NEW YORK - People with type 2 diabetes are 15 percent more likely to die from any cause and 14 percent more likely to die from a cardiovascular cause than non-diabetics at any given time, according to data from several Swedish registries.

The rates are significantly lower than previous estimates. Fifteen years ago, research was suggesting that having diabetes doubled the risk of premature death.

But the new study also found that the risk was dramatically elevated among people whose type 2 diabetes appeared by age 54. The worse their glycemic control and the more evidence of renal problems, the higher the risk.

In contrast, by age 75, type 2 diabetes posed little additional risk for people with good control and no kidney issues, according to the results.

"The overall increased risk of 15 percent among type 2 diabetics in general is a very low figure that has not been found in earlier type 2 diabetes studies," coauthor Dr. Marcus Lind of Uddevalla Hospital said in a telephone interview.

"The other thing that was interesting is that when we looked at patients with good glycemic control and no renal complications, if they were 75 years age, they had a lower risk than those in the general population. That hasn't been shown before," he said.

"What we are seeing is, if you are younger, aggressive management makes a difference," said Dr. Robert Ratner, chief scientific and medical officer of the American Diabetes Association, who was not involved in the research. At age 75, "you don't have to worry about it as much."

The study, published in the October 29 New England Journal of Medicine, is the largest to date to look at premature death in general - and death from cardiovascular causes in particular - among people with type 2 diabetes.

It compared more than 435,000 diabetics who were followed for a mean of 4.6 years with more than 2 million matched controls who were tracked for a mean of 4.8 years. The diabetics had had glucose problems for an average of 5.7 years.

In terms of actual death rates, cardiovascular mortality during the study period was 7.9 percent for diabetics versus 6.1 percent for controls (adjusted hazard ratio, 1.14; 95 percent confidence interval: 1.13-1.15). The respective rates for death from any cause were 17.7 percent and 14.5 percent (aHR, 1.15; 95 percent CI: 1.14-1.16).

For patients under age 55 with glycated hemoglobin levels below 7.0 percent, the risk of death from any cause nearly doubled (aHR, 1.92; 95 percent CI: 1.75-2.11).

"Those who are younger than 55, those who have target glycemic control and no signs of any renal complications, they had a clearly-elevated risk," said Dr. Lind.

But for people over 75, the hazard was actually 5 percent lower than it was for people without diabetes (aHR, 0.95; 95 percent CI: 0.94-0.96).

When the research team factored in people with normoalbuminuria, the risks were slightly mitigated.

Heart attack was the most common cause of death among diabetics.

When glycated hemoglobin levels were at 9.7 percent and higher for people below age 55, the hazard of death from any cause more than quadrupled. The hazard of death from cardiovascular causes rose more than five-fold.

Once again, the danger was far less extreme for people over 75, the researchers found.

"Excess mortality in type 2 diabetes was substantially higher with worsening glycemic control, severe renal complications, impaired renal function, and younger age," they concluded.

Renal function is a key element, Dr. Ratner said.

The study "reinforces the importance of early aggressive management of diabetes in order to prevent premature death and the fact is that the prevention of renal disease is probably the most potent thing we can do to reduce cardiovascular events," he said.

Dr. Lind said the risk may appear lower in the elderly because older people with diabetes are more likely to be getting aggressive treatment for their high blood pressure and high lipid levels, therapy that other people who also have hypertension and high cholesterol levels might not be receiving.

"I think that's the reason the rates are a bit lower" for seniors, he said.

Dr. Ratner said he believes the data for older diabetics simply reflects the fact that "you're seeing the survival cohort. They've made it past the difficult time."

We're all going to die, he said. "The issue is when does it happen? With diabetes, it's happening years ahead of time - in their 50s and early 60s, more so than when they reach 75. The younger you are, the greater that risk. That's when aggressive therapy should be given."

NEW YORK - People with type 2 diabetes are 15 percent more likely to die from any cause and 14 percent more likely to die from a cardiovascular cause than non-diabetics at any given time, according to data from several Swedish registries.

The rates are significantly lower than previous estimates. Fifteen years ago, research was suggesting that having diabetes doubled the risk of premature death.

But the new study also found that the risk was dramatically elevated among people whose type 2 diabetes appeared by age 54. The worse their glycemic control and the more evidence of renal problems, the higher the risk.

In contrast, by age 75, type 2 diabetes posed little additional risk for people with good control and no kidney issues, according to the results.

"The overall increased risk of 15 percent among type 2 diabetics in general is a very low figure that has not been found in earlier type 2 diabetes studies," coauthor Dr. Marcus Lind of Uddevalla Hospital said in a telephone interview.

"The other thing that was interesting is that when we looked at patients with good glycemic control and no renal complications, if they were 75 years age, they had a lower risk than those in the general population. That hasn't been shown before," he said.

"What we are seeing is, if you are younger, aggressive management makes a difference," said Dr. Robert Ratner, chief scientific and medical officer of the American Diabetes Association, who was not involved in the research. At age 75, "you don't have to worry about it as much."

The study, published in the October 29 New England Journal of Medicine, is the largest to date to look at premature death in general - and death from cardiovascular causes in particular - among people with type 2 diabetes.

It compared more than 435,000 diabetics who were followed for a mean of 4.6 years with more than 2 million matched controls who were tracked for a mean of 4.8 years. The diabetics had had glucose problems for an average of 5.7 years.

In terms of actual death rates, cardiovascular mortality during the study period was 7.9 percent for diabetics versus 6.1 percent for controls (adjusted hazard ratio, 1.14; 95 percent confidence interval: 1.13-1.15). The respective rates for death from any cause were 17.7 percent and 14.5 percent (aHR, 1.15; 95 percent CI: 1.14-1.16).

For patients under age 55 with glycated hemoglobin levels below 7.0 percent, the risk of death from any cause nearly doubled (aHR, 1.92; 95 percent CI: 1.75-2.11).

"Those who are younger than 55, those who have target glycemic control and no signs of any renal complications, they had a clearly-elevated risk," said Dr. Lind.

But for people over 75, the hazard was actually 5 percent lower than it was for people without diabetes (aHR, 0.95; 95 percent CI: 0.94-0.96).

When the research team factored in people with normoalbuminuria, the risks were slightly mitigated.

Heart attack was the most common cause of death among diabetics.

When glycated hemoglobin levels were at 9.7 percent and higher for people below age 55, the hazard of death from any cause more than quadrupled. The hazard of death from cardiovascular causes rose more than five-fold.

Once again, the danger was far less extreme for people over 75, the researchers found.

"Excess mortality in type 2 diabetes was substantially higher with worsening glycemic control, severe renal complications, impaired renal function, and younger age," they concluded.

Renal function is a key element, Dr. Ratner said.

The study "reinforces the importance of early aggressive management of diabetes in order to prevent premature death and the fact is that the prevention of renal disease is probably the most potent thing we can do to reduce cardiovascular events," he said.

Dr. Lind said the risk may appear lower in the elderly because older people with diabetes are more likely to be getting aggressive treatment for their high blood pressure and high lipid levels, therapy that other people who also have hypertension and high cholesterol levels might not be receiving.

"I think that's the reason the rates are a bit lower" for seniors, he said.

Dr. Ratner said he believes the data for older diabetics simply reflects the fact that "you're seeing the survival cohort. They've made it past the difficult time."

We're all going to die, he said. "The issue is when does it happen? With diabetes, it's happening years ahead of time - in their 50s and early 60s, more so than when they reach 75. The younger you are, the greater that risk. That's when aggressive therapy should be given."

NEW YORK - People with type 2 diabetes are 15 percent more likely to die from any cause and 14 percent more likely to die from a cardiovascular cause than non-diabetics at any given time, according to data from several Swedish registries.

The rates are significantly lower than previous estimates. Fifteen years ago, research was suggesting that having diabetes doubled the risk of premature death.

But the new study also found that the risk was dramatically elevated among people whose type 2 diabetes appeared by age 54. The worse their glycemic control and the more evidence of renal problems, the higher the risk.

In contrast, by age 75, type 2 diabetes posed little additional risk for people with good control and no kidney issues, according to the results.

"The overall increased risk of 15 percent among type 2 diabetics in general is a very low figure that has not been found in earlier type 2 diabetes studies," coauthor Dr. Marcus Lind of Uddevalla Hospital said in a telephone interview.

"The other thing that was interesting is that when we looked at patients with good glycemic control and no renal complications, if they were 75 years age, they had a lower risk than those in the general population. That hasn't been shown before," he said.

"What we are seeing is, if you are younger, aggressive management makes a difference," said Dr. Robert Ratner, chief scientific and medical officer of the American Diabetes Association, who was not involved in the research. At age 75, "you don't have to worry about it as much."

The study, published in the October 29 New England Journal of Medicine, is the largest to date to look at premature death in general - and death from cardiovascular causes in particular - among people with type 2 diabetes.

It compared more than 435,000 diabetics who were followed for a mean of 4.6 years with more than 2 million matched controls who were tracked for a mean of 4.8 years. The diabetics had had glucose problems for an average of 5.7 years.

In terms of actual death rates, cardiovascular mortality during the study period was 7.9 percent for diabetics versus 6.1 percent for controls (adjusted hazard ratio, 1.14; 95 percent confidence interval: 1.13-1.15). The respective rates for death from any cause were 17.7 percent and 14.5 percent (aHR, 1.15; 95 percent CI: 1.14-1.16).

For patients under age 55 with glycated hemoglobin levels below 7.0 percent, the risk of death from any cause nearly doubled (aHR, 1.92; 95 percent CI: 1.75-2.11).

"Those who are younger than 55, those who have target glycemic control and no signs of any renal complications, they had a clearly-elevated risk," said Dr. Lind.

But for people over 75, the hazard was actually 5 percent lower than it was for people without diabetes (aHR, 0.95; 95 percent CI: 0.94-0.96).

