Severe and enduring anorexia ner­vosa (SE-AN) is persistent anorexia nervosa (AN) lasting for ≥7 years with or without a history of treat­ment. Evidence points to the effec­tiveness of a patient-tailored plan for treating SE-AN over any universal fix. Proper medication, therapeutic alliance, and strategic discharge planning are the ingre­dients for treating SE-AN that avoids re-hospitalization (Table).

Nutritional support and pharmacotherapy required
Comprehensive metabolic analysis and initiating nutrition should be the first pri­ority for the medical team. Starved-state patients can have electrolyte and metabolic derangements that place them at risk of fatal arrhythmias or multi-system organ failure. Do not hesitate to initiate nasogastric tube feeding under the observation of a certified nutritionist when necessary for survival. A double-blind, randomized controlled trial demonstrated the benefit of olanzap­ine compared with placebo to increase body mass index (BMI) of hospitalized AN patients. Olanzapine was titrated from 2.5 to 10 mg/d over a 13-week period, and was associated with higher patient achieve­ment of a BMI > 18.5 kg/m2.¹

Although the patient is receiving nutri­tional support in conjunction with psycho­tropic medication, the road to BMI recovery can be long. Don’t forget that SE-AN can be incapacitating. In SE-AN, the fear of gaining weight is so severe that the idea of starvation-induced death initially might seem more palatable. Although counterintuitive, as the patient recovers metabolically, self-image deteriorates. Statements praising any new weight gain can derail any therapeutic relationship.

Therapeutic alliance is key
Establishing high-quality therapeutic alliance, as measured by the Helping Relationships Questionnaire, has been shown to have a positive outcome on eating disorder symptoms and comorbid depressed mood in later phases of SE-AN treatment.^2,3 Although therapeutic alliance is individual­ized, maintaining open communication and reiterating how it is the patient’s decision to consume whole food at a level at which the feeding tube can be discontinued are good places to start treatment.

Proper discharge timing and transition to outpatient care for SE-AN patients is paramount. In multicenter studies, treat­ment ends too early in 57.8% of patients; discharge at sub-ideal BMI is linked to rehospitalization.³ Slower weight gain and delayed establishment of therapeutic alli­ance are predictors of patients who exit treatment programs too early.³ Clinicians who remain vigilant for the above metrics are less likely to feed into the unacceptably high rate of treatment failure for SE-AN.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Severe and enduring anorexia ner­vosa (SE-AN) is persistent anorexia nervosa (AN) lasting for ≥7 years with or without a history of treat­ment. Evidence points to the effec­tiveness of a patient-tailored plan for treating SE-AN over any universal fix. Proper medication, therapeutic alliance, and strategic discharge planning are the ingre­dients for treating SE-AN that avoids re-hospitalization (Table).

Nutritional support and pharmacotherapy required
Comprehensive metabolic analysis and initiating nutrition should be the first pri­ority for the medical team. Starved-state patients can have electrolyte and metabolic derangements that place them at risk of fatal arrhythmias or multi-system organ failure. Do not hesitate to initiate nasogastric tube feeding under the observation of a certified nutritionist when necessary for survival. A double-blind, randomized controlled trial demonstrated the benefit of olanzap­ine compared with placebo to increase body mass index (BMI) of hospitalized AN patients. Olanzapine was titrated from 2.5 to 10 mg/d over a 13-week period, and was associated with higher patient achieve­ment of a BMI > 18.5 kg/m2.¹

Although the patient is receiving nutri­tional support in conjunction with psycho­tropic medication, the road to BMI recovery can be long. Don’t forget that SE-AN can be incapacitating. In SE-AN, the fear of gaining weight is so severe that the idea of starvation-induced death initially might seem more palatable. Although counterintuitive, as the patient recovers metabolically, self-image deteriorates. Statements praising any new weight gain can derail any therapeutic relationship.

Therapeutic alliance is key
Establishing high-quality therapeutic alliance, as measured by the Helping Relationships Questionnaire, has been shown to have a positive outcome on eating disorder symptoms and comorbid depressed mood in later phases of SE-AN treatment.^2,3 Although therapeutic alliance is individual­ized, maintaining open communication and reiterating how it is the patient’s decision to consume whole food at a level at which the feeding tube can be discontinued are good places to start treatment.

Proper discharge timing and transition to outpatient care for SE-AN patients is paramount. In multicenter studies, treat­ment ends too early in 57.8% of patients; discharge at sub-ideal BMI is linked to rehospitalization.³ Slower weight gain and delayed establishment of therapeutic alli­ance are predictors of patients who exit treatment programs too early.³ Clinicians who remain vigilant for the above metrics are less likely to feed into the unacceptably high rate of treatment failure for SE-AN.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Severe and enduring anorexia ner­vosa (SE-AN) is persistent anorexia nervosa (AN) lasting for ≥7 years with or without a history of treat­ment. Evidence points to the effec­tiveness of a patient-tailored plan for treating SE-AN over any universal fix. Proper medication, therapeutic alliance, and strategic discharge planning are the ingre­dients for treating SE-AN that avoids re-hospitalization (Table).

