Red blood cells

During their approximately 100-day lifespan in the bloodstream, red blood cells (RBCs) lose membrane surface area, volume, and hemoglobin content.

A study published in PLOS Computational Biology shows that, of these 3 changes, only surface-area loss can be explained by RBCs shedding small, hemoglobin-containing vesicles budding off their cells’ membrane.

Therefore, an unknown process must be primarily responsible for loss of RBC volume and hemoglobin reduction.

Roy Malka, PhD, of Massachusetts General Hospital in Boston, and his colleagues noted that variations in RBCs’ mean volume and hemoglobin content are associated with important clinical conditions, but the mechanisms controlling these physical characteristics are not well understood.

Vesicle shedding was thought to be the most important mechanism, but the researchers found evidence to suggest that a dominant role for vesicle shedding would violate empirical geometric and biophysical constraints.

So they concluded that an unknown mechanism must control loss of RBC volume and hemoglobin reduction. And this mechanism is likely responsible for 60% to 90% of volume loss and hemoglobin reduction.

The group’s work combined mathematical modeling of the mechanism that changes the physical properties of RBCs, clinical measurements of both cellular volume and hemoglobin content, and data from a new system for characterizing the non-water cellular mass of individual cells.

The researchers said the quantitative characterization of RBC loss processes will help focus future research into the molecular mechanisms of RBC maturation. And it may ultimately help in the early detection of clinical conditions where the RBC maturation pattern is altered.

Red blood cells

During their approximately 100-day lifespan in the bloodstream, red blood cells (RBCs) lose membrane surface area, volume, and hemoglobin content.

A study published in PLOS Computational Biology shows that, of these 3 changes, only surface-area loss can be explained by RBCs shedding small, hemoglobin-containing vesicles budding off their cells’ membrane.

Therefore, an unknown process must be primarily responsible for loss of RBC volume and hemoglobin reduction.

Roy Malka, PhD, of Massachusetts General Hospital in Boston, and his colleagues noted that variations in RBCs’ mean volume and hemoglobin content are associated with important clinical conditions, but the mechanisms controlling these physical characteristics are not well understood.

Vesicle shedding was thought to be the most important mechanism, but the researchers found evidence to suggest that a dominant role for vesicle shedding would violate empirical geometric and biophysical constraints.

So they concluded that an unknown mechanism must control loss of RBC volume and hemoglobin reduction. And this mechanism is likely responsible for 60% to 90% of volume loss and hemoglobin reduction.

The group’s work combined mathematical modeling of the mechanism that changes the physical properties of RBCs, clinical measurements of both cellular volume and hemoglobin content, and data from a new system for characterizing the non-water cellular mass of individual cells.

The researchers said the quantitative characterization of RBC loss processes will help focus future research into the molecular mechanisms of RBC maturation. And it may ultimately help in the early detection of clinical conditions where the RBC maturation pattern is altered.

Red blood cells

During their approximately 100-day lifespan in the bloodstream, red blood cells (RBCs) lose membrane surface area, volume, and hemoglobin content.

A study published in PLOS Computational Biology shows that, of these 3 changes, only surface-area loss can be explained by RBCs shedding small, hemoglobin-containing vesicles budding off their cells’ membrane.

Therefore, an unknown process must be primarily responsible for loss of RBC volume and hemoglobin reduction.

Roy Malka, PhD, of Massachusetts General Hospital in Boston, and his colleagues noted that variations in RBCs’ mean volume and hemoglobin content are associated with important clinical conditions, but the mechanisms controlling these physical characteristics are not well understood.

Vesicle shedding was thought to be the most important mechanism, but the researchers found evidence to suggest that a dominant role for vesicle shedding would violate empirical geometric and biophysical constraints.

So they concluded that an unknown mechanism must control loss of RBC volume and hemoglobin reduction. And this mechanism is likely responsible for 60% to 90% of volume loss and hemoglobin reduction.

The group’s work combined mathematical modeling of the mechanism that changes the physical properties of RBCs, clinical measurements of both cellular volume and hemoglobin content, and data from a new system for characterizing the non-water cellular mass of individual cells.

The researchers said the quantitative characterization of RBC loss processes will help focus future research into the molecular mechanisms of RBC maturation. And it may ultimately help in the early detection of clinical conditions where the RBC maturation pattern is altered.

Micrograph showing MCL

The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for use in previously untreated patients with mantle cell

lymphoma (MCL).

This is the first drug to be approved in the US for previously untreated patients with MCL.

The approval extends the utility of bortezomib beyond relapsed or refractory MCL, for which it has been approved since 2006.

The new approval is based on results of a phase 3 trial.

The study was a comparison of VcR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in 487 patients newly diagnosed with stage II, III, or IV MCL.

Survival and response

VcR-CAP demonstrated a 59% relative improvement in the study’s primary endpoint of progression-free survival. At a median follow-up of 40 months, the median progression-free survival was 25 months in the VcR-CAP arm and 14 months in the R-CHOP arm (hazard ratio [HR]=0.63, P<0.001).

However, there was no significant improvement in overall survival. The median overall survival was not reached in the VcR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80; P=0.173).

Patients in the VcR-CAP arm had a higher rate of complete response/unconfirmed complete response than those in the R-CHOP arm—53% and 42%, respectively (P=0.007). But there was no significant difference in overall response—92% and 90%, respectively (P=0.275).

The time to progression was significantly longer in the VcR-CAP arm—30.5 months, compared to 16.1 months in the R-CHOP arm (HR=0.58; P<0.001). And the median time to subsequent treatment was significantly longer in the VcR-CAP arm—44.5 months vs 24.8 months (HR 0.50; P<0.001).

Adverse events

VcR-CAP was associated with additional but manageable toxicity compared to R-CHOP.

Serious adverse events were reported in 38% of patients in the VcR-CAP arm and 30% in the R-CHOP arm. Grade 3 or higher adverse events were reported in 93% and 85%, respectively.

There were similar rates of all-grade peripheral neuropathy between the VcR-CAP arm and the R-CHOP arm—30% and 29%, respectively. But the rate of grade 3 or higher peripheral neuropathy was significantly higher in the VcR-CAP arm—7.5% vs 4.1%.

The incidence of all-grade thrombocytopenia was substantially higher in the VcR-CAP arm than the R-CHOP arm—72% and 19%, respectively. But there was no significant difference in bleeding events—6% and 5%, respectively.

The incidence of all-grade neutropenia was 88% in the VcR-CAP arm and 74% in the R-CHOP arm. The rate of grade 3 or higher febrile neutropenia was 14% and 15%, respectively, and the rate of infection was 60% and 46%, respectively.

These data were presented at ASCO 2014 as abstract 8500.

Bortezomib is marketed as Velcade by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization in the US, and Janssen Pharmaceutical Companies are responsible for commercialization in the rest of the world.

For more details on the drug, visit www.velcade.com.

Micrograph showing MCL

The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for use in previously untreated patients with mantle cell

lymphoma (MCL).

This is the first drug to be approved in the US for previously untreated patients with MCL.

