use of narcotics for pain relief by injured workers in such cases ranged from 60% in New Jersey to 88% in Arkansas (median, 76%), while use of any pain medication ranged from 85% in Minnesota to 95% in Florida, Georgia, Tennessee, and Texas (median, 94%), the report showed.

The study involved claims with injuries that occurred from Oct. 1, 2009, through Sept. 30, 2010, with prescriptions filled through March 31, 2012. Longer-term users received a prescription for opioids within 3 months of their injury and had three or more visits to fill opioid prescriptions between the 7th and the 12th month after the injury.

The 25 states in the study "represent more than 70% of the workers’ compensation benefits paid in the United States," the WCRI noted.

The study was based on approximately 264,000 nonsurgical claims and more than 1.5 million prescriptions for pain medications. Data were extracted from the WCRI Detailed Benchmark/Evaluation database and consisted of detailed prescription transactions "collected from workers’ compensation payers and their medical bill review and pharmacy benefit management vendors," the report noted.

[email protected]

In Louisiana, opioid use lasted more than 6 months in 17% of nonsurgical workers’ compensation claims involving employees who received at least one prescription for pain medication, the Workers Compensation Research Institute reported.

In cases with more than 7 days of lost time, that was the highest rate seen among the 25 states in the study, with New York second at 12% and Pennsylvania and Texas tied for third at 11%. There were four states tied for the lowest rate, at 4%: Missouri, New Jersey, Indiana, and Wisconsin, according to the WCRI report.

Overall, use of narcotics for pain relief by injured workers in such cases ranged from 60% in New Jersey to 88% in Arkansas (median, 76%), while use of any pain medication ranged from 85% in Minnesota to 95% in Florida, Georgia, Tennessee, and Texas (median, 94%), the report showed.

The study involved claims with injuries that occurred from Oct. 1, 2009, through Sept. 30, 2010, with prescriptions filled through March 31, 2012. Longer-term users received a prescription for opioids within 3 months of their injury and had three or more visits to fill opioid prescriptions between the 7th and the 12th month after the injury.

The 25 states in the study "represent more than 70% of the workers’ compensation benefits paid in the United States," the WCRI noted.

The study was based on approximately 264,000 nonsurgical claims and more than 1.5 million prescriptions for pain medications. Data were extracted from the WCRI Detailed Benchmark/Evaluation database and consisted of detailed prescription transactions "collected from workers’ compensation payers and their medical bill review and pharmacy benefit management vendors," the report noted.

[email protected]

In Louisiana, opioid use lasted more than 6 months in 17% of nonsurgical workers’ compensation claims involving employees who received at least one prescription for pain medication, the Workers Compensation Research Institute reported.

In cases with more than 7 days of lost time, that was the highest rate seen among the 25 states in the study, with New York second at 12% and Pennsylvania and Texas tied for third at 11%. There were four states tied for the lowest rate, at 4%: Missouri, New Jersey, Indiana, and Wisconsin, according to the WCRI report.

Overall, use of narcotics for pain relief by injured workers in such cases ranged from 60% in New Jersey to 88% in Arkansas (median, 76%), while use of any pain medication ranged from 85% in Minnesota to 95% in Florida, Georgia, Tennessee, and Texas (median, 94%), the report showed.

The study involved claims with injuries that occurred from Oct. 1, 2009, through Sept. 30, 2010, with prescriptions filled through March 31, 2012. Longer-term users received a prescription for opioids within 3 months of their injury and had three or more visits to fill opioid prescriptions between the 7th and the 12th month after the injury.

The 25 states in the study "represent more than 70% of the workers’ compensation benefits paid in the United States," the WCRI noted.

The study was based on approximately 264,000 nonsurgical claims and more than 1.5 million prescriptions for pain medications. Data were extracted from the WCRI Detailed Benchmark/Evaluation database and consisted of detailed prescription transactions "collected from workers’ compensation payers and their medical bill review and pharmacy benefit management vendors," the report noted.

[email protected]