Nutritional support and pharmacotherapy required
Comprehensive metabolic analysis and initiating nutrition should be the first pri­ority for the medical team. Starved-state patients can have electrolyte and metabolic derangements that place them at risk of fatal arrhythmias or multi-system organ failure. Do not hesitate to initiate nasogastric tube feeding under the observation of a certified nutritionist when necessary for survival. A double-blind, randomized controlled trial demonstrated the benefit of olanzap­ine compared with placebo to increase body mass index (BMI) of hospitalized AN patients. Olanzapine was titrated from 2.5 to 10 mg/d over a 13-week period, and was associated with higher patient achieve­ment of a BMI > 18.5 kg/m2.¹

Although the patient is receiving nutri­tional support in conjunction with psycho­tropic medication, the road to BMI recovery can be long. Don’t forget that SE-AN can be incapacitating. In SE-AN, the fear of gaining weight is so severe that the idea of starvation-induced death initially might seem more palatable. Although counterintuitive, as the patient recovers metabolically, self-image deteriorates. Statements praising any new weight gain can derail any therapeutic relationship.

Therapeutic alliance is key
Establishing high-quality therapeutic alliance, as measured by the Helping Relationships Questionnaire, has been shown to have a positive outcome on eating disorder symptoms and comorbid depressed mood in later phases of SE-AN treatment.^2,3 Although therapeutic alliance is individual­ized, maintaining open communication and reiterating how it is the patient’s decision to consume whole food at a level at which the feeding tube can be discontinued are good places to start treatment.

Proper discharge timing and transition to outpatient care for SE-AN patients is paramount. In multicenter studies, treat­ment ends too early in 57.8% of patients; discharge at sub-ideal BMI is linked to rehospitalization.³ Slower weight gain and delayed establishment of therapeutic alli­ance are predictors of patients who exit treatment programs too early.³ Clinicians who remain vigilant for the above metrics are less likely to feed into the unacceptably high rate of treatment failure for SE-AN.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Doctor and patient in hospital

Credit: CDC

New research indicates that anticoagulant therapy alone may be safer than catheter-directed thrombolysis (CDT) for treating deep vein thrombosis (DVT).

The study revealed similar rates of in-hospital mortality among patients treated with CDT and those receiving anticoagulation alone.

However, patients who received CDT were more likely to develop pulmonary emboli, experience intracranial hemorrhaging, and require blood transfusions.

Several previous studies have suggested that CDT can reduce the incidence of post-thrombotic syndrome in DVT patients. But CDT is controversial, with conflicting directives on its use because of inconclusive comparative safety outcomes.

So Riyaz Bashir, MD, of Temple University School of Medicine in Philadelphia, Pennsylvania, and his colleagues set out to compare CDT with anticoagulation alone.

They reported their findings in JAMA Internal Medicine.

The researchers examined in-hospital mortality, as well as secondary outcomes of bleeding complications, length of stay, and hospital charges, in a group of 90,618 patients hospitalized for DVT from 2005 through 2010 as part of the Nationwide Inpatient Sample database.

In all, 3649 patients (4.1%) underwent CDT. The CDT utilization rate increased from 2.3% in 2005 to 5.9% in 2010.

The in-hospital mortality rates were not significantly different in the CDT and anticoagulation-only groups, at 1.2% and 0.9%, respectively (P=0.15).

However, rates of adverse events were higher among patients treated with CDT. This included blood transfusion (11.1% vs 6.5%, P<0.001), pulmonary embolism (17.9% vs 11.4%, P<0.001), intracranial hemorrhage (0.9% vs 0.3%, P=0.03), and vena cava filter placement (34.8% vs 15.6%, P<0.001).

Patients in the CDT group also had longer average lengths of stay (7.2 vs 5 days, P<0.001) and higher hospital charges ($85,094 vs $28,164, P<0.001) compared with the anticoagulation-only group.

The researchers pointed out that their results are based on observational data, so the findings could be subject to residual confounding. Therefore, randomized trials are needed to better evaluate the effects of CDT.

However, the team also said that, as we don’t yet have this information, it may be reasonable to restrict CDT use to those patients who have a low bleeding risk and a high risk for post-thrombotic syndrome.

Doctor and patient in hospital

Credit: CDC

New research indicates that anticoagulant therapy alone may be safer than catheter-directed thrombolysis (CDT) for treating deep vein thrombosis (DVT).

The study revealed similar rates of in-hospital mortality among patients treated with CDT and those receiving anticoagulation alone.

However, patients who received CDT were more likely to develop pulmonary emboli, experience intracranial hemorrhaging, and require blood transfusions.

Several previous studies have suggested that CDT can reduce the incidence of post-thrombotic syndrome in DVT patients. But CDT is controversial, with conflicting directives on its use because of inconclusive comparative safety outcomes.

So Riyaz Bashir, MD, of Temple University School of Medicine in Philadelphia, Pennsylvania, and his colleagues set out to compare CDT with anticoagulation alone.

They reported their findings in JAMA Internal Medicine.

The researchers examined in-hospital mortality, as well as secondary outcomes of bleeding complications, length of stay, and hospital charges, in a group of 90,618 patients hospitalized for DVT from 2005 through 2010 as part of the Nationwide Inpatient Sample database.

In all, 3649 patients (4.1%) underwent CDT. The CDT utilization rate increased from 2.3% in 2005 to 5.9% in 2010.

The in-hospital mortality rates were not significantly different in the CDT and anticoagulation-only groups, at 1.2% and 0.9%, respectively (P=0.15).

However, rates of adverse events were higher among patients treated with CDT. This included blood transfusion (11.1% vs 6.5%, P<0.001), pulmonary embolism (17.9% vs 11.4%, P<0.001), intracranial hemorrhage (0.9% vs 0.3%, P=0.03), and vena cava filter placement (34.8% vs 15.6%, P<0.001).