The approval extends the utility of bortezomib beyond relapsed or refractory MCL, for which it has been approved since 2006.

The new approval is based on results of a phase 3 trial.

The study was a comparison of VcR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in 487 patients newly diagnosed with stage II, III, or IV MCL.

Survival and response

VcR-CAP demonstrated a 59% relative improvement in the study’s primary endpoint of progression-free survival. At a median follow-up of 40 months, the median progression-free survival was 25 months in the VcR-CAP arm and 14 months in the R-CHOP arm (hazard ratio [HR]=0.63, P<0.001).

However, there was no significant improvement in overall survival. The median overall survival was not reached in the VcR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80; P=0.173).

Patients in the VcR-CAP arm had a higher rate of complete response/unconfirmed complete response than those in the R-CHOP arm—53% and 42%, respectively (P=0.007). But there was no significant difference in overall response—92% and 90%, respectively (P=0.275).

The time to progression was significantly longer in the VcR-CAP arm—30.5 months, compared to 16.1 months in the R-CHOP arm (HR=0.58; P<0.001). And the median time to subsequent treatment was significantly longer in the VcR-CAP arm—44.5 months vs 24.8 months (HR 0.50; P<0.001).

Adverse events

VcR-CAP was associated with additional but manageable toxicity compared to R-CHOP.

Serious adverse events were reported in 38% of patients in the VcR-CAP arm and 30% in the R-CHOP arm. Grade 3 or higher adverse events were reported in 93% and 85%, respectively.

There were similar rates of all-grade peripheral neuropathy between the VcR-CAP arm and the R-CHOP arm—30% and 29%, respectively. But the rate of grade 3 or higher peripheral neuropathy was significantly higher in the VcR-CAP arm—7.5% vs 4.1%.

The incidence of all-grade thrombocytopenia was substantially higher in the VcR-CAP arm than the R-CHOP arm—72% and 19%, respectively. But there was no significant difference in bleeding events—6% and 5%, respectively.

The incidence of all-grade neutropenia was 88% in the VcR-CAP arm and 74% in the R-CHOP arm. The rate of grade 3 or higher febrile neutropenia was 14% and 15%, respectively, and the rate of infection was 60% and 46%, respectively.

These data were presented at ASCO 2014 as abstract 8500.

Bortezomib is marketed as Velcade by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization in the US, and Janssen Pharmaceutical Companies are responsible for commercialization in the rest of the world.

For more details on the drug, visit www.velcade.com.

Micrograph showing MCL

The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for use in previously untreated patients with mantle cell

lymphoma (MCL).

This is the first drug to be approved in the US for previously untreated patients with MCL.

The approval extends the utility of bortezomib beyond relapsed or refractory MCL, for which it has been approved since 2006.

The new approval is based on results of a phase 3 trial.

The study was a comparison of VcR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in 487 patients newly diagnosed with stage II, III, or IV MCL.

Survival and response

VcR-CAP demonstrated a 59% relative improvement in the study’s primary endpoint of progression-free survival. At a median follow-up of 40 months, the median progression-free survival was 25 months in the VcR-CAP arm and 14 months in the R-CHOP arm (hazard ratio [HR]=0.63, P<0.001).

However, there was no significant improvement in overall survival. The median overall survival was not reached in the VcR-CAP arm and was 56.3 months in the R-CHOP arm (HR=0.80; P=0.173).

Patients in the VcR-CAP arm had a higher rate of complete response/unconfirmed complete response than those in the R-CHOP arm—53% and 42%, respectively (P=0.007). But there was no significant difference in overall response—92% and 90%, respectively (P=0.275).

The time to progression was significantly longer in the VcR-CAP arm—30.5 months, compared to 16.1 months in the R-CHOP arm (HR=0.58; P<0.001). And the median time to subsequent treatment was significantly longer in the VcR-CAP arm—44.5 months vs 24.8 months (HR 0.50; P<0.001).

Adverse events

VcR-CAP was associated with additional but manageable toxicity compared to R-CHOP.

Serious adverse events were reported in 38% of patients in the VcR-CAP arm and 30% in the R-CHOP arm. Grade 3 or higher adverse events were reported in 93% and 85%, respectively.

There were similar rates of all-grade peripheral neuropathy between the VcR-CAP arm and the R-CHOP arm—30% and 29%, respectively. But the rate of grade 3 or higher peripheral neuropathy was significantly higher in the VcR-CAP arm—7.5% vs 4.1%.

The incidence of all-grade thrombocytopenia was substantially higher in the VcR-CAP arm than the R-CHOP arm—72% and 19%, respectively. But there was no significant difference in bleeding events—6% and 5%, respectively.

The incidence of all-grade neutropenia was 88% in the VcR-CAP arm and 74% in the R-CHOP arm. The rate of grade 3 or higher febrile neutropenia was 14% and 15%, respectively, and the rate of infection was 60% and 46%, respectively.

These data were presented at ASCO 2014 as abstract 8500.

Bortezomib is marketed as Velcade by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization in the US, and Janssen Pharmaceutical Companies are responsible for commercialization in the rest of the world.

For more details on the drug, visit www.velcade.com.

Red blood cells positive for

Staphylococcus

infection

Credit: Bill Branson

New research suggests the antibiotic vancomycin is still effective in treating Staphylococcus aureus bloodstream (SAB) infections, despite increases in minimum inhibitory concentration (MIC) values.

Researchers found no difference in mortality between patients with low-vancomycin MIC and those with high-vancomycin MIC.

So it seems physicians can continue using vancomycin when MIC values are elevated but within the susceptible range, rather than

switching to newer antibiotics.

Andre Kalil, MD, of the University of Nebraska Medical Center in Omaha, and his colleagues described this research in JAMA.

In recent years, physicians treating Staphylococcus infections with vancomycin have seen an increase in the MIC, the lowest concentration of an antimicrobial agent that inhibits the growth of a microorganism.

MIC values lower than 4 mg/L suggest Staphylococcus is susceptible to vancomycin. However, when the MIC value exceeds 1.5 mg/L, some physicians have taken it as an indication that vancomycin may not be working at maximum effectiveness.

Some reports have suggested that elevations in vancomycin MIC values may be associated with increased treatment failure and death.

To determine the effectiveness of vancomycin, Dr Kalil and his colleagues analyzed data from 38 studies covering 8291 episodes of SAB infection.

The team evaluated the association between vancomycin MIC elevation and mortality. Among all SAB infections studied, the overall mortality was 26.1%.

The adjusted absolute risk of mortality did not differ significantly between patients with high-vancomycin MIC and those with low-vancomycin MIC—26.8% and 25.8%, respectively.

In studies that included only methicillin-resistant Staphylococcus aureus infections, the mortality among SAB episodes in patients with high-vancomycin MIC was 27.6%, compared with a mortality of 27.4% among patients with low-vancomycin MIC.

“The study provides strong evidence that vancomycin remains highly useful,” Dr Kalil said. “Even though vancomycin is an older drug, it is still killing staph very efficiently. There are newer antibiotics available to treat Staphylococcus aureus infections, but this study demonstrates that physicians don’t necessarily need to switch to these new drugs when the MIC is increased but still within the susceptible range.”