When the research team factored in people with normoalbuminuria, the risks were slightly mitigated.

Heart attack was the most common cause of death among diabetics.

When glycated hemoglobin levels were at 9.7 percent and higher for people below age 55, the hazard of death from any cause more than quadrupled. The hazard of death from cardiovascular causes rose more than five-fold.

Once again, the danger was far less extreme for people over 75, the researchers found.

"Excess mortality in type 2 diabetes was substantially higher with worsening glycemic control, severe renal complications, impaired renal function, and younger age," they concluded.

Renal function is a key element, Dr. Ratner said.

The study "reinforces the importance of early aggressive management of diabetes in order to prevent premature death and the fact is that the prevention of renal disease is probably the most potent thing we can do to reduce cardiovascular events," he said.

Dr. Lind said the risk may appear lower in the elderly because older people with diabetes are more likely to be getting aggressive treatment for their high blood pressure and high lipid levels, therapy that other people who also have hypertension and high cholesterol levels might not be receiving.

"I think that's the reason the rates are a bit lower" for seniors, he said.

Dr. Ratner said he believes the data for older diabetics simply reflects the fact that "you're seeing the survival cohort. They've made it past the difficult time."

We're all going to die, he said. "The issue is when does it happen? With diabetes, it's happening years ahead of time - in their 50s and early 60s, more so than when they reach 75. The younger you are, the greater that risk. That's when aggressive therapy should be given."

Red cells for transfusion

ANAHEIM, CA—The timing of gamma irradiation influences in vitro characteristics of red cell concentrates (RCCs), according to a new study.

The research showed that RCCs sustain more damage the longer they are stored prior to gamma irradiation and the longer they are stored after irradiation.

However, RCCs from female donors appeared to be less susceptible to irradiation injury, and the additive solution used seemed to affect the level of injury as well.

Dirk de Korte, PhD, of Sanquin Blood Bank in Amsterdam, Netherlands, presented these results at the 2015 AABB Annual Meeting (abstract S72-040A).

The study included 7 centers, each of which used its standard RCCs. Five centers used SAGM as additive solution, 1 used AS-3, and 1 used PAGGSM. Two centers used whole blood filtration to prepare leukoreduced RCCs, and 5 centers used buffy coat removal and RCC filtration.

Each center produced 4 pools of 7 RCCs, 2 male and 2 female pools. The units were stored for 43 days, and 1 pool was gamma-irradiated every week.

The researchers also performed weekly sampling to assess in vitro quality parameters. They took an extra sample 24 hours after irradiation and 72 hours after irradiation.

The team found that the age of RCCs at the time of irradiation influenced the rate of increase of hemolysis and the absolute level of hemolysis (P<0.0001).

Hemolysis was higher in units irradiated early and then stored. And the rate of change of hemolysis increased if RCCs were stored for longer before irradiation.

The researchers also found that the age of RCCs at the time of irradiation influenced the rate of increase of potassium and the absolute level of potassium (P<0.0001).

The rate of change of potassium decreased if RCCs were stored longer before irradiation, as potassium was already partly released if the cells were stored longer. Within 7 days of irradiation, potassium levels exceeded those observed in control cells stored for 43 days.

Hemolysis and potassium levels also appeared to be affected by donor sex and the additive solution used.

Hemolysis was lower in RCCs from female donors (P=0.045) and in cells exposed to AS-3 or PAGGSM rather than SAGM (P=0.0597).

Potassium release was lower in cells from female donors (P=0.0032) and in cells exposed to AS-3 rather than PAGGSM or SAGM (P=0.0391).

“This study shows or confirms interesting differences between red cells from males and females, and, of course, we are interested in the underlying mechanism,” Dr de Korte said.

He also said the results of this study will be used to formulate guidance on the maximal pre- and post-irradiation storage time for RCCs with respect to either acceptable hemolysis or potassium release.

Dr de Korte said that, if hemolysis is used as guidance, irradiation should be performed within the first 28 days of storage, and the cells should be used within these 28 days.

If potassium is used as guidance, cells should be used within 7 days of irradiation if the irradiation occurs during the first 10 to 14 days of storage, or the cells should be used immediately after irradiation if irradiation takes place later during storage.

Red cells for transfusion

ANAHEIM, CA—The timing of gamma irradiation influences in vitro characteristics of red cell concentrates (RCCs), according to a new study.

The research showed that RCCs sustain more damage the longer they are stored prior to gamma irradiation and the longer they are stored after irradiation.

However, RCCs from female donors appeared to be less susceptible to irradiation injury, and the additive solution used seemed to affect the level of injury as well.

Dirk de Korte, PhD, of Sanquin Blood Bank in Amsterdam, Netherlands, presented these results at the 2015 AABB Annual Meeting (abstract S72-040A).

The study included 7 centers, each of which used its standard RCCs. Five centers used SAGM as additive solution, 1 used AS-3, and 1 used PAGGSM. Two centers used whole blood filtration to prepare leukoreduced RCCs, and 5 centers used buffy coat removal and RCC filtration.

Each center produced 4 pools of 7 RCCs, 2 male and 2 female pools. The units were stored for 43 days, and 1 pool was gamma-irradiated every week.

The researchers also performed weekly sampling to assess in vitro quality parameters. They took an extra sample 24 hours after irradiation and 72 hours after irradiation.

The team found that the age of RCCs at the time of irradiation influenced the rate of increase of hemolysis and the absolute level of hemolysis (P<0.0001).

Hemolysis was higher in units irradiated early and then stored. And the rate of change of hemolysis increased if RCCs were stored for longer before irradiation.

The researchers also found that the age of RCCs at the time of irradiation influenced the rate of increase of potassium and the absolute level of potassium (P<0.0001).

The rate of change of potassium decreased if RCCs were stored longer before irradiation, as potassium was already partly released if the cells were stored longer. Within 7 days of irradiation, potassium levels exceeded those observed in control cells stored for 43 days.

Hemolysis and potassium levels also appeared to be affected by donor sex and the additive solution used.

Hemolysis was lower in RCCs from female donors (P=0.045) and in cells exposed to AS-3 or PAGGSM rather than SAGM (P=0.0597).

Potassium release was lower in cells from female donors (P=0.0032) and in cells exposed to AS-3 rather than PAGGSM or SAGM (P=0.0391).

“This study shows or confirms interesting differences between red cells from males and females, and, of course, we are interested in the underlying mechanism,” Dr de Korte said.

He also said the results of this study will be used to formulate guidance on the maximal pre- and post-irradiation storage time for RCCs with respect to either acceptable hemolysis or potassium release.

Dr de Korte said that, if hemolysis is used as guidance, irradiation should be performed within the first 28 days of storage, and the cells should be used within these 28 days.

If potassium is used as guidance, cells should be used within 7 days of irradiation if the irradiation occurs during the first 10 to 14 days of storage, or the cells should be used immediately after irradiation if irradiation takes place later during storage.

Red cells for transfusion

ANAHEIM, CA—The timing of gamma irradiation influences in vitro characteristics of red cell concentrates (RCCs), according to a new study.

The research showed that RCCs sustain more damage the longer they are stored prior to gamma irradiation and the longer they are stored after irradiation.

However, RCCs from female donors appeared to be less susceptible to irradiation injury, and the additive solution used seemed to affect the level of injury as well.

Dirk de Korte, PhD, of Sanquin Blood Bank in Amsterdam, Netherlands, presented these results at the 2015 AABB Annual Meeting (abstract S72-040A).

The study included 7 centers, each of which used its standard RCCs. Five centers used SAGM as additive solution, 1 used AS-3, and 1 used PAGGSM. Two centers used whole blood filtration to prepare leukoreduced RCCs, and 5 centers used buffy coat removal and RCC filtration.

Each center produced 4 pools of 7 RCCs, 2 male and 2 female pools. The units were stored for 43 days, and 1 pool was gamma-irradiated every week.

The researchers also performed weekly sampling to assess in vitro quality parameters. They took an extra sample 24 hours after irradiation and 72 hours after irradiation.

The team found that the age of RCCs at the time of irradiation influenced the rate of increase of hemolysis and the absolute level of hemolysis (P<0.0001).

Hemolysis was higher in units irradiated early and then stored. And the rate of change of hemolysis increased if RCCs were stored for longer before irradiation.

The researchers also found that the age of RCCs at the time of irradiation influenced the rate of increase of potassium and the absolute level of potassium (P<0.0001).

The rate of change of potassium decreased if RCCs were stored longer before irradiation, as potassium was already partly released if the cells were stored longer. Within 7 days of irradiation, potassium levels exceeded those observed in control cells stored for 43 days.

Hemolysis and potassium levels also appeared to be affected by donor sex and the additive solution used.

Hemolysis was lower in RCCs from female donors (P=0.045) and in cells exposed to AS-3 or PAGGSM rather than SAGM (P=0.0597).

Potassium release was lower in cells from female donors (P=0.0032) and in cells exposed to AS-3 rather than PAGGSM or SAGM (P=0.0391).

“This study shows or confirms interesting differences between red cells from males and females, and, of course, we are interested in the underlying mechanism,” Dr de Korte said.

He also said the results of this study will be used to formulate guidance on the maximal pre- and post-irradiation storage time for RCCs with respect to either acceptable hemolysis or potassium release.

Dr de Korte said that, if hemolysis is used as guidance, irradiation should be performed within the first 28 days of storage, and the cells should be used within these 28 days.

If potassium is used as guidance, cells should be used within 7 days of irradiation if the irradiation occurs during the first 10 to 14 days of storage, or the cells should be used immediately after irradiation if irradiation takes place later during storage.

Child with cancer

Photo by Bill Branson

Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.

CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.

Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing

an autoimmune disease.

Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.

They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.

The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.

The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).

In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.

So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.

SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).

SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).

The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.

The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.

They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.

The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.

Child with cancer

Photo by Bill Branson

Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.

CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.

Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing

an autoimmune disease.

Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.

They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.

The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.

The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).

In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.

So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.

SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).

SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).

The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.

The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.

They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.

The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.

Child with cancer

Photo by Bill Branson

Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.

CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.

Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing

an autoimmune disease.

Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.

They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.

The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.

The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).

In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.

So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.

SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).

SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).

The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.

The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.

They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.

The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

New research indicates that most childhood malaria infections in Papua New Guinea (PNG) are the result of relapsed, not new, infections.

The data suggest that, among children ages 5 to 10 living in a malaria-hyperendemic region of PNG, relapses cause about 4 of every 5 Plasmodium vivax infections and 3 of every 5 Plasmodium ovale infections.

Investigators therefore concluded that relapses are important for sustaining malaria transmission in PNG.

The team reported their findings in PLOS Medicine.

“Our research has shown that one of the biggest problems in realizing malaria eradication is relapsing P vivax infections, which are critical for sustained transmission in the region,” said study author Leanne Robinson, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“P vivax parasites are able to hide in the liver for long periods of time before ‘reawakening’ to cause disease and continue the transmission cycle. Mass drug administration that includes a drug that kills parasites in the liver is likely to be a highly effective strategy for eliminating malaria in PNG.”

To investigate this possibility, Dr Robinson and her colleagues analyzed 524 children, ages 5 to 10, living in a region of PNG where Plasmodium falciparum and P vivax are hyperendemic.

Roughly half the children (n=261) received an antimalarial treatment regimen that targets both blood-stage and liver-stage parasites (3 days of chloroquine, 3 days of artemether-lumefantrine, and 20 days of primaquine).

The other half (n=263) received antimalarial treatment targeting only blood-stage parasites (3 days of chloroquine, 3 days of artemether-lumefantrine, and 20 days of placebo).

The subjects were followed for 8 months. Compared to children in the placebo arm, those in the primaquine arm had a reduced risk of having at least 1 P vivax or P ovale infection during the follow-up period. The hazard ratio was 0.18 for P vivax (P<0.001) and 0.31 for P ovale (P=0.011).

“Children treated with drugs that targeted the liver and blood stages of infection had 80% fewer malaria infections than those treated with drugs that only targeted the blood stage of infection,” Dr Robinson said.

Children in the primaquine arm also had a reduced risk of having at least 1 clinical P vivax episode. The hazard ratio was 0.25 (P=0.002).

In addition, primaquine reduced the molecular force of P vivax blood-stage infection in the first 3 months of follow-up. The incidence rate ratio was 0.21 (P<0.001).

And children who received primaquine were less likely to carry P vivax gametocytes than children who received placebo, with an incidence rate ratio of 0.27 (P<0.001).

To build upon these findings, the investigators fed the trial data into a mathematical transmission model.

The model predicted that a mass drug administration program using blood-stage treatment alone would have only a transient effect on P vivax transmission levels. But a mass drug administration program that includes blood- and liver-stage treatment would be an effective strategy for P vivax elimination.

“We need a better way of identifying children who are chronically infected with malaria so that they can be treated,” said study author Ivo Mueller, PhD, of the Walter and Eliza Hall Institute.

“It is the only way to stop the malaria transmission cycle in PNG and is likely to be the case for eliminating malaria in other parts of the Asia-Pacific and Americas.”

Dr Mueller and an international team of collaborators are currently developing a test that identifies people with dormant malaria parasites in their liver.

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

New research indicates that most childhood malaria infections in Papua New Guinea (PNG) are the result of relapsed, not new, infections.

The data suggest that, among children ages 5 to 10 living in a malaria-hyperendemic region of PNG, relapses cause about 4 of every 5 Plasmodium vivax infections and 3 of every 5 Plasmodium ovale infections.

Investigators therefore concluded that relapses are important for sustaining malaria transmission in PNG.

The team reported their findings in PLOS Medicine.

“Our research has shown that one of the biggest problems in realizing malaria eradication is relapsing P vivax infections, which are critical for sustained transmission in the region,” said study author Leanne Robinson, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“P vivax parasites are able to hide in the liver for long periods of time before ‘reawakening’ to cause disease and continue the transmission cycle. Mass drug administration that includes a drug that kills parasites in the liver is likely to be a highly effective strategy for eliminating malaria in PNG.”

To investigate this possibility, Dr Robinson and her colleagues analyzed 524 children, ages 5 to 10, living in a region of PNG where Plasmodium falciparum and P vivax are hyperendemic.

Roughly half the children (n=261) received an antimalarial treatment regimen that targets both blood-stage and liver-stage parasites (3 days of chloroquine, 3 days of artemether-lumefantrine, and 20 days of primaquine).

The other half (n=263) received antimalarial treatment targeting only blood-stage parasites (3 days of chloroquine, 3 days of artemether-lumefantrine, and 20 days of placebo).

The subjects were followed for 8 months. Compared to children in the placebo arm, those in the primaquine arm had a reduced risk of having at least 1 P vivax or P ovale infection during the follow-up period. The hazard ratio was 0.18 for P vivax (P<0.001) and 0.31 for P ovale (P=0.011).

“Children treated with drugs that targeted the liver and blood stages of infection had 80% fewer malaria infections than those treated with drugs that only targeted the blood stage of infection,” Dr Robinson said.

Children in the primaquine arm also had a reduced risk of having at least 1 clinical P vivax episode. The hazard ratio was 0.25 (P=0.002).

In addition, primaquine reduced the molecular force of P vivax blood-stage infection in the first 3 months of follow-up. The incidence rate ratio was 0.21 (P<0.001).

And children who received primaquine were less likely to carry P vivax gametocytes than children who received placebo, with an incidence rate ratio of 0.27 (P<0.001).

To build upon these findings, the investigators fed the trial data into a mathematical transmission model.

The model predicted that a mass drug administration program using blood-stage treatment alone would have only a transient effect on P vivax transmission levels. But a mass drug administration program that includes blood- and liver-stage treatment would be an effective strategy for P vivax elimination.

“We need a better way of identifying children who are chronically infected with malaria so that they can be treated,” said study author Ivo Mueller, PhD, of the Walter and Eliza Hall Institute.

“It is the only way to stop the malaria transmission cycle in PNG and is likely to be the case for eliminating malaria in other parts of the Asia-Pacific and Americas.”

Dr Mueller and an international team of collaborators are currently developing a test that identifies people with dormant malaria parasites in their liver.

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

New research indicates that most childhood malaria infections in Papua New Guinea (PNG) are the result of relapsed, not new, infections.

The data suggest that, among children ages 5 to 10 living in a malaria-hyperendemic region of PNG, relapses cause about 4 of every 5 Plasmodium vivax infections and 3 of every 5 Plasmodium ovale infections.

Investigators therefore concluded that relapses are important for sustaining malaria transmission in PNG.

The team reported their findings in PLOS Medicine.

“Our research has shown that one of the biggest problems in realizing malaria eradication is relapsing P vivax infections, which are critical for sustained transmission in the region,” said study author Leanne Robinson, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.

“P vivax parasites are able to hide in the liver for long periods of time before ‘reawakening’ to cause disease and continue the transmission cycle. Mass drug administration that includes a drug that kills parasites in the liver is likely to be a highly effective strategy for eliminating malaria in PNG.”

To investigate this possibility, Dr Robinson and her colleagues analyzed 524 children, ages 5 to 10, living in a region of PNG where Plasmodium falciparum and P vivax are hyperendemic.

Roughly half the children (n=261) received an antimalarial treatment regimen that targets both blood-stage and liver-stage parasites (3 days of chloroquine, 3 days of artemether-lumefantrine, and 20 days of primaquine).

The other half (n=263) received antimalarial treatment targeting only blood-stage parasites (3 days of chloroquine, 3 days of artemether-lumefantrine, and 20 days of placebo).

The subjects were followed for 8 months. Compared to children in the placebo arm, those in the primaquine arm had a reduced risk of having at least 1 P vivax or P ovale infection during the follow-up period. The hazard ratio was 0.18 for P vivax (P<0.001) and 0.31 for P ovale (P=0.011).

“Children treated with drugs that targeted the liver and blood stages of infection had 80% fewer malaria infections than those treated with drugs that only targeted the blood stage of infection,” Dr Robinson said.

Children in the primaquine arm also had a reduced risk of having at least 1 clinical P vivax episode. The hazard ratio was 0.25 (P=0.002).

In addition, primaquine reduced the molecular force of P vivax blood-stage infection in the first 3 months of follow-up. The incidence rate ratio was 0.21 (P<0.001).

And children who received primaquine were less likely to carry P vivax gametocytes than children who received placebo, with an incidence rate ratio of 0.27 (P<0.001).

To build upon these findings, the investigators fed the trial data into a mathematical transmission model.

The model predicted that a mass drug administration program using blood-stage treatment alone would have only a transient effect on P vivax transmission levels. But a mass drug administration program that includes blood- and liver-stage treatment would be an effective strategy for P vivax elimination.

“We need a better way of identifying children who are chronically infected with malaria so that they can be treated,” said study author Ivo Mueller, PhD, of the Walter and Eliza Hall Institute.

“It is the only way to stop the malaria transmission cycle in PNG and is likely to be the case for eliminating malaria in other parts of the Asia-Pacific and Americas.”

Dr Mueller and an international team of collaborators are currently developing a test that identifies people with dormant malaria parasites in their liver.

Leg in a cast

Photo by Nikki McLeod

Researchers say they have developed prediction models and a scoring system that can help identify a high risk of venous thromboembolism (VTE) in a patient who has a plaster leg cast.

The group utilized data from 3 large studies to develop and validate 3 prediction models and a risk score, known as the L-TRiP (cast) score, which are intended to help doctors decide whether patients with casts require thromboprophylaxis.

The models and the scoring system all predicted VTE with fairly high accuracy, but the researchers said this study had 2 major limitations.