Patients in the CDT group also had longer average lengths of stay (7.2 vs 5 days, P<0.001) and higher hospital charges ($85,094 vs $28,164, P<0.001) compared with the anticoagulation-only group.

The researchers pointed out that their results are based on observational data, so the findings could be subject to residual confounding. Therefore, randomized trials are needed to better evaluate the effects of CDT.

However, the team also said that, as we don’t yet have this information, it may be reasonable to restrict CDT use to those patients who have a low bleeding risk and a high risk for post-thrombotic syndrome.

Doctor and patient in hospital

Credit: CDC

New research indicates that anticoagulant therapy alone may be safer than catheter-directed thrombolysis (CDT) for treating deep vein thrombosis (DVT).

The study revealed similar rates of in-hospital mortality among patients treated with CDT and those receiving anticoagulation alone.

However, patients who received CDT were more likely to develop pulmonary emboli, experience intracranial hemorrhaging, and require blood transfusions.

Several previous studies have suggested that CDT can reduce the incidence of post-thrombotic syndrome in DVT patients. But CDT is controversial, with conflicting directives on its use because of inconclusive comparative safety outcomes.

So Riyaz Bashir, MD, of Temple University School of Medicine in Philadelphia, Pennsylvania, and his colleagues set out to compare CDT with anticoagulation alone.

They reported their findings in JAMA Internal Medicine.

The researchers examined in-hospital mortality, as well as secondary outcomes of bleeding complications, length of stay, and hospital charges, in a group of 90,618 patients hospitalized for DVT from 2005 through 2010 as part of the Nationwide Inpatient Sample database.

In all, 3649 patients (4.1%) underwent CDT. The CDT utilization rate increased from 2.3% in 2005 to 5.9% in 2010.

The in-hospital mortality rates were not significantly different in the CDT and anticoagulation-only groups, at 1.2% and 0.9%, respectively (P=0.15).

However, rates of adverse events were higher among patients treated with CDT. This included blood transfusion (11.1% vs 6.5%, P<0.001), pulmonary embolism (17.9% vs 11.4%, P<0.001), intracranial hemorrhage (0.9% vs 0.3%, P=0.03), and vena cava filter placement (34.8% vs 15.6%, P<0.001).

Patients in the CDT group also had longer average lengths of stay (7.2 vs 5 days, P<0.001) and higher hospital charges ($85,094 vs $28,164, P<0.001) compared with the anticoagulation-only group.

The researchers pointed out that their results are based on observational data, so the findings could be subject to residual confounding. Therefore, randomized trials are needed to better evaluate the effects of CDT.

However, the team also said that, as we don’t yet have this information, it may be reasonable to restrict CDT use to those patients who have a low bleeding risk and a high risk for post-thrombotic syndrome.

Blood for transfusion

Credit: UAB Hospital

A change in transfusion protocol has resulted in fewer potentially preventable deaths among soldiers, researchers have reported in JAMA Surgery.

In 2006, hospitals treating soldiers from Iraq and Afghanistan implemented a protocol called damage control resuscitation (DCR).

It involves administering blood products early and in a balanced ratio, using an aggressive approach to correct coagulopathy, and minimizing the use of crystalloid fluids.

The research showed that soldiers who died in the hospital after DCR was implemented were more likely than their predecessors to be severely injured and have a severe brain injury.

And this is consistent with a decrease in potentially preventable deaths, according to study author Nicholas R. Langan, MD, of the Madigan Army Medical Center in Tacoma, Washington, and his colleagues.

To conduct the study, the researchers reviewed data from the Joint Theater Trauma Registry of US forward combat hospitals. This included 57,179 soldiers, 2565 (4.5%) of whom died in the hospital. Seventy-four percent of these patients were severely injured, and 80% died within 24 hours of admission.

To assess the impact of DCR, the researchers divided patients into 2 groups: those treated before DCR implementation, from 2002 through 2005, and those treated with the DCR protocol, from 2006 through 2011.

The analysis showed that DCR policies were successfully implemented. There was a significant decrease in mean crystalloid infusion volume in the first 24 hours after hospitalization, from 6.1 L to 3.2 L (P<0.05).

There was a significant increase in fresh-frozen plasma use—from 3.2 U to 10.1 U (P=0.01)—and packed red blood cell use—from 8.4 U to 11.4 U (P=0.01)—in the first 24 hours after hospitalization.

And the mean ratio of packed red blood cells to fresh-frozen plasma changed from 2.6:1 in the pre-DCR period to 1.4:1 during the DCR period (P<0.01).

On the other hand, there was no significant difference in cryoprecipitate use, platelet use, or the ratio of packed red blood cells to cryoprecipitate or platelets.

The change in treatment protocol was associated with a change in the incidence of early and late, but not intermediate, deaths. The incidence of early death (within the first 24 hours) increased from 77% pre-DCR to 80% during DCR (P=0.02).

The incidence of late death (more than 7 days after injury) decreased from 10% pre-DCR to 6% during DCR (P<0.01). And the rate of intermediate death (1-7 days after injury) measured 13% for both periods (P=0.95).

The percentage of patients with any severe injury increased significantly from the pre-DCR period to the DCR period, from 64% to 80% (P<0.05). And the percentage of patients with severe head injuries increased significantly, from 57% to 73% (P<0.05).