“The prevention of a rapid switch to newer drugs has another great benefit to our patients—less unnecessary exposure to these drugs, which will translate into less development of antibiotic resistance.”

Dr Kalil said the study may have implications for clinical practice and public health.

The results suggest standards for vancomycin MIC likely do not need to be lowered, routine differentiation of MIC values between 1 mg/L and 2 mg/L appears unnecessary, and the use of alternative drugs may not be required for Staphylococcus aureus isolates with elevated but susceptible vancomycin MIC values.

Red blood cells positive for

Staphylococcus

infection

Credit: Bill Branson

New research suggests the antibiotic vancomycin is still effective in treating Staphylococcus aureus bloodstream (SAB) infections, despite increases in minimum inhibitory concentration (MIC) values.

Researchers found no difference in mortality between patients with low-vancomycin MIC and those with high-vancomycin MIC.

So it seems physicians can continue using vancomycin when MIC values are elevated but within the susceptible range, rather than

switching to newer antibiotics.

Andre Kalil, MD, of the University of Nebraska Medical Center in Omaha, and his colleagues described this research in JAMA.

In recent years, physicians treating Staphylococcus infections with vancomycin have seen an increase in the MIC, the lowest concentration of an antimicrobial agent that inhibits the growth of a microorganism.

MIC values lower than 4 mg/L suggest Staphylococcus is susceptible to vancomycin. However, when the MIC value exceeds 1.5 mg/L, some physicians have taken it as an indication that vancomycin may not be working at maximum effectiveness.

Some reports have suggested that elevations in vancomycin MIC values may be associated with increased treatment failure and death.

To determine the effectiveness of vancomycin, Dr Kalil and his colleagues analyzed data from 38 studies covering 8291 episodes of SAB infection.

The team evaluated the association between vancomycin MIC elevation and mortality. Among all SAB infections studied, the overall mortality was 26.1%.

The adjusted absolute risk of mortality did not differ significantly between patients with high-vancomycin MIC and those with low-vancomycin MIC—26.8% and 25.8%, respectively.

In studies that included only methicillin-resistant Staphylococcus aureus infections, the mortality among SAB episodes in patients with high-vancomycin MIC was 27.6%, compared with a mortality of 27.4% among patients with low-vancomycin MIC.

“The study provides strong evidence that vancomycin remains highly useful,” Dr Kalil said. “Even though vancomycin is an older drug, it is still killing staph very efficiently. There are newer antibiotics available to treat Staphylococcus aureus infections, but this study demonstrates that physicians don’t necessarily need to switch to these new drugs when the MIC is increased but still within the susceptible range.”

“The prevention of a rapid switch to newer drugs has another great benefit to our patients—less unnecessary exposure to these drugs, which will translate into less development of antibiotic resistance.”

Dr Kalil said the study may have implications for clinical practice and public health.

The results suggest standards for vancomycin MIC likely do not need to be lowered, routine differentiation of MIC values between 1 mg/L and 2 mg/L appears unnecessary, and the use of alternative drugs may not be required for Staphylococcus aureus isolates with elevated but susceptible vancomycin MIC values.

Red blood cells positive for

Staphylococcus

infection

Credit: Bill Branson

New research suggests the antibiotic vancomycin is still effective in treating Staphylococcus aureus bloodstream (SAB) infections, despite increases in minimum inhibitory concentration (MIC) values.

Researchers found no difference in mortality between patients with low-vancomycin MIC and those with high-vancomycin MIC.

So it seems physicians can continue using vancomycin when MIC values are elevated but within the susceptible range, rather than

switching to newer antibiotics.

Andre Kalil, MD, of the University of Nebraska Medical Center in Omaha, and his colleagues described this research in JAMA.

In recent years, physicians treating Staphylococcus infections with vancomycin have seen an increase in the MIC, the lowest concentration of an antimicrobial agent that inhibits the growth of a microorganism.

MIC values lower than 4 mg/L suggest Staphylococcus is susceptible to vancomycin. However, when the MIC value exceeds 1.5 mg/L, some physicians have taken it as an indication that vancomycin may not be working at maximum effectiveness.

Some reports have suggested that elevations in vancomycin MIC values may be associated with increased treatment failure and death.

To determine the effectiveness of vancomycin, Dr Kalil and his colleagues analyzed data from 38 studies covering 8291 episodes of SAB infection.

The team evaluated the association between vancomycin MIC elevation and mortality. Among all SAB infections studied, the overall mortality was 26.1%.

The adjusted absolute risk of mortality did not differ significantly between patients with high-vancomycin MIC and those with low-vancomycin MIC—26.8% and 25.8%, respectively.

In studies that included only methicillin-resistant Staphylococcus aureus infections, the mortality among SAB episodes in patients with high-vancomycin MIC was 27.6%, compared with a mortality of 27.4% among patients with low-vancomycin MIC.

“The study provides strong evidence that vancomycin remains highly useful,” Dr Kalil said. “Even though vancomycin is an older drug, it is still killing staph very efficiently. There are newer antibiotics available to treat Staphylococcus aureus infections, but this study demonstrates that physicians don’t necessarily need to switch to these new drugs when the MIC is increased but still within the susceptible range.”

“The prevention of a rapid switch to newer drugs has another great benefit to our patients—less unnecessary exposure to these drugs, which will translate into less development of antibiotic resistance.”

Dr Kalil said the study may have implications for clinical practice and public health.

The results suggest standards for vancomycin MIC likely do not need to be lowered, routine differentiation of MIC values between 1 mg/L and 2 mg/L appears unnecessary, and the use of alternative drugs may not be required for Staphylococcus aureus isolates with elevated but susceptible vancomycin MIC values.

T cells

Credit: NIAID

A fundamental theory about how the thymus “educates” T cells appears to be wrong, according to research published in Nature Communications.

It’s known that stem cells leave the bone marrow and travel to the thymus to become one of two CD4 T-cell types: effector cells or regulatory T cells (Tregs).

One widely held concept of why the cells become one type or the other is that they are exposed to different ligands in the thymus, said Leszek Ignatowicz, PhD, of Georgia Regents University in Augusta.

But when he and his colleagues limited the cells’ exposure to only one ligand, the same mix of T cells still emerged.

“We asked a simple question, ‘Is it going to affect their development,’ and the answer was ‘no,’” Dr Ignatowicz said. “The cells still mature in the thymus, so something else must be determining it.”

The finding provides more insight into immunity that could one day enable a new approach to vaccines that steer the thymus to produce more of whatever T-cell type a patient needs: more effector cells if they have an infection or cancer, more Tregs if they have autoimmune diseases such as arthritis and multiple sclerosis.

“We could help steer the education process in the desired direction,” Dr Ignatowicz said.

To uncover their findings, he and his colleagues studied two types of mice, each expressing a single ligand in the thymus. The researchers thought one would prompt strong ligand binding and favor Treg development, and the other would favor a weaker ligand bond and effector cell development.

The mix of resulting T cells was the same as if both were exposed to the usual thousands of ligands, although the experiment did reveal one difference.