First, due to the retrospective nature of the study, the team was unable to determine which of the patients may have received thromboprophylaxis. And second, blood samples were taken 3 months after VTE.

Banne Nemeth, MD, of Leiden University Medical Center in Leiden, Netherlands, and colleagues conducted this research and reported the results in PLOS Medicine.

Developing prediction tools

The researchers first analyzed data from the MEGA study, a population-based, case-control study in the Netherlands that included 4446 patients with VTE and 6118 controls.

From these data, the team attempted to identify biomarkers, genetic factors, and environmental factors predictive of VTE and build 3 different prediction models. Their full prediction model consists of 32 predictors for VTE, including 3 genetic factors and 6 biomarkers.

Their restricted model consists of 11 predictors for VTE, including 2 genetic factors and 1 biomarker. And their clinical model consists of 14 environmental predictors that can all be determined without drawing blood or performing any laboratory assays.

The predictors in the clinical model were given numerical values that, when summed, produce the L-TRiP (cast) score (Leiden–Thrombosis Risk Prediction for patients with cast immobilization score) to stratify patients into high- or low-risk groups for VTE.

To determine the discriminatory power of the models and the score in patients with casts, the researchers calculated the area under the curve (AUC) for each tool.

The AUC was 0.85 for the full model, 0.84 for the restricted model, 0.77 for the clinical model, and 0.76 for the L-TRiP (cast) score.

Validating the tools

The researchers validated the prediction models and risk score in 2 independent cohorts, THE-VTE study (784 VTE cases and 523 controls from the Netherlands and the UK) and the Milan study (2117 cases and 2088 controls from Italy).

In THE-VTE study, the AUC was 0.75 for the clinical model and 0.77 for the L-TRiP (cast) score. (There were no data provided for the full model or the restricted model in this cohort.)

In the Milan study, the AUC was 0.93 for the full model, 0.92 for the restricted model, 0.96 for the clinical model, and 0.95 for the L-TRiP (cast) score.

The researchers said these results suggest that genetic and biomarker information may provide added value in predicting VTE.

However, their clinical model (which consists solely of environmental factors) proved only slightly inferior to the full model in the derivation cohort and performed as well or better than the full model in the validation cohorts.

So it is unclear whether genetic and biomarker information will lead to higher accuracy in the prediction algorithm.

Leg in a cast

Photo by Nikki McLeod

Researchers say they have developed prediction models and a scoring system that can help identify a high risk of venous thromboembolism (VTE) in a patient who has a plaster leg cast.

The group utilized data from 3 large studies to develop and validate 3 prediction models and a risk score, known as the L-TRiP (cast) score, which are intended to help doctors decide whether patients with casts require thromboprophylaxis.

The models and the scoring system all predicted VTE with fairly high accuracy, but the researchers said this study had 2 major limitations.

First, due to the retrospective nature of the study, the team was unable to determine which of the patients may have received thromboprophylaxis. And second, blood samples were taken 3 months after VTE.

Banne Nemeth, MD, of Leiden University Medical Center in Leiden, Netherlands, and colleagues conducted this research and reported the results in PLOS Medicine.

Developing prediction tools

The researchers first analyzed data from the MEGA study, a population-based, case-control study in the Netherlands that included 4446 patients with VTE and 6118 controls.

From these data, the team attempted to identify biomarkers, genetic factors, and environmental factors predictive of VTE and build 3 different prediction models. Their full prediction model consists of 32 predictors for VTE, including 3 genetic factors and 6 biomarkers.

Their restricted model consists of 11 predictors for VTE, including 2 genetic factors and 1 biomarker. And their clinical model consists of 14 environmental predictors that can all be determined without drawing blood or performing any laboratory assays.

The predictors in the clinical model were given numerical values that, when summed, produce the L-TRiP (cast) score (Leiden–Thrombosis Risk Prediction for patients with cast immobilization score) to stratify patients into high- or low-risk groups for VTE.

To determine the discriminatory power of the models and the score in patients with casts, the researchers calculated the area under the curve (AUC) for each tool.

The AUC was 0.85 for the full model, 0.84 for the restricted model, 0.77 for the clinical model, and 0.76 for the L-TRiP (cast) score.

Validating the tools

The researchers validated the prediction models and risk score in 2 independent cohorts, THE-VTE study (784 VTE cases and 523 controls from the Netherlands and the UK) and the Milan study (2117 cases and 2088 controls from Italy).

In THE-VTE study, the AUC was 0.75 for the clinical model and 0.77 for the L-TRiP (cast) score. (There were no data provided for the full model or the restricted model in this cohort.)

In the Milan study, the AUC was 0.93 for the full model, 0.92 for the restricted model, 0.96 for the clinical model, and 0.95 for the L-TRiP (cast) score.

The researchers said these results suggest that genetic and biomarker information may provide added value in predicting VTE.

However, their clinical model (which consists solely of environmental factors) proved only slightly inferior to the full model in the derivation cohort and performed as well or better than the full model in the validation cohorts.

So it is unclear whether genetic and biomarker information will lead to higher accuracy in the prediction algorithm.

Leg in a cast

Photo by Nikki McLeod

Researchers say they have developed prediction models and a scoring system that can help identify a high risk of venous thromboembolism (VTE) in a patient who has a plaster leg cast.

The group utilized data from 3 large studies to develop and validate 3 prediction models and a risk score, known as the L-TRiP (cast) score, which are intended to help doctors decide whether patients with casts require thromboprophylaxis.

The models and the scoring system all predicted VTE with fairly high accuracy, but the researchers said this study had 2 major limitations.

First, due to the retrospective nature of the study, the team was unable to determine which of the patients may have received thromboprophylaxis. And second, blood samples were taken 3 months after VTE.

Banne Nemeth, MD, of Leiden University Medical Center in Leiden, Netherlands, and colleagues conducted this research and reported the results in PLOS Medicine.

Developing prediction tools

The researchers first analyzed data from the MEGA study, a population-based, case-control study in the Netherlands that included 4446 patients with VTE and 6118 controls.

From these data, the team attempted to identify biomarkers, genetic factors, and environmental factors predictive of VTE and build 3 different prediction models. Their full prediction model consists of 32 predictors for VTE, including 3 genetic factors and 6 biomarkers.

Their restricted model consists of 11 predictors for VTE, including 2 genetic factors and 1 biomarker. And their clinical model consists of 14 environmental predictors that can all be determined without drawing blood or performing any laboratory assays.

The predictors in the clinical model were given numerical values that, when summed, produce the L-TRiP (cast) score (Leiden–Thrombosis Risk Prediction for patients with cast immobilization score) to stratify patients into high- or low-risk groups for VTE.

To determine the discriminatory power of the models and the score in patients with casts, the researchers calculated the area under the curve (AUC) for each tool.

The AUC was 0.85 for the full model, 0.84 for the restricted model, 0.77 for the clinical model, and 0.76 for the L-TRiP (cast) score.

Validating the tools

The researchers validated the prediction models and risk score in 2 independent cohorts, THE-VTE study (784 VTE cases and 523 controls from the Netherlands and the UK) and the Milan study (2117 cases and 2088 controls from Italy).

In THE-VTE study, the AUC was 0.75 for the clinical model and 0.77 for the L-TRiP (cast) score. (There were no data provided for the full model or the restricted model in this cohort.)

In the Milan study, the AUC was 0.93 for the full model, 0.92 for the restricted model, 0.96 for the clinical model, and 0.95 for the L-TRiP (cast) score.

The researchers said these results suggest that genetic and biomarker information may provide added value in predicting VTE.

However, their clinical model (which consists solely of environmental factors) proved only slightly inferior to the full model in the derivation cohort and performed as well or better than the full model in the validation cohorts.

So it is unclear whether genetic and biomarker information will lead to higher accuracy in the prediction algorithm.

Analysis of cancer registry data from Denmark, Iceland, and Sweden over more than 60 years found that survivors of childhood cancer had a 1.4-fold higher risk of autoimmune disease compared with matched controls.

Results showed significantly increased rates of hospital visits for 11 of 33 autoimmune diseases investigated. The most prominent excesses were for insulin-dependent diabetes mellitus, Addison’s disease, and Hashimoto’s thyroiditis, accounting for more than half the total number of excess autoimmune cases (Ann Rheum Dis 2015 Nov 6. doi: 10.1136/annrheumdis-2015-207659). The investigators could not rule out the influence of surveillance bias, given that hospitalization rate ratios were highest in the first 5 years after cancer diagnosis, potentially a consequence of closer surveillance during that period. For most autoimmune diseases, however, the excess risk persisted through the second and third decades after cancer diagnosis.

The Nordic childhood cancer survivor cohort comprised 25,635 individuals diagnosed with cancer before the age of 20 years, from the 1940s-1950s (start of cancer registries in Denmark, Iceland, and Sweden) to 2008. Expected autoimmune disease rates were based on rates of hospital visits for the comparison cohort, which included 128,023 individuals matched for age, sex, and country of the corresponding survivor. The standardized hospitalization rate ratio is the observed number of autoimmune diseases among survivors divided by the expected rate. Childhood malignancies with the most pronounced risk increases were leukemia (standardized hospitalization rate ratio, 1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).

“Cure is no longer a sufficient goal in childhood cancer care. As the vast majority of these patients survive, attention must be to paid to their long-term quality of life and health challenges,” wrote Dr. Anna Salifors Holmqvist of the department of clinical sciences, pediatric oncology and hematology, Skane University Hospital, Lund University, Sweden.

Increased risks were noted for a wide range of relatively rare autoimmune diseases after treatment for several types of childhood malignancies, and underlying mechanisms should be addressed in future studies, noted Dr. Holmqvist and her colleagues.

Analysis of cancer registry data from Denmark, Iceland, and Sweden over more than 60 years found that survivors of childhood cancer had a 1.4-fold higher risk of autoimmune disease compared with matched controls.