As patients who died during the DCR period were more likely to have such “nonsurvivable” wounds, the researchers said this suggests that DCR is associated with a decrease in deaths among potentially salvageable patients.

Blood for transfusion

Credit: UAB Hospital

A change in transfusion protocol has resulted in fewer potentially preventable deaths among soldiers, researchers have reported in JAMA Surgery.

In 2006, hospitals treating soldiers from Iraq and Afghanistan implemented a protocol called damage control resuscitation (DCR).

It involves administering blood products early and in a balanced ratio, using an aggressive approach to correct coagulopathy, and minimizing the use of crystalloid fluids.

The research showed that soldiers who died in the hospital after DCR was implemented were more likely than their predecessors to be severely injured and have a severe brain injury.

And this is consistent with a decrease in potentially preventable deaths, according to study author Nicholas R. Langan, MD, of the Madigan Army Medical Center in Tacoma, Washington, and his colleagues.

To conduct the study, the researchers reviewed data from the Joint Theater Trauma Registry of US forward combat hospitals. This included 57,179 soldiers, 2565 (4.5%) of whom died in the hospital. Seventy-four percent of these patients were severely injured, and 80% died within 24 hours of admission.

To assess the impact of DCR, the researchers divided patients into 2 groups: those treated before DCR implementation, from 2002 through 2005, and those treated with the DCR protocol, from 2006 through 2011.

The analysis showed that DCR policies were successfully implemented. There was a significant decrease in mean crystalloid infusion volume in the first 24 hours after hospitalization, from 6.1 L to 3.2 L (P<0.05).

There was a significant increase in fresh-frozen plasma use—from 3.2 U to 10.1 U (P=0.01)—and packed red blood cell use—from 8.4 U to 11.4 U (P=0.01)—in the first 24 hours after hospitalization.

And the mean ratio of packed red blood cells to fresh-frozen plasma changed from 2.6:1 in the pre-DCR period to 1.4:1 during the DCR period (P<0.01).

On the other hand, there was no significant difference in cryoprecipitate use, platelet use, or the ratio of packed red blood cells to cryoprecipitate or platelets.

The change in treatment protocol was associated with a change in the incidence of early and late, but not intermediate, deaths. The incidence of early death (within the first 24 hours) increased from 77% pre-DCR to 80% during DCR (P=0.02).

The incidence of late death (more than 7 days after injury) decreased from 10% pre-DCR to 6% during DCR (P<0.01). And the rate of intermediate death (1-7 days after injury) measured 13% for both periods (P=0.95).

The percentage of patients with any severe injury increased significantly from the pre-DCR period to the DCR period, from 64% to 80% (P<0.05). And the percentage of patients with severe head injuries increased significantly, from 57% to 73% (P<0.05).

As patients who died during the DCR period were more likely to have such “nonsurvivable” wounds, the researchers said this suggests that DCR is associated with a decrease in deaths among potentially salvageable patients.

Blood for transfusion

Credit: UAB Hospital

A change in transfusion protocol has resulted in fewer potentially preventable deaths among soldiers, researchers have reported in JAMA Surgery.

In 2006, hospitals treating soldiers from Iraq and Afghanistan implemented a protocol called damage control resuscitation (DCR).

It involves administering blood products early and in a balanced ratio, using an aggressive approach to correct coagulopathy, and minimizing the use of crystalloid fluids.

The research showed that soldiers who died in the hospital after DCR was implemented were more likely than their predecessors to be severely injured and have a severe brain injury.

And this is consistent with a decrease in potentially preventable deaths, according to study author Nicholas R. Langan, MD, of the Madigan Army Medical Center in Tacoma, Washington, and his colleagues.

To conduct the study, the researchers reviewed data from the Joint Theater Trauma Registry of US forward combat hospitals. This included 57,179 soldiers, 2565 (4.5%) of whom died in the hospital. Seventy-four percent of these patients were severely injured, and 80% died within 24 hours of admission.

To assess the impact of DCR, the researchers divided patients into 2 groups: those treated before DCR implementation, from 2002 through 2005, and those treated with the DCR protocol, from 2006 through 2011.

The analysis showed that DCR policies were successfully implemented. There was a significant decrease in mean crystalloid infusion volume in the first 24 hours after hospitalization, from 6.1 L to 3.2 L (P<0.05).

There was a significant increase in fresh-frozen plasma use—from 3.2 U to 10.1 U (P=0.01)—and packed red blood cell use—from 8.4 U to 11.4 U (P=0.01)—in the first 24 hours after hospitalization.

And the mean ratio of packed red blood cells to fresh-frozen plasma changed from 2.6:1 in the pre-DCR period to 1.4:1 during the DCR period (P<0.01).

On the other hand, there was no significant difference in cryoprecipitate use, platelet use, or the ratio of packed red blood cells to cryoprecipitate or platelets.

The change in treatment protocol was associated with a change in the incidence of early and late, but not intermediate, deaths. The incidence of early death (within the first 24 hours) increased from 77% pre-DCR to 80% during DCR (P=0.02).

The incidence of late death (more than 7 days after injury) decreased from 10% pre-DCR to 6% during DCR (P<0.01). And the rate of intermediate death (1-7 days after injury) measured 13% for both periods (P=0.95).

The percentage of patients with any severe injury increased significantly from the pre-DCR period to the DCR period, from 64% to 80% (P<0.05). And the percentage of patients with severe head injuries increased significantly, from 57% to 73% (P<0.05).