Ligands—and, eventually, bacteria and other invaders—get the attention of T cells by activating their receptors. Both CD4 T-cell types generally have the same receptors, but they are organized differently.

The researchers found that as long as the binding was weak, as it was in the first mouse, there was a lot of overlap in the receptors the ligand bound to in both T-cell types. However, in the second mouse, where the ligand prompted strong binding, there was far less overlap.

“We are now trying to find what causes that difference,” Dr Ignatowicz said.

T cells

Credit: NIAID

A fundamental theory about how the thymus “educates” T cells appears to be wrong, according to research published in Nature Communications.

It’s known that stem cells leave the bone marrow and travel to the thymus to become one of two CD4 T-cell types: effector cells or regulatory T cells (Tregs).

One widely held concept of why the cells become one type or the other is that they are exposed to different ligands in the thymus, said Leszek Ignatowicz, PhD, of Georgia Regents University in Augusta.

But when he and his colleagues limited the cells’ exposure to only one ligand, the same mix of T cells still emerged.

“We asked a simple question, ‘Is it going to affect their development,’ and the answer was ‘no,’” Dr Ignatowicz said. “The cells still mature in the thymus, so something else must be determining it.”

The finding provides more insight into immunity that could one day enable a new approach to vaccines that steer the thymus to produce more of whatever T-cell type a patient needs: more effector cells if they have an infection or cancer, more Tregs if they have autoimmune diseases such as arthritis and multiple sclerosis.

“We could help steer the education process in the desired direction,” Dr Ignatowicz said.

To uncover their findings, he and his colleagues studied two types of mice, each expressing a single ligand in the thymus. The researchers thought one would prompt strong ligand binding and favor Treg development, and the other would favor a weaker ligand bond and effector cell development.

The mix of resulting T cells was the same as if both were exposed to the usual thousands of ligands, although the experiment did reveal one difference.

Ligands—and, eventually, bacteria and other invaders—get the attention of T cells by activating their receptors. Both CD4 T-cell types generally have the same receptors, but they are organized differently.

The researchers found that as long as the binding was weak, as it was in the first mouse, there was a lot of overlap in the receptors the ligand bound to in both T-cell types. However, in the second mouse, where the ligand prompted strong binding, there was far less overlap.

“We are now trying to find what causes that difference,” Dr Ignatowicz said.

T cells

Credit: NIAID

A fundamental theory about how the thymus “educates” T cells appears to be wrong, according to research published in Nature Communications.

It’s known that stem cells leave the bone marrow and travel to the thymus to become one of two CD4 T-cell types: effector cells or regulatory T cells (Tregs).

One widely held concept of why the cells become one type or the other is that they are exposed to different ligands in the thymus, said Leszek Ignatowicz, PhD, of Georgia Regents University in Augusta.

But when he and his colleagues limited the cells’ exposure to only one ligand, the same mix of T cells still emerged.

“We asked a simple question, ‘Is it going to affect their development,’ and the answer was ‘no,’” Dr Ignatowicz said. “The cells still mature in the thymus, so something else must be determining it.”

The finding provides more insight into immunity that could one day enable a new approach to vaccines that steer the thymus to produce more of whatever T-cell type a patient needs: more effector cells if they have an infection or cancer, more Tregs if they have autoimmune diseases such as arthritis and multiple sclerosis.

“We could help steer the education process in the desired direction,” Dr Ignatowicz said.

To uncover their findings, he and his colleagues studied two types of mice, each expressing a single ligand in the thymus. The researchers thought one would prompt strong ligand binding and favor Treg development, and the other would favor a weaker ligand bond and effector cell development.

The mix of resulting T cells was the same as if both were exposed to the usual thousands of ligands, although the experiment did reveal one difference.

Ligands—and, eventually, bacteria and other invaders—get the attention of T cells by activating their receptors. Both CD4 T-cell types generally have the same receptors, but they are organized differently.

The researchers found that as long as the binding was weak, as it was in the first mouse, there was a lot of overlap in the receptors the ligand bound to in both T-cell types. However, in the second mouse, where the ligand prompted strong binding, there was far less overlap.

“We are now trying to find what causes that difference,” Dr Ignatowicz said.

As Ebola virus spreads from West Africa, it has become apparent that ObGyns in the United States may need to evaluate patients who have been exposed to the disease. The Centers for Disease Control and Prevention (CDC) has a dedicated Web site for Ebola that outlines signs and symptoms, transmission, risk of exposure, diagnosis and treatment options, and clinical guidance for health-care workers.¹

What are the symptoms of Ebola?
If a woman from West Africa presents with a fever, the CDC advises that she be asked specifically about recent travel to affected areas (currently Liberia, Sierra Leone, Guinea, and Nigeria). Clinical signs and symptoms of Ebola include a fever of 38.6°C [101.5°F] or higher with additional symptoms¹:

• severe headache
• muscle pain
• weakness
• vomiting
• diarrhea
• abdominal (stomach) pain
• unexplained hemorrhage.

Symptoms may appear from 2–21 days after exposure to Ebola. If a person with early symptoms of Ebola has had contact with the blood or body fluids of a person sick with Ebola, objects contaminated with the blood or body fluids of a person sick with Ebola, or with Ebola-infected animals, the patient should be isolated and public health professionals immediately notified, says the CDC. Blood samples from the patient should be tested to confirm infection (visit the CDC’s Ebola Web site for a list of diagnostic tests).¹

More women than men infected
In a recently published perspective from the CDC on what ObGyns should be aware of regarding Ebola, Jamieson and colleagues reported that, according to UNICEF data, in this current outbreak more women than men are infected.² They say this is most likely because women in West Africa are the primary caregivers for sick relatives, as well as make up the majority of health-care providers and birth attendants.

Pregnancy and Ebola
Based on limited, historic data from other Ebola outbreaks in Africa, there is no evidence suggesting that pregnant women are more susceptible to Ebola, although say Jamieson and colleagues, there is limited evidence suggesting that pregnant women are more at risk for severe illness and death from Ebola.² It also appears that pregnant women with Ebola are at increased risk for spontaneous abortion and pregnancy-related hemorrhage. In 1996 in Kikwit, Democratic Republic of the Congo, pregnant women were more likely than the overall patient population with Ebola to have hemorrhagic complications, specifically vaginal and uterine bleeding associated with abortion or delivery. Children born to mothers with Ebola have not survived, though the cause of death has not been identified specifically.²

Breastfeeding and Ebola
The CDC has issued recommendations for breastfeeding or infant feeding by women with suspected or confirmed exposure to Ebola. Two key points are made³:

• Mothers with probable or confirmed Ebola virus disease should not have close contact with their infants when safe alternatives to breastfeeding and infant care exist
• Where resources are limited, non−breastfed infants are at increased risk of death from starvation and other infectious diseases. These risks must be carefully weighed against the risk of Ebola virus disease.