Results showed significantly increased rates of hospital visits for 11 of 33 autoimmune diseases investigated. The most prominent excesses were for insulin-dependent diabetes mellitus, Addison’s disease, and Hashimoto’s thyroiditis, accounting for more than half the total number of excess autoimmune cases (Ann Rheum Dis 2015 Nov 6. doi: 10.1136/annrheumdis-2015-207659). The investigators could not rule out the influence of surveillance bias, given that hospitalization rate ratios were highest in the first 5 years after cancer diagnosis, potentially a consequence of closer surveillance during that period. For most autoimmune diseases, however, the excess risk persisted through the second and third decades after cancer diagnosis.

The Nordic childhood cancer survivor cohort comprised 25,635 individuals diagnosed with cancer before the age of 20 years, from the 1940s-1950s (start of cancer registries in Denmark, Iceland, and Sweden) to 2008. Expected autoimmune disease rates were based on rates of hospital visits for the comparison cohort, which included 128,023 individuals matched for age, sex, and country of the corresponding survivor. The standardized hospitalization rate ratio is the observed number of autoimmune diseases among survivors divided by the expected rate. Childhood malignancies with the most pronounced risk increases were leukemia (standardized hospitalization rate ratio, 1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).

“Cure is no longer a sufficient goal in childhood cancer care. As the vast majority of these patients survive, attention must be to paid to their long-term quality of life and health challenges,” wrote Dr. Anna Salifors Holmqvist of the department of clinical sciences, pediatric oncology and hematology, Skane University Hospital, Lund University, Sweden.

Increased risks were noted for a wide range of relatively rare autoimmune diseases after treatment for several types of childhood malignancies, and underlying mechanisms should be addressed in future studies, noted Dr. Holmqvist and her colleagues.

Analysis of cancer registry data from Denmark, Iceland, and Sweden over more than 60 years found that survivors of childhood cancer had a 1.4-fold higher risk of autoimmune disease compared with matched controls.

Results showed significantly increased rates of hospital visits for 11 of 33 autoimmune diseases investigated. The most prominent excesses were for insulin-dependent diabetes mellitus, Addison’s disease, and Hashimoto’s thyroiditis, accounting for more than half the total number of excess autoimmune cases (Ann Rheum Dis 2015 Nov 6. doi: 10.1136/annrheumdis-2015-207659). The investigators could not rule out the influence of surveillance bias, given that hospitalization rate ratios were highest in the first 5 years after cancer diagnosis, potentially a consequence of closer surveillance during that period. For most autoimmune diseases, however, the excess risk persisted through the second and third decades after cancer diagnosis.

The Nordic childhood cancer survivor cohort comprised 25,635 individuals diagnosed with cancer before the age of 20 years, from the 1940s-1950s (start of cancer registries in Denmark, Iceland, and Sweden) to 2008. Expected autoimmune disease rates were based on rates of hospital visits for the comparison cohort, which included 128,023 individuals matched for age, sex, and country of the corresponding survivor. The standardized hospitalization rate ratio is the observed number of autoimmune diseases among survivors divided by the expected rate. Childhood malignancies with the most pronounced risk increases were leukemia (standardized hospitalization rate ratio, 1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).

“Cure is no longer a sufficient goal in childhood cancer care. As the vast majority of these patients survive, attention must be to paid to their long-term quality of life and health challenges,” wrote Dr. Anna Salifors Holmqvist of the department of clinical sciences, pediatric oncology and hematology, Skane University Hospital, Lund University, Sweden.

Increased risks were noted for a wide range of relatively rare autoimmune diseases after treatment for several types of childhood malignancies, and underlying mechanisms should be addressed in future studies, noted Dr. Holmqvist and her colleagues.

The letter from the insurance company was addressed to my patient. The two pages of information boiled down to one simple sentence: “After a thorough review, our decision to not cover the medication Provigil (modafinil) is unchanged.” The letter went on to explain that there was no further recourse, and that the medication would not be approved because it was not Food and Drug Administration–approved for the condition my patient had: major depression. If she chose to take it, there would be no reimbursement. In many psychiatric conditions, the FDA-approved options are very limited; for some disorders, there simply are no approved medications, despite the fact that research has shown medications to be helpful. For a medication that now has a generic, there is no reason for the pharmaceutical agency to incur the cost of getting a medication approved by the FDA for a specific use.

Psychiatrists are all familiar with the process of medication preauthorization. Insurance companies require the physician to make an extra effort in order to prescribe certain medications. Often, as in the case of modafinil, the medications are expensive, and one might wonder why a generic medication costs $25 a pill. The name-brand medication, Provigil, costs more than $33 for a single dose. Sometimes, however, a preauthorization process is put in place for very inexpensive medications that might cost only a few dollars a month. Preauthorization requirements waste enormous amounts of physician time and don’t necessarily save money for insurers.

What many physicians don’t realize is that there is no national oversight to this process. In some arenas, the insurers can set the hoops as high as they want and in perpetual motion, thereby making the process a long and miserable adventure – all while the patient suffers.

Nothing about my patient’s depression has been easy to treat. We started working together 8 years ago; her suffering at that time was extreme and her presentation was unusual. I arranged for her admission to a specialty unit in a psychiatric hospital, and she remained under their care for several months – an astounding period of time in an era where the average length of stay is 7 to 10 days. She was discharged – very much improved – on an unusual cocktail of medications.

Over time, we tapered some of the medications because of side effects. Five years ago, her insurance changed and after I answered a 13-question prior authorization form, the medication was denied because she did not have narcolepsy or any of the sleep disorders for which the FDA does approve the use of Provigil. An appeal was denied, and I prescribed stimulants instead. It wasn’t until recently, when the patient’s depression returned full-force, and every medication option I could think of had been tried, that I decided to try modafinil again, especially since I have found it helpful in another patient with a treatment-resistant depression.

I wrote a prescription and heard from the pharmacy that Provigil required preauthorization. I prescribed Nuvigil instead, but that too required preauthorization. A 20-minute phone call resulted in directions on how to find a form and fax a request for the medication. It contained many of the same questions from years ago, and the request was denied.

Several more phone calls led me to a reviewer with the pharmacy benefits company in Nevada, who told me I could find a form on the website, send in an appeal to the insurance company in Iowa, and I would hear within 15 business days if my patient could get the medication. When I said that was not acceptable – the patient was suffering and needed the medication now – I was told I would receive a call from a peer reviewer within 48 hours. A week later, a pharmacist called and asked the exact same questions that I had already answered. When I said that no, I had not ordered polysomnography or multiple sleep latency tests because they were not medically indicated, she denied approval of the medication and said she had no leeway to approve its use if the questions were not answered correctly. I found it curious that this step was called a “peer-to-peer” review. By this point, I had spent about an hour in a two-step process where the second step was exactly the same as the first step. It’s okay; the insurance company doesn’t mind the inefficient use of everyone’s time.

I was told that to file an appeal, I would need more forms off the website, and I was given (at my request) directions on where to find those forms. But first, I needed to get the patient to sign a form to authorize to release information on her behalf. The patient lives a 90-minute drive from my office and does not have a fax machine, and this delayed the process. It remained unclear to me why the patient’s permission was needed when it had not been needed for the first two steps of the process. The authorization was to be mailed or faxed to one location, while the appeal letter was to be mailed (fax or electronic submissions were not options) to another address.

In the appeal letter, I discussed her past history of a lengthy hospitalization, a long list of other medications that had been tried, and a study that documented the efficacy of modafinil as an adjunct agent in the treatment of depression.

As the weeks ticked by, I contacted the chief medical officer of the insurance company and complained; I had spent hours on an arbitrary, repetitive, and inefficient process that was yielding no results. I asked how he sleeps at night.

The response was infuriating: “I know that the appeal is being set up in the queue. I am sorry that this process has been drawn out for you and your patient.” In the queue? Had he ever sat with a sobbing, depressed patient who couldn’t get out of bed all day? A family member was taking off work to stay with her, and her life was on hold. The chief medical officer didn’t give any indication as to how long this queue might be. The family was hurting both emotionally and financially.

I tried one of my U.S. senators. His office replied that preauthorization oversight was not a legislative issue. I spoke with the insurance commission in Maryland where I practice, and I filed a formal complaint with the insurance commissioner in Iowa. I was told it could take up to 45 days for a response, but the next day, I heard back: The plan is funded through a family member’s employer and is not under the jurisdiction of the insurance commissioner. Simply put, the insurance company can set up as many hurdles as they like and take as long as they want to respond, regardless of the patient’s need.

Eight weeks after I wrote the prescription, a copy of the denial letter arrived in my mail. A physician in Iowa has determined that the medication is not medically necessary for a patient he or she had never seen in Maryland. I’ve turned to the American Psychiatric Association. With so many psychiatrists complaining about the burdens of preauthorization, this case would be a good example; one of its attorneys has agreed to write a letter to the Department of Labor. Perhaps that will help, but as of this writing, I have not yet seen that letter. All in all, it has been hours of my time, and lots of waiting, all without regard to the person who could possibly find some relief with a medication that is available to some, but not to her.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

The letter from the insurance company was addressed to my patient. The two pages of information boiled down to one simple sentence: “After a thorough review, our decision to not cover the medication Provigil (modafinil) is unchanged.” The letter went on to explain that there was no further recourse, and that the medication would not be approved because it was not Food and Drug Administration–approved for the condition my patient had: major depression. If she chose to take it, there would be no reimbursement. In many psychiatric conditions, the FDA-approved options are very limited; for some disorders, there simply are no approved medications, despite the fact that research has shown medications to be helpful. For a medication that now has a generic, there is no reason for the pharmaceutical agency to incur the cost of getting a medication approved by the FDA for a specific use.