As patients who died during the DCR period were more likely to have such “nonsurvivable” wounds, the researchers said this suggests that DCR is associated with a decrease in deaths among potentially salvageable patients.

Image showing mitosis, with

the endoplasmic reticulum

in green, mitochondria in red,

and chromosomes in blue

Credit: Wellcome Images

Researchers say they’ve uncovered the structure of one of the most important protein complexes involved in cell division, and their finding has implications for cancer treatment.

The team mapped the anaphase-promoting complex (APC/C), which performs a wide range of tasks associated with mitosis.

The researchers believe that seeing APC/C in unprecedented detail could transform our understanding of how cells divide and reveal binding sites for future cancer drugs.

“It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature,” said David Barford, DPhil, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

“We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis and ultimately lead to the discovery of new cancer drugs.”

Dr Barford and his colleagues detailed their discovery in Nature.

The researchers reconstituted human APC/C and used a combination of electron microscopy and imaging software to visualize it at a resolution of less than a billionth of a meter.

The resolution was so fine that it allowed the team to see the secondary structure—the set of basic building blocks that combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 subunits of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not been mapped.

Each of the APC/C’s subunits bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes, including the initiation of DNA replication, the segregation of chromosomes along spindles, and cytokinesis. Disrupting each of these processes could selectively kill cancer cells or prevent them from dividing.

“The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research,” said Paul Workman, PhD, of The Institute of Cancer Research, London.

“The new study is a major step forward in our understanding of cell division. When this process goes awry, it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”

Image showing mitosis, with

the endoplasmic reticulum

in green, mitochondria in red,

and chromosomes in blue

Credit: Wellcome Images

Researchers say they’ve uncovered the structure of one of the most important protein complexes involved in cell division, and their finding has implications for cancer treatment.

The team mapped the anaphase-promoting complex (APC/C), which performs a wide range of tasks associated with mitosis.

The researchers believe that seeing APC/C in unprecedented detail could transform our understanding of how cells divide and reveal binding sites for future cancer drugs.

“It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature,” said David Barford, DPhil, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

“We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis and ultimately lead to the discovery of new cancer drugs.”

Dr Barford and his colleagues detailed their discovery in Nature.

The researchers reconstituted human APC/C and used a combination of electron microscopy and imaging software to visualize it at a resolution of less than a billionth of a meter.

The resolution was so fine that it allowed the team to see the secondary structure—the set of basic building blocks that combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 subunits of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not been mapped.

Each of the APC/C’s subunits bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes, including the initiation of DNA replication, the segregation of chromosomes along spindles, and cytokinesis. Disrupting each of these processes could selectively kill cancer cells or prevent them from dividing.

“The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research,” said Paul Workman, PhD, of The Institute of Cancer Research, London.

“The new study is a major step forward in our understanding of cell division. When this process goes awry, it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”

Image showing mitosis, with

the endoplasmic reticulum

in green, mitochondria in red,

and chromosomes in blue

Credit: Wellcome Images

Researchers say they’ve uncovered the structure of one of the most important protein complexes involved in cell division, and their finding has implications for cancer treatment.

The team mapped the anaphase-promoting complex (APC/C), which performs a wide range of tasks associated with mitosis.

The researchers believe that seeing APC/C in unprecedented detail could transform our understanding of how cells divide and reveal binding sites for future cancer drugs.

“It’s very rewarding to finally tie down the detailed structure of this important protein, which is both one of the most important and most complicated found in all of nature,” said David Barford, DPhil, of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

“We hope our discovery will open up whole new avenues of research that increase our understanding of the process of mitosis and ultimately lead to the discovery of new cancer drugs.”

Dr Barford and his colleagues detailed their discovery in Nature.

The researchers reconstituted human APC/C and used a combination of electron microscopy and imaging software to visualize it at a resolution of less than a billionth of a meter.

The resolution was so fine that it allowed the team to see the secondary structure—the set of basic building blocks that combine to form every protein. Alpha-helix rods and folded beta-sheet constructions were clearly visible within the 20 subunits of the APC/C, defining the overall architecture of the complex.

Previous studies led by the same team had shown a globular structure for APC/C in much lower resolution, but the secondary structure had not been mapped.

Each of the APC/C’s subunits bond and mesh with other units at different points in the cell cycle, allowing it to control a range of mitotic processes, including the initiation of DNA replication, the segregation of chromosomes along spindles, and cytokinesis. Disrupting each of these processes could selectively kill cancer cells or prevent them from dividing.

“The fantastic insights into molecular structure provided by this study are a vivid illustration of the critical role played by fundamental cell biology in cancer research,” said Paul Workman, PhD, of The Institute of Cancer Research, London.

“The new study is a major step forward in our understanding of cell division. When this process goes awry, it is a critical difference that separates cancer cells from their healthy counterparts. Understanding exactly how cancer cells divide inappropriately is crucial to the discovery of innovative cancer treatments to improve outcomes for cancer patients.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

A next-generation bioreactor can produce fully functional platelets, according to research published in Blood.

The bioreactor recapitulates human bone marrow and blood vessel microenvironments.

And when the researchers introduced megakaryocytes derived from human induced pluripotent stem cell cultures (hiPSC-MKs), the bioreactor produced platelets with the structural and functional properties of natural platelets.

The team said this work is a major advancement that could help address blood transfusion needs worldwide.