CDC recommends that decisions about how to best feed an infant whose mother has probable or confirmed Ebola be made on a case-by-case basis, balancing nutritional needs with the risk of contracting the disease. There is not enough evidence to suggest when it is safe to resume breastfeeding after a mother’s recovery, unless her breast milk can be shown to be Ebola-free.³

Protecting health-care personnel
The CDC Ebola Web site¹ provides specific protocols designed to keep health-care workers safe. These include detailed guidelines for evaluating returned travelers, instructions for specimen collection, transport, testing, submission, use of protective equipment, and isolation procedures.

Share your thoughts on this news! Send your Letter to the Editor to [email protected]. Please include your name, and the city and state in which you practice

As Ebola virus spreads from West Africa, it has become apparent that ObGyns in the United States may need to evaluate patients who have been exposed to the disease. The Centers for Disease Control and Prevention (CDC) has a dedicated Web site for Ebola that outlines signs and symptoms, transmission, risk of exposure, diagnosis and treatment options, and clinical guidance for health-care workers.¹

What are the symptoms of Ebola?
If a woman from West Africa presents with a fever, the CDC advises that she be asked specifically about recent travel to affected areas (currently Liberia, Sierra Leone, Guinea, and Nigeria). Clinical signs and symptoms of Ebola include a fever of 38.6°C [101.5°F] or higher with additional symptoms¹:

• severe headache
• muscle pain
• weakness
• vomiting
• diarrhea
• abdominal (stomach) pain
• unexplained hemorrhage.

Symptoms may appear from 2–21 days after exposure to Ebola. If a person with early symptoms of Ebola has had contact with the blood or body fluids of a person sick with Ebola, objects contaminated with the blood or body fluids of a person sick with Ebola, or with Ebola-infected animals, the patient should be isolated and public health professionals immediately notified, says the CDC. Blood samples from the patient should be tested to confirm infection (visit the CDC’s Ebola Web site for a list of diagnostic tests).¹

More women than men infected
In a recently published perspective from the CDC on what ObGyns should be aware of regarding Ebola, Jamieson and colleagues reported that, according to UNICEF data, in this current outbreak more women than men are infected.² They say this is most likely because women in West Africa are the primary caregivers for sick relatives, as well as make up the majority of health-care providers and birth attendants.

Pregnancy and Ebola
Based on limited, historic data from other Ebola outbreaks in Africa, there is no evidence suggesting that pregnant women are more susceptible to Ebola, although say Jamieson and colleagues, there is limited evidence suggesting that pregnant women are more at risk for severe illness and death from Ebola.² It also appears that pregnant women with Ebola are at increased risk for spontaneous abortion and pregnancy-related hemorrhage. In 1996 in Kikwit, Democratic Republic of the Congo, pregnant women were more likely than the overall patient population with Ebola to have hemorrhagic complications, specifically vaginal and uterine bleeding associated with abortion or delivery. Children born to mothers with Ebola have not survived, though the cause of death has not been identified specifically.²

Breastfeeding and Ebola
The CDC has issued recommendations for breastfeeding or infant feeding by women with suspected or confirmed exposure to Ebola. Two key points are made³:

• Mothers with probable or confirmed Ebola virus disease should not have close contact with their infants when safe alternatives to breastfeeding and infant care exist
• Where resources are limited, non−breastfed infants are at increased risk of death from starvation and other infectious diseases. These risks must be carefully weighed against the risk of Ebola virus disease.

CDC recommends that decisions about how to best feed an infant whose mother has probable or confirmed Ebola be made on a case-by-case basis, balancing nutritional needs with the risk of contracting the disease. There is not enough evidence to suggest when it is safe to resume breastfeeding after a mother’s recovery, unless her breast milk can be shown to be Ebola-free.³

Protecting health-care personnel
The CDC Ebola Web site¹ provides specific protocols designed to keep health-care workers safe. These include detailed guidelines for evaluating returned travelers, instructions for specimen collection, transport, testing, submission, use of protective equipment, and isolation procedures.

Share your thoughts on this news! Send your Letter to the Editor to [email protected]. Please include your name, and the city and state in which you practice

As Ebola virus spreads from West Africa, it has become apparent that ObGyns in the United States may need to evaluate patients who have been exposed to the disease. The Centers for Disease Control and Prevention (CDC) has a dedicated Web site for Ebola that outlines signs and symptoms, transmission, risk of exposure, diagnosis and treatment options, and clinical guidance for health-care workers.¹

What are the symptoms of Ebola?
If a woman from West Africa presents with a fever, the CDC advises that she be asked specifically about recent travel to affected areas (currently Liberia, Sierra Leone, Guinea, and Nigeria). Clinical signs and symptoms of Ebola include a fever of 38.6°C [101.5°F] or higher with additional symptoms¹:

• severe headache
• muscle pain
• weakness
• vomiting
• diarrhea
• abdominal (stomach) pain
• unexplained hemorrhage.

Symptoms may appear from 2–21 days after exposure to Ebola. If a person with early symptoms of Ebola has had contact with the blood or body fluids of a person sick with Ebola, objects contaminated with the blood or body fluids of a person sick with Ebola, or with Ebola-infected animals, the patient should be isolated and public health professionals immediately notified, says the CDC. Blood samples from the patient should be tested to confirm infection (visit the CDC’s Ebola Web site for a list of diagnostic tests).¹

More women than men infected
In a recently published perspective from the CDC on what ObGyns should be aware of regarding Ebola, Jamieson and colleagues reported that, according to UNICEF data, in this current outbreak more women than men are infected.² They say this is most likely because women in West Africa are the primary caregivers for sick relatives, as well as make up the majority of health-care providers and birth attendants.

Pregnancy and Ebola
Based on limited, historic data from other Ebola outbreaks in Africa, there is no evidence suggesting that pregnant women are more susceptible to Ebola, although say Jamieson and colleagues, there is limited evidence suggesting that pregnant women are more at risk for severe illness and death from Ebola.² It also appears that pregnant women with Ebola are at increased risk for spontaneous abortion and pregnancy-related hemorrhage. In 1996 in Kikwit, Democratic Republic of the Congo, pregnant women were more likely than the overall patient population with Ebola to have hemorrhagic complications, specifically vaginal and uterine bleeding associated with abortion or delivery. Children born to mothers with Ebola have not survived, though the cause of death has not been identified specifically.²

Breastfeeding and Ebola
The CDC has issued recommendations for breastfeeding or infant feeding by women with suspected or confirmed exposure to Ebola. Two key points are made³:

• Mothers with probable or confirmed Ebola virus disease should not have close contact with their infants when safe alternatives to breastfeeding and infant care exist
• Where resources are limited, non−breastfed infants are at increased risk of death from starvation and other infectious diseases. These risks must be carefully weighed against the risk of Ebola virus disease.

CDC recommends that decisions about how to best feed an infant whose mother has probable or confirmed Ebola be made on a case-by-case basis, balancing nutritional needs with the risk of contracting the disease. There is not enough evidence to suggest when it is safe to resume breastfeeding after a mother’s recovery, unless her breast milk can be shown to be Ebola-free.³

Protecting health-care personnel
The CDC Ebola Web site¹ provides specific protocols designed to keep health-care workers safe. These include detailed guidelines for evaluating returned travelers, instructions for specimen collection, transport, testing, submission, use of protective equipment, and isolation procedures.