Psychiatrists are all familiar with the process of medication preauthorization. Insurance companies require the physician to make an extra effort in order to prescribe certain medications. Often, as in the case of modafinil, the medications are expensive, and one might wonder why a generic medication costs $25 a pill. The name-brand medication, Provigil, costs more than $33 for a single dose. Sometimes, however, a preauthorization process is put in place for very inexpensive medications that might cost only a few dollars a month. Preauthorization requirements waste enormous amounts of physician time and don’t necessarily save money for insurers.

What many physicians don’t realize is that there is no national oversight to this process. In some arenas, the insurers can set the hoops as high as they want and in perpetual motion, thereby making the process a long and miserable adventure – all while the patient suffers.

Nothing about my patient’s depression has been easy to treat. We started working together 8 years ago; her suffering at that time was extreme and her presentation was unusual. I arranged for her admission to a specialty unit in a psychiatric hospital, and she remained under their care for several months – an astounding period of time in an era where the average length of stay is 7 to 10 days. She was discharged – very much improved – on an unusual cocktail of medications.

Over time, we tapered some of the medications because of side effects. Five years ago, her insurance changed and after I answered a 13-question prior authorization form, the medication was denied because she did not have narcolepsy or any of the sleep disorders for which the FDA does approve the use of Provigil. An appeal was denied, and I prescribed stimulants instead. It wasn’t until recently, when the patient’s depression returned full-force, and every medication option I could think of had been tried, that I decided to try modafinil again, especially since I have found it helpful in another patient with a treatment-resistant depression.

I wrote a prescription and heard from the pharmacy that Provigil required preauthorization. I prescribed Nuvigil instead, but that too required preauthorization. A 20-minute phone call resulted in directions on how to find a form and fax a request for the medication. It contained many of the same questions from years ago, and the request was denied.

Several more phone calls led me to a reviewer with the pharmacy benefits company in Nevada, who told me I could find a form on the website, send in an appeal to the insurance company in Iowa, and I would hear within 15 business days if my patient could get the medication. When I said that was not acceptable – the patient was suffering and needed the medication now – I was told I would receive a call from a peer reviewer within 48 hours. A week later, a pharmacist called and asked the exact same questions that I had already answered. When I said that no, I had not ordered polysomnography or multiple sleep latency tests because they were not medically indicated, she denied approval of the medication and said she had no leeway to approve its use if the questions were not answered correctly. I found it curious that this step was called a “peer-to-peer” review. By this point, I had spent about an hour in a two-step process where the second step was exactly the same as the first step. It’s okay; the insurance company doesn’t mind the inefficient use of everyone’s time.

I was told that to file an appeal, I would need more forms off the website, and I was given (at my request) directions on where to find those forms. But first, I needed to get the patient to sign a form to authorize to release information on her behalf. The patient lives a 90-minute drive from my office and does not have a fax machine, and this delayed the process. It remained unclear to me why the patient’s permission was needed when it had not been needed for the first two steps of the process. The authorization was to be mailed or faxed to one location, while the appeal letter was to be mailed (fax or electronic submissions were not options) to another address.

In the appeal letter, I discussed her past history of a lengthy hospitalization, a long list of other medications that had been tried, and a study that documented the efficacy of modafinil as an adjunct agent in the treatment of depression.

As the weeks ticked by, I contacted the chief medical officer of the insurance company and complained; I had spent hours on an arbitrary, repetitive, and inefficient process that was yielding no results. I asked how he sleeps at night.

The response was infuriating: “I know that the appeal is being set up in the queue. I am sorry that this process has been drawn out for you and your patient.” In the queue? Had he ever sat with a sobbing, depressed patient who couldn’t get out of bed all day? A family member was taking off work to stay with her, and her life was on hold. The chief medical officer didn’t give any indication as to how long this queue might be. The family was hurting both emotionally and financially.

I tried one of my U.S. senators. His office replied that preauthorization oversight was not a legislative issue. I spoke with the insurance commission in Maryland where I practice, and I filed a formal complaint with the insurance commissioner in Iowa. I was told it could take up to 45 days for a response, but the next day, I heard back: The plan is funded through a family member’s employer and is not under the jurisdiction of the insurance commissioner. Simply put, the insurance company can set up as many hurdles as they like and take as long as they want to respond, regardless of the patient’s need.

Eight weeks after I wrote the prescription, a copy of the denial letter arrived in my mail. A physician in Iowa has determined that the medication is not medically necessary for a patient he or she had never seen in Maryland. I’ve turned to the American Psychiatric Association. With so many psychiatrists complaining about the burdens of preauthorization, this case would be a good example; one of its attorneys has agreed to write a letter to the Department of Labor. Perhaps that will help, but as of this writing, I have not yet seen that letter. All in all, it has been hours of my time, and lots of waiting, all without regard to the person who could possibly find some relief with a medication that is available to some, but not to her.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

The letter from the insurance company was addressed to my patient. The two pages of information boiled down to one simple sentence: “After a thorough review, our decision to not cover the medication Provigil (modafinil) is unchanged.” The letter went on to explain that there was no further recourse, and that the medication would not be approved because it was not Food and Drug Administration–approved for the condition my patient had: major depression. If she chose to take it, there would be no reimbursement. In many psychiatric conditions, the FDA-approved options are very limited; for some disorders, there simply are no approved medications, despite the fact that research has shown medications to be helpful. For a medication that now has a generic, there is no reason for the pharmaceutical agency to incur the cost of getting a medication approved by the FDA for a specific use.

Psychiatrists are all familiar with the process of medication preauthorization. Insurance companies require the physician to make an extra effort in order to prescribe certain medications. Often, as in the case of modafinil, the medications are expensive, and one might wonder why a generic medication costs $25 a pill. The name-brand medication, Provigil, costs more than $33 for a single dose. Sometimes, however, a preauthorization process is put in place for very inexpensive medications that might cost only a few dollars a month. Preauthorization requirements waste enormous amounts of physician time and don’t necessarily save money for insurers.

What many physicians don’t realize is that there is no national oversight to this process. In some arenas, the insurers can set the hoops as high as they want and in perpetual motion, thereby making the process a long and miserable adventure – all while the patient suffers.

Nothing about my patient’s depression has been easy to treat. We started working together 8 years ago; her suffering at that time was extreme and her presentation was unusual. I arranged for her admission to a specialty unit in a psychiatric hospital, and she remained under their care for several months – an astounding period of time in an era where the average length of stay is 7 to 10 days. She was discharged – very much improved – on an unusual cocktail of medications.

Over time, we tapered some of the medications because of side effects. Five years ago, her insurance changed and after I answered a 13-question prior authorization form, the medication was denied because she did not have narcolepsy or any of the sleep disorders for which the FDA does approve the use of Provigil. An appeal was denied, and I prescribed stimulants instead. It wasn’t until recently, when the patient’s depression returned full-force, and every medication option I could think of had been tried, that I decided to try modafinil again, especially since I have found it helpful in another patient with a treatment-resistant depression.

I wrote a prescription and heard from the pharmacy that Provigil required preauthorization. I prescribed Nuvigil instead, but that too required preauthorization. A 20-minute phone call resulted in directions on how to find a form and fax a request for the medication. It contained many of the same questions from years ago, and the request was denied.

Several more phone calls led me to a reviewer with the pharmacy benefits company in Nevada, who told me I could find a form on the website, send in an appeal to the insurance company in Iowa, and I would hear within 15 business days if my patient could get the medication. When I said that was not acceptable – the patient was suffering and needed the medication now – I was told I would receive a call from a peer reviewer within 48 hours. A week later, a pharmacist called and asked the exact same questions that I had already answered. When I said that no, I had not ordered polysomnography or multiple sleep latency tests because they were not medically indicated, she denied approval of the medication and said she had no leeway to approve its use if the questions were not answered correctly. I found it curious that this step was called a “peer-to-peer” review. By this point, I had spent about an hour in a two-step process where the second step was exactly the same as the first step. It’s okay; the insurance company doesn’t mind the inefficient use of everyone’s time.

I was told that to file an appeal, I would need more forms off the website, and I was given (at my request) directions on where to find those forms. But first, I needed to get the patient to sign a form to authorize to release information on her behalf. The patient lives a 90-minute drive from my office and does not have a fax machine, and this delayed the process. It remained unclear to me why the patient’s permission was needed when it had not been needed for the first two steps of the process. The authorization was to be mailed or faxed to one location, while the appeal letter was to be mailed (fax or electronic submissions were not options) to another address.

In the appeal letter, I discussed her past history of a lengthy hospitalization, a long list of other medications that had been tried, and a study that documented the efficacy of modafinil as an adjunct agent in the treatment of depression.

As the weeks ticked by, I contacted the chief medical officer of the insurance company and complained; I had spent hours on an arbitrary, repetitive, and inefficient process that was yielding no results. I asked how he sleeps at night.

The response was infuriating: “I know that the appeal is being set up in the queue. I am sorry that this process has been drawn out for you and your patient.” In the queue? Had he ever sat with a sobbing, depressed patient who couldn’t get out of bed all day? A family member was taking off work to stay with her, and her life was on hold. The chief medical officer didn’t give any indication as to how long this queue might be. The family was hurting both emotionally and financially.

I tried one of my U.S. senators. His office replied that preauthorization oversight was not a legislative issue. I spoke with the insurance commission in Maryland where I practice, and I filed a formal complaint with the insurance commissioner in Iowa. I was told it could take up to 45 days for a response, but the next day, I heard back: The plan is funded through a family member’s employer and is not under the jurisdiction of the insurance commissioner. Simply put, the insurance company can set up as many hurdles as they like and take as long as they want to respond, regardless of the patient’s need.

Eight weeks after I wrote the prescription, a copy of the denial letter arrived in my mail. A physician in Iowa has determined that the medication is not medically necessary for a patient he or she had never seen in Maryland. I’ve turned to the American Psychiatric Association. With so many psychiatrists complaining about the burdens of preauthorization, this case would be a good example; one of its attorneys has agreed to write a letter to the Department of Labor. Perhaps that will help, but as of this writing, I have not yet seen that letter. All in all, it has been hours of my time, and lots of waiting, all without regard to the person who could possibly find some relief with a medication that is available to some, but not to her.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.