“The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us to meet the growing need for blood transfusions,” said lead study author Jonathan Thon, PhD, of Brigham and Women’s Hospital in Boston.

His group’s bioreactor uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics.

The bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

“[B]eing able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production,” said senior study author Joseph Italiano, Jr, PhD, also of Brigham and Women’s Hospital.

He and his colleagues showed that physiological shear stresses in the bioreactor triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets.

In static culture, hiPSC-MKs began producing proplatelets at 6 hours post-isolation and reached maximal production at 18 hours. However, hiPSC-MKs under physiological shear stress began producing proplatelets immediately upon trapping and extended/released proplatelets within the first 2 hours of culture.

About 90% of hiPSC-MKs under shear stress produced proplatelets, compared to 10% of hiPSC-MKs in static cultures.

The hiPSC-MK-derived bioreactor platelets displayed forward scatter, side scatter, and surface biomarker expression characteristic of human platelets. Electron microscopy showed the 2 types of platelets were ultrastructurally indistinguishable from one another.

Furthermore, bioreactor platelets displayed morphology and microtubule expression comparable to human platelets. And bioreactor platelets spread normally upon contact-activation with glass, forming both filpodia and lamellipodia.

“Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization,” said William Savage, MD, PhD, medical director at Kraft Family Blood Donor Center at Brigham and Women’s Hospital, who did not contribute to the study.

“A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time.”

Based on the promising results of this study, the researchers would like to begin clinical trials testing the bioreactor platelets in 2017.

“The regulatory bar is appropriately set high for blood products,” Dr Thon said. “And it is important to us that we show platelet quality, function, and safety over these next 3 years, since we’ll likely be recipients of these platelets ourselves at some point.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

A next-generation bioreactor can produce fully functional platelets, according to research published in Blood.

The bioreactor recapitulates human bone marrow and blood vessel microenvironments.

And when the researchers introduced megakaryocytes derived from human induced pluripotent stem cell cultures (hiPSC-MKs), the bioreactor produced platelets with the structural and functional properties of natural platelets.

The team said this work is a major advancement that could help address blood transfusion needs worldwide.

“The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us to meet the growing need for blood transfusions,” said lead study author Jonathan Thon, PhD, of Brigham and Women’s Hospital in Boston.

His group’s bioreactor uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics.

The bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

“[B]eing able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production,” said senior study author Joseph Italiano, Jr, PhD, also of Brigham and Women’s Hospital.

He and his colleagues showed that physiological shear stresses in the bioreactor triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets.

In static culture, hiPSC-MKs began producing proplatelets at 6 hours post-isolation and reached maximal production at 18 hours. However, hiPSC-MKs under physiological shear stress began producing proplatelets immediately upon trapping and extended/released proplatelets within the first 2 hours of culture.

About 90% of hiPSC-MKs under shear stress produced proplatelets, compared to 10% of hiPSC-MKs in static cultures.

The hiPSC-MK-derived bioreactor platelets displayed forward scatter, side scatter, and surface biomarker expression characteristic of human platelets. Electron microscopy showed the 2 types of platelets were ultrastructurally indistinguishable from one another.

Furthermore, bioreactor platelets displayed morphology and microtubule expression comparable to human platelets. And bioreactor platelets spread normally upon contact-activation with glass, forming both filpodia and lamellipodia.

“Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization,” said William Savage, MD, PhD, medical director at Kraft Family Blood Donor Center at Brigham and Women’s Hospital, who did not contribute to the study.

“A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time.”

Based on the promising results of this study, the researchers would like to begin clinical trials testing the bioreactor platelets in 2017.

“The regulatory bar is appropriately set high for blood products,” Dr Thon said. “And it is important to us that we show platelet quality, function, and safety over these next 3 years, since we’ll likely be recipients of these platelets ourselves at some point.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

A next-generation bioreactor can produce fully functional platelets, according to research published in Blood.

The bioreactor recapitulates human bone marrow and blood vessel microenvironments.

And when the researchers introduced megakaryocytes derived from human induced pluripotent stem cell cultures (hiPSC-MKs), the bioreactor produced platelets with the structural and functional properties of natural platelets.

The team said this work is a major advancement that could help address blood transfusion needs worldwide.

“The ability to generate an alternative source of functional human platelets with virtually no disease transmission represents a paradigm shift in how we collect platelets that may allow us to meet the growing need for blood transfusions,” said lead study author Jonathan Thon, PhD, of Brigham and Women’s Hospital in Boston.

His group’s bioreactor uses biologically inspired engineering to fully integrate the major components of bone marrow, modeling both its composition and blood flow characteristics.

The bioreactor recapitulates features such as bone marrow stiffness, extracellular matrix composition, micro-channel size, and blood flow stability under high-resolution live-cell microscopy to make human platelets.

“[B]eing able to develop a device that successfully models bone marrow represents a crucial bridge connecting our understanding of the physiological triggers of platelet formation to support drug development and scale platelet production,” said senior study author Joseph Italiano, Jr, PhD, also of Brigham and Women’s Hospital.

He and his colleagues showed that physiological shear stresses in the bioreactor triggered proplatelet initiation, reproduced ex vivo bone marrow proplatelet production, and generated functional platelets.

In static culture, hiPSC-MKs began producing proplatelets at 6 hours post-isolation and reached maximal production at 18 hours. However, hiPSC-MKs under physiological shear stress began producing proplatelets immediately upon trapping and extended/released proplatelets within the first 2 hours of culture.