Share your thoughts on this news! Send your Letter to the Editor to [email protected]. Please include your name, and the city and state in which you practice

I had a young cousin with thalassemia major. She had the textbook chipmunk facies, but you otherwise would not have known she was ill. Despite requiring blood transfusions every 3 weeks, she led a fairly normal life, graduating from college and holding down a good job.

In 2012, we found out that she had hepatitis C. She received treatment, but it did not succeed. By this point, she’d already developed cardiomyopathy, and she would later develop atrial fibrillation and heart failure. Earlier this year, Gilead was kind enough to give her its new drug sofosbuvir for free, but given her comorbidities, she could not tolerate it.

Recently, she was discharged after a protracted admission for heart failure. At that point, her hematologist, cardiologist, and hepatologist held a family meeting with her parents and siblings and pointed out the futility of her situation. Her family brought her home. They did what Filipino families in desperation do. They prayed and reached out to a “faith healer” – someone who uses poultices made from taro leaves, mutters incantations, and provides homemade remedies for any ailment. From a patient’s perspective, they provide hope where no one else will; from an outsider’s perspective, they are simply preying on the vulnerable.

Despite her family’s efforts, my cousin died about a month after coming home. She was only 27 years old. She woke up one morning feeling short of breath, weighed down by anasarca. She was brought to the hospital. Surrounded by her family, she asked her brother why he was crying. She asked her family not to bother calling her boyfriend; she’d talk to him when he came around. Then she fell asleep for the last time.

She did not know that she was dying. Her family had chosen to keep this from her.

When I learned about the circumstances of her passing I was angry and indignant at first. Why wouldn’t they tell her? What about patient self-determination and letting her be the judge of whether she wanted to be taken back to the hospital? Why would they deprive her of the opportunity to say goodbye? How is it that this sort of paternalistic, “I know what’s best for you” attitude still exists?

But I tried to put myself in her shoes, and it didn’t take long for me to question my certitude.

We romanticize the last moments of our lives. We imagine it to be filled with equanimity, a dignified acceptance of the inevitable. But that cannot always be the case. I can just as easily imagine myself to be angry, bitter, and, worst of all, fearful. Overwhelmed with sadness that it makes my last moments joyless rather than joyful.

Dying is intensely personal. Billions of people have led lives and reached endings unique to them. We may make noise about patient self-determination, but really, what is that if not just another manifestation of our arrogance that we know best? Is not insisting on patient self-determination just the other side of the same protect-the-patient-by-withholding-information coin?

I was humbled by my own ambivalence toward how her family handled her death, and a bit ashamed that I would be so quick to judge them. They did what they thought was best; who am I to question that? I may understand the science of life and death, but I cannot claim to understand living and dying.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I had a young cousin with thalassemia major. She had the textbook chipmunk facies, but you otherwise would not have known she was ill. Despite requiring blood transfusions every 3 weeks, she led a fairly normal life, graduating from college and holding down a good job.

In 2012, we found out that she had hepatitis C. She received treatment, but it did not succeed. By this point, she’d already developed cardiomyopathy, and she would later develop atrial fibrillation and heart failure. Earlier this year, Gilead was kind enough to give her its new drug sofosbuvir for free, but given her comorbidities, she could not tolerate it.

Recently, she was discharged after a protracted admission for heart failure. At that point, her hematologist, cardiologist, and hepatologist held a family meeting with her parents and siblings and pointed out the futility of her situation. Her family brought her home. They did what Filipino families in desperation do. They prayed and reached out to a “faith healer” – someone who uses poultices made from taro leaves, mutters incantations, and provides homemade remedies for any ailment. From a patient’s perspective, they provide hope where no one else will; from an outsider’s perspective, they are simply preying on the vulnerable.

Despite her family’s efforts, my cousin died about a month after coming home. She was only 27 years old. She woke up one morning feeling short of breath, weighed down by anasarca. She was brought to the hospital. Surrounded by her family, she asked her brother why he was crying. She asked her family not to bother calling her boyfriend; she’d talk to him when he came around. Then she fell asleep for the last time.

She did not know that she was dying. Her family had chosen to keep this from her.

When I learned about the circumstances of her passing I was angry and indignant at first. Why wouldn’t they tell her? What about patient self-determination and letting her be the judge of whether she wanted to be taken back to the hospital? Why would they deprive her of the opportunity to say goodbye? How is it that this sort of paternalistic, “I know what’s best for you” attitude still exists?

But I tried to put myself in her shoes, and it didn’t take long for me to question my certitude.

We romanticize the last moments of our lives. We imagine it to be filled with equanimity, a dignified acceptance of the inevitable. But that cannot always be the case. I can just as easily imagine myself to be angry, bitter, and, worst of all, fearful. Overwhelmed with sadness that it makes my last moments joyless rather than joyful.

Dying is intensely personal. Billions of people have led lives and reached endings unique to them. We may make noise about patient self-determination, but really, what is that if not just another manifestation of our arrogance that we know best? Is not insisting on patient self-determination just the other side of the same protect-the-patient-by-withholding-information coin?

I was humbled by my own ambivalence toward how her family handled her death, and a bit ashamed that I would be so quick to judge them. They did what they thought was best; who am I to question that? I may understand the science of life and death, but I cannot claim to understand living and dying.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I had a young cousin with thalassemia major. She had the textbook chipmunk facies, but you otherwise would not have known she was ill. Despite requiring blood transfusions every 3 weeks, she led a fairly normal life, graduating from college and holding down a good job.

In 2012, we found out that she had hepatitis C. She received treatment, but it did not succeed. By this point, she’d already developed cardiomyopathy, and she would later develop atrial fibrillation and heart failure. Earlier this year, Gilead was kind enough to give her its new drug sofosbuvir for free, but given her comorbidities, she could not tolerate it.

Recently, she was discharged after a protracted admission for heart failure. At that point, her hematologist, cardiologist, and hepatologist held a family meeting with her parents and siblings and pointed out the futility of her situation. Her family brought her home. They did what Filipino families in desperation do. They prayed and reached out to a “faith healer” – someone who uses poultices made from taro leaves, mutters incantations, and provides homemade remedies for any ailment. From a patient’s perspective, they provide hope where no one else will; from an outsider’s perspective, they are simply preying on the vulnerable.

Despite her family’s efforts, my cousin died about a month after coming home. She was only 27 years old. She woke up one morning feeling short of breath, weighed down by anasarca. She was brought to the hospital. Surrounded by her family, she asked her brother why he was crying. She asked her family not to bother calling her boyfriend; she’d talk to him when he came around. Then she fell asleep for the last time.

She did not know that she was dying. Her family had chosen to keep this from her.

When I learned about the circumstances of her passing I was angry and indignant at first. Why wouldn’t they tell her? What about patient self-determination and letting her be the judge of whether she wanted to be taken back to the hospital? Why would they deprive her of the opportunity to say goodbye? How is it that this sort of paternalistic, “I know what’s best for you” attitude still exists?