“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.

The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.

The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.

A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.

“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.

Tumor promoters

The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.

“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.

Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.

LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.

The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.

Well tolerated

At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).

A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.

Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.

The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.

The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.

The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.

Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.

The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.

BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.

“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.

The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.

The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.

A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.

“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.

Tumor promoters

The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.

“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.

Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.

LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.

The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.

Well tolerated

At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).

A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.

Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.

The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.

The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.

The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.

Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.

The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.

BOSTON – An experimental agent that targets the byproducts of gene fusions has shown surprising clinical activity against notoriously treatment-refractory cancers in early results from a phase I trial.

“I think that’s what remarkable about this is that we have all these different histologies and many different fusions, but all seem to be having some kind of [response] to this molecule,” said lead investigator Dr. David S. Hong, deputy chair and associate professor in the department of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston.

The molecule, LOXO-101 is a selective inhibitor of abnormal TRKA, TRKAB, and TRKC kinases that arise from gene fusions. TRK fusions have been implicated in tumor development in preclinical studies, he reported at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

One patient, a 41-year-old woman with undifferentiated soft tissue sarcoma of the groin that had metastasized to her lungs had rapid and “substantial” tumor and lung-nodule regression that radiographically fell just shy of a complete response, Dr. Hong said.

The drug also induced robust partial responses in a 55-year-old man with a gastrointestinal stromal tumor (GIST) for whom five prior targeted agents had failed, and a 33-year-old man with mammary analogue secretory carcinoma of the salivary gland (MASC) that had progressed on chemotherapy with docetaxel, carboplatin, and 5-fluorauracil.

A fourth patient, a man (age unspecified) who had papillary thyroid cancer with palpable lymphadenopathy, had no palpable nodes at 1-month follow-up, and appears to be responding to the drug, Dr. Hong added.

“This is really a dramatic example, I think, of a targeted therapy that is not histology specific, and this is another area in oncology where it’s new, and we’re just feeling our way,” commented Dr. Lee C. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md., who moderated the briefing where Dr. Hong presented the data.

Tumor promoters

The TRK family of proteins consists of separate tyrosine kinases that, when functioning normally, are important for the development of peripheral central nervous system processes such as pain and thermoregulation, Dr. Hong explained.

“The NTRK 1, 2, and 3 genes which encode for the TRK proteins are subject to these gene rearrangements and fusions, and the resulting TRK gene fusions may become erroneously expressed, and the kinase domain constitutively activated,” he said.

Gene fusions resulting in constitutively active TRKA, B, and C kinases can occur in the range of about 2%-25% in a wide variety of tumors, including adenocarcinomas of the lung, gliomas, thyroid tumors, head and neck cancers, sarcomas, and other types. These fusions have also been detected in more than 75% of MASC tumors, secretory breast carcinomas, and infantile (congenital) fibrosarcoma.

LOXO-101 is an orally delivered small molecule that was rationally designed to target the TRK fusions while largely leaving other kinases alone. In preclinical studies, the compound showed potent tumor growth inhibition and regression in mice bearing NTRK fusions.

The phase I trial is a dose-finding study including a total of 24 patients with various treatment-refractory advanced or metastatic solid tumors. Patients were enrolled regardless of fusional status.

Well tolerated

At the selected dose of 100 mg twice daily, patients appeared to tolerate the drug very well, with few off-target adverse events, Dr. Hong said. The most common side effect was mild dizziness. Grade 3 or 4 adverse events occurring at all doses levels include fatigue (one patient), anemia (two), abdominal pain (one), increased alkaline phosphatase (one), increased aspartate aminotransferase, delirium, and syncope (two each).

A total of six of the 24 patients had TRK fusions in their tumors, and three of these patients were available for assessment as of Oct. 20, 2015.

Dr. Hong and colleagues previously reportedon the case of the 41-year old woman with sarcoma. She was found to have a fusion of LMNA (a gene that encodes for nuclear membrane proteins) with NTRK1. She was started on the 100-mg b.i.d. dose of LOX-101 and had rapid resolution of dyspnea and hypoxemia. She had a confirmed partial response, and a CT scan showed that her multiple pulmonary nodules had regressed, with just a single, small disease site remaining at most recent follow-up. This patient continues on treatment and has been followed for more than 8 months.

The man with GIST had experienced disease progression while on therapy with imatinib, sunitinib, sorafenib, nilotinib, and regorafenib. He was treated in the 150-mg b.i.d. dose cohort, had a confirmed partial response, and remains on study after 4-plus months.

The third patient, the 33-year-old man with MASC, was assigned to the 100-mg b.i.d. dose. He too had a partial response, with radiologic evidence of substantial tumor shrinkage, and a persistent, tumor-related cough that disappeared after about 10 days of treatment, and remains on study after more than 3 months of follow-up.

The investigators have begun accruing patients for a phase II “basket” trial in adult patients with advanced or metastatic solid tumors displaying TRK fusions, including non–small cell lung cancers, thyroid tumors, sarcomas, colorectal cancer, salivary gland cancers, primary central nervous system cancers, and all other solid tumors.

Dr. Hong said that the results indicate the importance of tumor profiling for the majority of patients, especially those whose disease is refractory to standard therapies.

The study was funded by Loxo Oncology. Dr. Hong disclosed receiving travel expenses from the company. Three coauthors are employees and shareholders of the company.

LAKE BUENA VISTA, FLA. – Levothyroxine therapy during pregnancy in women with subclinical hypothyroidism was associated with a decrease in low birth weight and low Apgar scores but not with a significant decrease in pregnancy loss in a large retrospective cohort study.

In 79 pregnant women with subclinical hypothyroidism (SCH) who received therapy with levothyroxine (LT4), and 285 with SCH who did not receive LT4 therapy, the frequency of low birth weight (less than 2,500 g) was 1.3% vs. 10%, respectively, and the frequency of Apgar scores of 7 or less at 5 minutes was 0% vs. 6.9%, Dr. S. Maraka reported at the International Thyroid Congress.

The rate of pregnancy loss was clinically, but not significantly, lower in the treated group (5.1% vs. 8.8%), and there was no difference between the groups with respect to 11 other maternal and neonatal outcomes, Dr. Maraka of the Mayo Clinic, Rochester, Minn., said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

Study subjects were women evaluated at the Mayo Clinic, Rochester, between January 2011 and December 2013, who had SCH during pregnancy. SCH was defined as thyroid stimulating hormone levels greater than 2.5 mIU/L during the first trimester, or greater than 3 mIU/L but no more than 10 mIU/L during the second and third trimesters. Those with a twin pregnancy or who used medications that might affect thyroid function were excluded.

The treated and untreated groups were similar with regard to age, history of pregnancy loss, and smoking status, but the treated group had higher body mass index and higher TSH levels, Dr. Maraka noted.

The findings that LT4 may improve pregnancy outcome in women with SCH are important because SCH has been associated with an increased risk of adverse pregnancy outcomes in some studies and it has been unclear whether LT4 therapy improves outcomes.

However, the association seen in the current study, which involves the largest cohort reporting pregnancy outcomes of women with SCH treated vs. untreated with LT4 therapy, requires confirmation in randomized trials before widespread use of LT4 therapy for SCH can be recommended, she concluded.

Dr. Maraka reported having no disclosures.

[email protected]

LAKE BUENA VISTA, FLA. – Levothyroxine therapy during pregnancy in women with subclinical hypothyroidism was associated with a decrease in low birth weight and low Apgar scores but not with a significant decrease in pregnancy loss in a large retrospective cohort study.

In 79 pregnant women with subclinical hypothyroidism (SCH) who received therapy with levothyroxine (LT4), and 285 with SCH who did not receive LT4 therapy, the frequency of low birth weight (less than 2,500 g) was 1.3% vs. 10%, respectively, and the frequency of Apgar scores of 7 or less at 5 minutes was 0% vs. 6.9%, Dr. S. Maraka reported at the International Thyroid Congress.

The rate of pregnancy loss was clinically, but not significantly, lower in the treated group (5.1% vs. 8.8%), and there was no difference between the groups with respect to 11 other maternal and neonatal outcomes, Dr. Maraka of the Mayo Clinic, Rochester, Minn., said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

Study subjects were women evaluated at the Mayo Clinic, Rochester, between January 2011 and December 2013, who had SCH during pregnancy. SCH was defined as thyroid stimulating hormone levels greater than 2.5 mIU/L during the first trimester, or greater than 3 mIU/L but no more than 10 mIU/L during the second and third trimesters. Those with a twin pregnancy or who used medications that might affect thyroid function were excluded.

The treated and untreated groups were similar with regard to age, history of pregnancy loss, and smoking status, but the treated group had higher body mass index and higher TSH levels, Dr. Maraka noted.

The findings that LT4 may improve pregnancy outcome in women with SCH are important because SCH has been associated with an increased risk of adverse pregnancy outcomes in some studies and it has been unclear whether LT4 therapy improves outcomes.

However, the association seen in the current study, which involves the largest cohort reporting pregnancy outcomes of women with SCH treated vs. untreated with LT4 therapy, requires confirmation in randomized trials before widespread use of LT4 therapy for SCH can be recommended, she concluded.

Dr. Maraka reported having no disclosures.

[email protected]

LAKE BUENA VISTA, FLA. – Levothyroxine therapy during pregnancy in women with subclinical hypothyroidism was associated with a decrease in low birth weight and low Apgar scores but not with a significant decrease in pregnancy loss in a large retrospective cohort study.

In 79 pregnant women with subclinical hypothyroidism (SCH) who received therapy with levothyroxine (LT4), and 285 with SCH who did not receive LT4 therapy, the frequency of low birth weight (less than 2,500 g) was 1.3% vs. 10%, respectively, and the frequency of Apgar scores of 7 or less at 5 minutes was 0% vs. 6.9%, Dr. S. Maraka reported at the International Thyroid Congress.