About 90% of hiPSC-MKs under shear stress produced proplatelets, compared to 10% of hiPSC-MKs in static cultures.

The hiPSC-MK-derived bioreactor platelets displayed forward scatter, side scatter, and surface biomarker expression characteristic of human platelets. Electron microscopy showed the 2 types of platelets were ultrastructurally indistinguishable from one another.

Furthermore, bioreactor platelets displayed morphology and microtubule expression comparable to human platelets. And bioreactor platelets spread normally upon contact-activation with glass, forming both filpodia and lamellipodia.

“Bioreactor-derived platelets theoretically have several advantages over conventional, donor-derived platelets in terms of safety and resource utilization,” said William Savage, MD, PhD, medical director at Kraft Family Blood Donor Center at Brigham and Women’s Hospital, who did not contribute to the study.

“A major factor that has limited our ability to compare bioreactor platelets to donor platelets is the inefficiency of growing platelets, a problem that slows progress of clinical research. This study addresses that gap, while contributing to our understanding of platelet biology at the same time.”

Based on the promising results of this study, the researchers would like to begin clinical trials testing the bioreactor platelets in 2017.

“The regulatory bar is appropriately set high for blood products,” Dr Thon said. “And it is important to us that we show platelet quality, function, and safety over these next 3 years, since we’ll likely be recipients of these platelets ourselves at some point.”

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

MILAN – A full 61.5% of patients with chronic myeloid leukemia in deep molecular remission for more than 1 year on long-term tyrosine kinase inhibitor therapy remained alive and free of relapse 6 months after stopping their TKI in the EURO-SKI trial.

Molecular relapse-free survival at 9 months was 58% and 55% at 12 months.

The preplanned interim analysis after 200 patients allowed the trialists to discard the study’s null hypothesis that molecular relapse-free survival at 6 months would be 40% or less (P less than .0001).

"With less strict inclusion and relapse criteria than the A-STIM study and other trials, stopping is safe and we can continue with the trial," Dr. Susanne Saussele said in a late-breaking abstract session at the annual meeting of the European Hematology Association.

Importantly, interim results from the EURO-SKI (European Stop TKI) study also suggest that the level of molecular response (MR) achieved prior to TKI withdrawal affects molecular relapse-free survival.

Among 197 patients with molecular laboratory results available for exact classification, 49% of patients in MR⁴ relapsed, compared with 39% in MR^4.5 and 39% in MR⁵.

"In the setting of standardized molecular testing within a CML [chronic myeloid leukemia] stopping trial, it seems that molecular remission has an impact on molecular free-survival," said Dr. Saussele of University Medical Centre Mannheim, Germany.

As no statistical test was performed and this was an interim analysis, MR^4.5 or MR⁵ cannot yet be used as a criterion to select patients to withdraw from treatment, she said in an interview.

The findings do confirm results from the recent A-STIM (According to Stop Imatinib) study showing that loss of major molecular response can be used as a practical criterion for restarting imatinib (J. Clin. Oncol. 2014;32:424-30).

Several studies including the STIM (Stop Imatinib) trial and the STOP 2G-TKI (Stop Second Generation Tyrosine Kinase Inhibitors) study have shown that imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) can be safely withdrawn in a substantial proportion of patients with CML in deep MR.

A number of questions remain open, however, such as which molecular level has to be reached before stopping TKI therapy, the minimal duration of TKI pretreatment or MR⁴ before stopping, and which prognostic factors influence molecular relapse-free survival, she said.

EURO-SKI was set up to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI treatment. Other aims are to evaluate methods of molecular monitoring, quality of life, and saved treatment costs per country.

Patients with chronic-phase CML from eight countries were eligible if they were on a TKI for at least 3 years and had a confirmed deep MR, defined as more than a 4 log reduction in BCR-ABL (breakpoint cluster region–Abelson) transcripts for more than 12 months confirmed by three consecutive polymerase chain reaction results.

MR⁴ status also had to be confirmed in an MR⁴-standardized laboratory according to criteria by Cross et al. (Leukemia 2012;26:2172-5)

Patients with previous or planned allogeneic stem cell transplantation or a prior TKI failure were excluded.

A total of 103 patients received pretreatment before TKI therapy, mostly with hydroxyurea alone (n = 71) or with interferon (n = 22). Their median age was 53 years.

First-line TKI was imatinib in 194 patients, nilotinib in 3, and dasatinib in 3.

The median duration of TKI therapy was 8 years and median MR⁴ duration before stopping TKI therapy was 5 years.

Dr. Saussele cautioned that adverse events and quality of life must be taken into account when considering TKI withdrawal in these patients.

A total of 222 adverse events were reported in 98 patients, with 57 events in 37 patients related to treatment stop. None were grade 4.

The most common adverse event was musculoskeletal or joint pain (39 events of all grades and 6 grade 3/4 events). This was first described in the Swedish EURO-SKI patients in 15-20% of patients after TKI withdrawal, prompting the investigators to send an advisory letter to all participating physicians, she remarked.

Other adverse events included sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, and weight loss.

The EURO-SKI trial was recently expanded to enroll 700 patients, with a quality of life analysis expected later this year. The next report on the primary endpoint is expected at the American Society of Hematology annual meeting, Dr. Saussele said.

Dr. Saussele reported honoraria and research and travel support from BMS, Novartis, and Pfizer.