But I tried to put myself in her shoes, and it didn’t take long for me to question my certitude.

We romanticize the last moments of our lives. We imagine it to be filled with equanimity, a dignified acceptance of the inevitable. But that cannot always be the case. I can just as easily imagine myself to be angry, bitter, and, worst of all, fearful. Overwhelmed with sadness that it makes my last moments joyless rather than joyful.

Dying is intensely personal. Billions of people have led lives and reached endings unique to them. We may make noise about patient self-determination, but really, what is that if not just another manifestation of our arrogance that we know best? Is not insisting on patient self-determination just the other side of the same protect-the-patient-by-withholding-information coin?

I was humbled by my own ambivalence toward how her family handled her death, and a bit ashamed that I would be so quick to judge them. They did what they thought was best; who am I to question that? I may understand the science of life and death, but I cannot claim to understand living and dying.

Dr. Chan practices rheumatology in Pawtucket, R.I.

The efficacy, not the tolerability, of bowel cleansing is the primary concern in patients undergoing colonoscopy, because of the substantial adverse consequences of inadequate bowel preparation, according to a consensus report published simultaneously in Gastroenterology, the American Journal of Gastroenterology, and Gastrointestinal Endoscopy.

As many as 20%-25% of all colonoscopies reportedly have inadequate bowel cleansing, which is associated with lower rates of lesion detection, longer procedure times, and increased electrocautery risks, in addition to the excess costs and risks of repeat procedures. “Efficacy should be a higher priority than tolerability, [so] the choice of a bowel-cleansing regimen should be based on cleansing efficacy first and patient tolerability second,” said Dr. David A. Johnson of Eastern Veterans Administration Medical School, Norfolk (Va.) and his associates on the U.S. Multi-Society Task Force on Colorectal Cancer.

© Eraxion / thinkstockphotos.com

The USMSTF comprised representatives from the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, who compiled recommendations and wrote this report based on a systematic review and meta-analysis of the literature concerning bowel preparation from 1980 to the present.

When selecting a bowel-cleansing regimen for patients, physicians should consider the patient’s medical history, medications, and, if applicable, the adequacy of bowel preparation for previous colonoscopies. High-quality evidence shows that a split-dose regimen of 4 liters of polyethylene glycol–electrolyte lavage solution (PEG-ELS) provides superior bowel cleansing to other doses and solutions. The second dose ideally should begin 4-6 hours and conclude at least 2 hours before the procedure time. However, same-day regimens are acceptable, especially for patients scheduled for an afternoon colonoscopy.

Using a split-dose regimen allows some flexibility with the diet on the day before the procedure. Instead of ingesting only clear liquids, patients can consume either a full liquid or a low-residue diet for part or all of the day preceding colonoscopy, which improves their tolerance of the bowel preparation.

Over-the-counter, nonapproved (by the FDA) bowel-cleansing agents have widely varying efficacy, ranging from adequate to excellent. They generally are safe, but “caution is required when using these agents in certain populations” such as patients with chronic kidney disease. The routine use of adjunctive agents intended to enhance purgation or visualization of the mucosa is not recommended, Dr. Johnson and his associates said (Gastroenterology 2014;147:903-24).

At present, the evidence is insufficient to allow recommendation of specific bowel-preparation regimens for special patient populations such as the elderly, children and adolescents, people with inflammatory bowel disease, patients who have undergone bariatric surgery, and people with spinal cord injury. However, sodium phosphate preparations should be avoided in the elderly, children, and people with IBD. Additional bowel purgatives can be considered for patients at risk for inadequate preparation, such as those with a history of constipation, those using opioids or other constipating medications, those who have undergone previous colon resection, and those with spinal cord injury.

The report also includes recommendations concerning patient education, the risk factors for inadequate bowel preparation, assessing the adequacy of bowel preparation before and during the procedure, and salvage options for cases in which preparation is inadequate. It is available at http://dx.doi.org/10.1053/j.gastro.2014.07.002.

The efficacy, not the tolerability, of bowel cleansing is the primary concern in patients undergoing colonoscopy, because of the substantial adverse consequences of inadequate bowel preparation, according to a consensus report published simultaneously in Gastroenterology, the American Journal of Gastroenterology, and Gastrointestinal Endoscopy.

As many as 20%-25% of all colonoscopies reportedly have inadequate bowel cleansing, which is associated with lower rates of lesion detection, longer procedure times, and increased electrocautery risks, in addition to the excess costs and risks of repeat procedures. “Efficacy should be a higher priority than tolerability, [so] the choice of a bowel-cleansing regimen should be based on cleansing efficacy first and patient tolerability second,” said Dr. David A. Johnson of Eastern Veterans Administration Medical School, Norfolk (Va.) and his associates on the U.S. Multi-Society Task Force on Colorectal Cancer.

© Eraxion / thinkstockphotos.com

The USMSTF comprised representatives from the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, who compiled recommendations and wrote this report based on a systematic review and meta-analysis of the literature concerning bowel preparation from 1980 to the present.

When selecting a bowel-cleansing regimen for patients, physicians should consider the patient’s medical history, medications, and, if applicable, the adequacy of bowel preparation for previous colonoscopies. High-quality evidence shows that a split-dose regimen of 4 liters of polyethylene glycol–electrolyte lavage solution (PEG-ELS) provides superior bowel cleansing to other doses and solutions. The second dose ideally should begin 4-6 hours and conclude at least 2 hours before the procedure time. However, same-day regimens are acceptable, especially for patients scheduled for an afternoon colonoscopy.

Using a split-dose regimen allows some flexibility with the diet on the day before the procedure. Instead of ingesting only clear liquids, patients can consume either a full liquid or a low-residue diet for part or all of the day preceding colonoscopy, which improves their tolerance of the bowel preparation.

Over-the-counter, nonapproved (by the FDA) bowel-cleansing agents have widely varying efficacy, ranging from adequate to excellent. They generally are safe, but “caution is required when using these agents in certain populations” such as patients with chronic kidney disease. The routine use of adjunctive agents intended to enhance purgation or visualization of the mucosa is not recommended, Dr. Johnson and his associates said (Gastroenterology 2014;147:903-24).

At present, the evidence is insufficient to allow recommendation of specific bowel-preparation regimens for special patient populations such as the elderly, children and adolescents, people with inflammatory bowel disease, patients who have undergone bariatric surgery, and people with spinal cord injury. However, sodium phosphate preparations should be avoided in the elderly, children, and people with IBD. Additional bowel purgatives can be considered for patients at risk for inadequate preparation, such as those with a history of constipation, those using opioids or other constipating medications, those who have undergone previous colon resection, and those with spinal cord injury.

The report also includes recommendations concerning patient education, the risk factors for inadequate bowel preparation, assessing the adequacy of bowel preparation before and during the procedure, and salvage options for cases in which preparation is inadequate. It is available at http://dx.doi.org/10.1053/j.gastro.2014.07.002.

The efficacy, not the tolerability, of bowel cleansing is the primary concern in patients undergoing colonoscopy, because of the substantial adverse consequences of inadequate bowel preparation, according to a consensus report published simultaneously in Gastroenterology, the American Journal of Gastroenterology, and Gastrointestinal Endoscopy.