The rate of pregnancy loss was clinically, but not significantly, lower in the treated group (5.1% vs. 8.8%), and there was no difference between the groups with respect to 11 other maternal and neonatal outcomes, Dr. Maraka of the Mayo Clinic, Rochester, Minn., said at the meeting held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.

Study subjects were women evaluated at the Mayo Clinic, Rochester, between January 2011 and December 2013, who had SCH during pregnancy. SCH was defined as thyroid stimulating hormone levels greater than 2.5 mIU/L during the first trimester, or greater than 3 mIU/L but no more than 10 mIU/L during the second and third trimesters. Those with a twin pregnancy or who used medications that might affect thyroid function were excluded.

The treated and untreated groups were similar with regard to age, history of pregnancy loss, and smoking status, but the treated group had higher body mass index and higher TSH levels, Dr. Maraka noted.

The findings that LT4 may improve pregnancy outcome in women with SCH are important because SCH has been associated with an increased risk of adverse pregnancy outcomes in some studies and it has been unclear whether LT4 therapy improves outcomes.

However, the association seen in the current study, which involves the largest cohort reporting pregnancy outcomes of women with SCH treated vs. untreated with LT4 therapy, requires confirmation in randomized trials before widespread use of LT4 therapy for SCH can be recommended, she concluded.

Dr. Maraka reported having no disclosures.

[email protected]

A 49-year-old woman presents to dermatology with a lesion on her back. It’s been there for at least 20 years, slowly growing to its present size; it is now so prominent that it shows through her clothes and is subject to traumatization. The visibility of the lesion, particularly when the patient wears a swimsuit, is a source of considerable embarrassment.

Notable medical history includes polycystic ovarian syndrome and related diabetes and dyslipidemia. Family history reveals that the patient’s mother died of heart disease in her 40s.

EXAMINATION
The lesion, which measures 3 cm x 3 cm, is an impressive, pedunculated, doughy, rubbery, skin-colored mass protruding from her left mid back. No redness or edema is seen on or around the lesion. On palpation, the lesion is found to be uniformly soft and rubbery.

The patient is quite obese and has numerous skin tags in skin folds, under the arms, and around the neck.

What is the diagnosis?

DISCUSSION
The lesion was excised with deep margins and submitted to pathology. The report showed benign histology, consistent with a fibroepitheliomatous polyp.

In one sense, it’s hard to believe this huge lesion was a “skin tag,” and there are other things it might have been. But the microscopic examination of the tissue proved it was simply a large version of the same skin tags we see around necks and in axillae. These lesions are known by various names, including fibroepitheliomatous polyps (FEP) and acrochordons. A more typical FEP would be the size of a grain of rice, but they can take on various forms and sizes.

There is a differential for lesions that look like FEPs; it includes seborrheic  keratoses, warts, molluscum contagiosum, neurofibromas, and fibrolipomas. Even melanoma and squamous cell carcinoma can assume a tag-like morphology. So it pays to take a close look at these lesions, checking to see if they’re soft and pliable, as well as skin colored. With any odd feature, including increased size, they need to be removed and sent for pathologic examination.

Heredity appears to play a role in the development of FEPs, as do age and obesity. There are studies showing an association between FEPs and insulin resistance and others identifying FEPs as a marker for increased risk for atherosclerotic vessel disease. In any case, 59% of the population has them by age 70, with men and women affected equally. Of the general population, 46% has some sort of skin tag somewhere.

Treatment may entail cryotherapy, excision, or electrodessication. With lesions as large as the case patient’s, excision is the only reasonable option. Deep margins are required, since a “shave” would leave a gaping, open wound. For the case patient, there was no postoperative sequelae aside from some scarring.

TAKE-HOME LEARNING POINTS
• Skin tags, also known as fibroepitheliomas, fibroepitheliomatous polyps, or acrochordons, are typically the size of a grain of rice, and tend to appear in skin folds (eg, axillae, neck, groin).

• Studies have shown that there may be an association between having skin tags and developing CAD or insulin resistance.

• Obesity, age, and heredity also appear to be factors in developing skin tags.

• Large or odd tags need to be captured and sent for pathologic examination.

• Skin tags are extremely common, affecting 59% of the population older than 70. 

A 49-year-old woman presents to dermatology with a lesion on her back. It’s been there for at least 20 years, slowly growing to its present size; it is now so prominent that it shows through her clothes and is subject to traumatization. The visibility of the lesion, particularly when the patient wears a swimsuit, is a source of considerable embarrassment.

Notable medical history includes polycystic ovarian syndrome and related diabetes and dyslipidemia. Family history reveals that the patient’s mother died of heart disease in her 40s.

EXAMINATION
The lesion, which measures 3 cm x 3 cm, is an impressive, pedunculated, doughy, rubbery, skin-colored mass protruding from her left mid back. No redness or edema is seen on or around the lesion. On palpation, the lesion is found to be uniformly soft and rubbery.

The patient is quite obese and has numerous skin tags in skin folds, under the arms, and around the neck.

What is the diagnosis?

DISCUSSION
The lesion was excised with deep margins and submitted to pathology. The report showed benign histology, consistent with a fibroepitheliomatous polyp.

In one sense, it’s hard to believe this huge lesion was a “skin tag,” and there are other things it might have been. But the microscopic examination of the tissue proved it was simply a large version of the same skin tags we see around necks and in axillae. These lesions are known by various names, including fibroepitheliomatous polyps (FEP) and acrochordons. A more typical FEP would be the size of a grain of rice, but they can take on various forms and sizes.

There is a differential for lesions that look like FEPs; it includes seborrheic  keratoses, warts, molluscum contagiosum, neurofibromas, and fibrolipomas. Even melanoma and squamous cell carcinoma can assume a tag-like morphology. So it pays to take a close look at these lesions, checking to see if they’re soft and pliable, as well as skin colored. With any odd feature, including increased size, they need to be removed and sent for pathologic examination.

Heredity appears to play a role in the development of FEPs, as do age and obesity. There are studies showing an association between FEPs and insulin resistance and others identifying FEPs as a marker for increased risk for atherosclerotic vessel disease. In any case, 59% of the population has them by age 70, with men and women affected equally. Of the general population, 46% has some sort of skin tag somewhere.

Treatment may entail cryotherapy, excision, or electrodessication. With lesions as large as the case patient’s, excision is the only reasonable option. Deep margins are required, since a “shave” would leave a gaping, open wound. For the case patient, there was no postoperative sequelae aside from some scarring.

TAKE-HOME LEARNING POINTS
• Skin tags, also known as fibroepitheliomas, fibroepitheliomatous polyps, or acrochordons, are typically the size of a grain of rice, and tend to appear in skin folds (eg, axillae, neck, groin).

• Studies have shown that there may be an association between having skin tags and developing CAD or insulin resistance.

• Obesity, age, and heredity also appear to be factors in developing skin tags.

• Large or odd tags need to be captured and sent for pathologic examination.

• Skin tags are extremely common, affecting 59% of the population older than 70. 

A 49-year-old woman presents to dermatology with a lesion on her back. It’s been there for at least 20 years, slowly growing to its present size; it is now so prominent that it shows through her clothes and is subject to traumatization. The visibility of the lesion, particularly when the patient wears a swimsuit, is a source of considerable embarrassment.

Notable medical history includes polycystic ovarian syndrome and related diabetes and dyslipidemia. Family history reveals that the patient’s mother died of heart disease in her 40s.

EXAMINATION
The lesion, which measures 3 cm x 3 cm, is an impressive, pedunculated, doughy, rubbery, skin-colored mass protruding from her left mid back. No redness or edema is seen on or around the lesion. On palpation, the lesion is found to be uniformly soft and rubbery.

The patient is quite obese and has numerous skin tags in skin folds, under the arms, and around the neck.

What is the diagnosis?

DISCUSSION
The lesion was excised with deep margins and submitted to pathology. The report showed benign histology, consistent with a fibroepitheliomatous polyp.

In one sense, it’s hard to believe this huge lesion was a “skin tag,” and there are other things it might have been. But the microscopic examination of the tissue proved it was simply a large version of the same skin tags we see around necks and in axillae. These lesions are known by various names, including fibroepitheliomatous polyps (FEP) and acrochordons. A more typical FEP would be the size of a grain of rice, but they can take on various forms and sizes.

There is a differential for lesions that look like FEPs; it includes seborrheic  keratoses, warts, molluscum contagiosum, neurofibromas, and fibrolipomas. Even melanoma and squamous cell carcinoma can assume a tag-like morphology. So it pays to take a close look at these lesions, checking to see if they’re soft and pliable, as well as skin colored. With any odd feature, including increased size, they need to be removed and sent for pathologic examination.

Heredity appears to play a role in the development of FEPs, as do age and obesity. There are studies showing an association between FEPs and insulin resistance and others identifying FEPs as a marker for increased risk for atherosclerotic vessel disease. In any case, 59% of the population has them by age 70, with men and women affected equally. Of the general population, 46% has some sort of skin tag somewhere.

Treatment may entail cryotherapy, excision, or electrodessication. With lesions as large as the case patient’s, excision is the only reasonable option. Deep margins are required, since a “shave” would leave a gaping, open wound. For the case patient, there was no postoperative sequelae aside from some scarring.

TAKE-HOME LEARNING POINTS
• Skin tags, also known as fibroepitheliomas, fibroepitheliomatous polyps, or acrochordons, are typically the size of a grain of rice, and tend to appear in skin folds (eg, axillae, neck, groin).

• Studies have shown that there may be an association between having skin tags and developing CAD or insulin resistance.

• Obesity, age, and heredity also appear to be factors in developing skin tags.

• Large or odd tags need to be captured and sent for pathologic examination.

• Skin tags are extremely common, affecting 59% of the population older than 70.