[email protected]

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: the American College of Chest Physicians advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates wrote (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Serum levels of both albumin and creatinine proved to be independent biomarkers of disease severity in men and women with amyotrophic lateral sclerosis, with lower levels denoting more serious disease and a shorter survival time, according to a report published online July 21 in JAMA Neurology.

To identify any potential correlations between hematologic biomarkers and ALS severity, researchers analyzed data concerning 638 patients from a regional registry of people diagnosed during 2007-2011 in the Piemonte and Valle d’Aosta areas of Italy. The 352 men and 286 women underwent complete physical examinations at the time of diagnosis, which included tests for 17 serum biomarkers. The only two serum biomarkers found to correlate with ALS severity were albumin level, which reflected inflammation, and creatinine, which reflected muscle wasting, said Dr. Adriano Chio, professor of neuroscience, University of Torino, Turin, Italy, and his associates.

Both biomarkers showed an inverse dose-response relationship with clinical function at diagnosis in men and women. Both had sensitivity and specificity values at predicting 1-year mortality that were similar to those of "the best established prognostic factors" for ALS, such as forced vital capacity, age, and scores on the ALS Functional Rating Scale-Revised, the investigators said (JAMA Neurol. 2014 July 21 [doi:10.1001/jamaneurol.2014.1129]).

Dr. Chio and his colleagues performed a validation study in a cohort of 122 patients (54 men, 68 women) at all stages of ALS who were treated at an ALS tertiary care center in another area of Italy. This study confirmed the findings from the discovery cohort. "Both creatinine and albumin are reliable and easily detectable blood markers of the severity of motor dysfunction in ALS and could be used in defining patients’ prognosis at the time of diagnosis," they said.

This study was supported by the Italian Ministry of Health and the European Community’s Health Seventh Framework Programme. Dr. Chio reported serving on scientific advisory board for Biogen Idec and Cytokinetics

Serum levels of both albumin and creatinine proved to be independent biomarkers of disease severity in men and women with amyotrophic lateral sclerosis, with lower levels denoting more serious disease and a shorter survival time, according to a report published online July 21 in JAMA Neurology.

To identify any potential correlations between hematologic biomarkers and ALS severity, researchers analyzed data concerning 638 patients from a regional registry of people diagnosed during 2007-2011 in the Piemonte and Valle d’Aosta areas of Italy. The 352 men and 286 women underwent complete physical examinations at the time of diagnosis, which included tests for 17 serum biomarkers. The only two serum biomarkers found to correlate with ALS severity were albumin level, which reflected inflammation, and creatinine, which reflected muscle wasting, said Dr. Adriano Chio, professor of neuroscience, University of Torino, Turin, Italy, and his associates.

Both biomarkers showed an inverse dose-response relationship with clinical function at diagnosis in men and women. Both had sensitivity and specificity values at predicting 1-year mortality that were similar to those of "the best established prognostic factors" for ALS, such as forced vital capacity, age, and scores on the ALS Functional Rating Scale-Revised, the investigators said (JAMA Neurol. 2014 July 21 [doi:10.1001/jamaneurol.2014.1129]).

Dr. Chio and his colleagues performed a validation study in a cohort of 122 patients (54 men, 68 women) at all stages of ALS who were treated at an ALS tertiary care center in another area of Italy. This study confirmed the findings from the discovery cohort. "Both creatinine and albumin are reliable and easily detectable blood markers of the severity of motor dysfunction in ALS and could be used in defining patients’ prognosis at the time of diagnosis," they said.

This study was supported by the Italian Ministry of Health and the European Community’s Health Seventh Framework Programme. Dr. Chio reported serving on scientific advisory board for Biogen Idec and Cytokinetics

Serum levels of both albumin and creatinine proved to be independent biomarkers of disease severity in men and women with amyotrophic lateral sclerosis, with lower levels denoting more serious disease and a shorter survival time, according to a report published online July 21 in JAMA Neurology.

To identify any potential correlations between hematologic biomarkers and ALS severity, researchers analyzed data concerning 638 patients from a regional registry of people diagnosed during 2007-2011 in the Piemonte and Valle d’Aosta areas of Italy. The 352 men and 286 women underwent complete physical examinations at the time of diagnosis, which included tests for 17 serum biomarkers. The only two serum biomarkers found to correlate with ALS severity were albumin level, which reflected inflammation, and creatinine, which reflected muscle wasting, said Dr. Adriano Chio, professor of neuroscience, University of Torino, Turin, Italy, and his associates.

Both biomarkers showed an inverse dose-response relationship with clinical function at diagnosis in men and women. Both had sensitivity and specificity values at predicting 1-year mortality that were similar to those of "the best established prognostic factors" for ALS, such as forced vital capacity, age, and scores on the ALS Functional Rating Scale-Revised, the investigators said (JAMA Neurol. 2014 July 21 [doi:10.1001/jamaneurol.2014.1129]).

Dr. Chio and his colleagues performed a validation study in a cohort of 122 patients (54 men, 68 women) at all stages of ALS who were treated at an ALS tertiary care center in another area of Italy. This study confirmed the findings from the discovery cohort. "Both creatinine and albumin are reliable and easily detectable blood markers of the severity of motor dysfunction in ALS and could be used in defining patients’ prognosis at the time of diagnosis," they said.

This study was supported by the Italian Ministry of Health and the European Community’s Health Seventh Framework Programme. Dr. Chio reported serving on scientific advisory board for Biogen Idec and Cytokinetics