As many as 20%-25% of all colonoscopies reportedly have inadequate bowel cleansing, which is associated with lower rates of lesion detection, longer procedure times, and increased electrocautery risks, in addition to the excess costs and risks of repeat procedures. “Efficacy should be a higher priority than tolerability, [so] the choice of a bowel-cleansing regimen should be based on cleansing efficacy first and patient tolerability second,” said Dr. David A. Johnson of Eastern Veterans Administration Medical School, Norfolk (Va.) and his associates on the U.S. Multi-Society Task Force on Colorectal Cancer.

© Eraxion / thinkstockphotos.com

The USMSTF comprised representatives from the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, who compiled recommendations and wrote this report based on a systematic review and meta-analysis of the literature concerning bowel preparation from 1980 to the present.

When selecting a bowel-cleansing regimen for patients, physicians should consider the patient’s medical history, medications, and, if applicable, the adequacy of bowel preparation for previous colonoscopies. High-quality evidence shows that a split-dose regimen of 4 liters of polyethylene glycol–electrolyte lavage solution (PEG-ELS) provides superior bowel cleansing to other doses and solutions. The second dose ideally should begin 4-6 hours and conclude at least 2 hours before the procedure time. However, same-day regimens are acceptable, especially for patients scheduled for an afternoon colonoscopy.

Using a split-dose regimen allows some flexibility with the diet on the day before the procedure. Instead of ingesting only clear liquids, patients can consume either a full liquid or a low-residue diet for part or all of the day preceding colonoscopy, which improves their tolerance of the bowel preparation.

Over-the-counter, nonapproved (by the FDA) bowel-cleansing agents have widely varying efficacy, ranging from adequate to excellent. They generally are safe, but “caution is required when using these agents in certain populations” such as patients with chronic kidney disease. The routine use of adjunctive agents intended to enhance purgation or visualization of the mucosa is not recommended, Dr. Johnson and his associates said (Gastroenterology 2014;147:903-24).

At present, the evidence is insufficient to allow recommendation of specific bowel-preparation regimens for special patient populations such as the elderly, children and adolescents, people with inflammatory bowel disease, patients who have undergone bariatric surgery, and people with spinal cord injury. However, sodium phosphate preparations should be avoided in the elderly, children, and people with IBD. Additional bowel purgatives can be considered for patients at risk for inadequate preparation, such as those with a history of constipation, those using opioids or other constipating medications, those who have undergone previous colon resection, and those with spinal cord injury.

The report also includes recommendations concerning patient education, the risk factors for inadequate bowel preparation, assessing the adequacy of bowel preparation before and during the procedure, and salvage options for cases in which preparation is inadequate. It is available at http://dx.doi.org/10.1053/j.gastro.2014.07.002.

Yes, TEVAR is clearly indicated.

Aortic dissection is a devastating condition afflicting an estimated two to eight per 100,000 people annually and comprises a large portion of the clinical entity known as the acute aortic syndromes. Patients presenting with an uncomplicated type B acute aortic dissection (TBAD) generally have low in-hospital mortality rates (2.4%-9%) when managed appropriately with anti-impulse therapy. However, survival continues to decrease with follow-up, with survival ranging between 80% and more than 95% at 1 year, progressing to approximately 75% at 3-4 years, and 48%-65% at 10 years. In late follow-up, the development of a new dissection with complications is estimated to occur in 20%-50% of patients. Complicated aortic dissections affect between 22% and 47%, and when present, mortality reaches more than 50% within the first week. TEVAR in these patients has been shown to be clearly indicated in a variety of studies with marked improvements in early mortality and late survival. Thus, one can see that aortic dissection is a disease that needs to be managed lifelong, and is associated with a high risk of mortality for the next 10 years after the initial presentation.^1,2,3

The long-term effects of a patent false lumen have been well documented. Several studies following patients with chronic TBAD have documented progressive enlargement in aortic diameter with a patent false lumen. The mean increase in maximum aortic diameter ranges from 3.8 to 7.1 mm annually with any flow in the false lumen (FL) versus 1-2 mm per year with a thrombosed FL. Patients with a patent FL had 7.5 times increased risk of a dissection-related death or need for surgery as compared to patients with thrombosis of the FL. Dissection-related death or need for surgery occurred at a significantly earlier follow-up period in the patients with a patent FL.^1,2,3

The aortic diameter may also influence the patency of the FL at presentation. In a review of 110 patients presenting with acute uncomplicated TBAD, 44% were identified to have a patent FL on initial imaging. Thirty-one percent of these patients had a maximum aortic diameter of 45 mm or more versus 14% of patients with a thrombosed FL (P = .053). Incidentally, patients with FL patency were on average 4 years younger than their thrombosed counterparts (62 vs. 66 years, P = .009).

Moreover, it appears that the long-term risks associated with a patent FL are further augmented by aortic dilatation at presentation. When combining both risk factors (FL patency and aortic diameter of 40 mm or more), only 22% of patients are dissection-related event–free at 5-year follow-up.Onitsuka et al.⁴ substantiated this finding on multivariate analysis. Interestingly, 10 of the 76 patients included in that study met both conditions, and seven of those patients (70%) experienced a dissection-related death or surgical conversion. Certainly patients meeting both criteria merit close follow-up for the development of aortic enlargement or symptoms of impending rupture.

The natural history of TBAD lends itself to at least some thrombus formation within the FL and is a common finding as the dissection becomes chronic. But in fact, partial thrombosis of the FL is associated with higher mortality in patients discharged from the hospital with stable TBAD at 1- and 3-year follow-up (15.4% and 31.6%, respectively). Matched patients with a patent FL had a 5.4% and 13.7% rate of mortality at 1 and 3 years, and patients with complete FL thrombosis were found to have mortality rates of 0% and 22.6% at the same follow-up.

Aortic remodeling after TEVAR

Placement of a thoracic endograft under these acute circumstances can often significantly alter the preoperative morphology of the true and false lumen. Schoder and colleagues⁵ followed changes in the TL and FL diameter in 20 patients after TEVAR for acute complicated dissection. Ninety percent of patients were found to have complete FL thrombosis of the thoracic aorta at 1 year, with a mean decrease in FL diameter of 11.6 mm. Two patients with a patent FL showed a mean increase in the maximal aortic diameter of 4.5 mm. In a similar study, Conrad et al.⁶ documented aortic remodeling of 21 patients in the year following TEVAR, 88% of whom had thrombosis of the FL. Most often the mobile septum is easily displaced by the radial force of the stent graft, with minimal limitation of expansion to the design diameter. Thus, endograft selection should be directed by the diameter of the normal unaffected aorta with minimal oversizing commonly limited to 5%-10%. Balloon profiling is not typically necessary.

The INSTEAD trial⁷ evaluated the management of uncomplicated type B aortic dissection and compared optimum medical therapy (OMT) to OMT with TEVAR. A total of 140 subjects were enrolled at seven European sites with 68 patients enrolled in OMT and 72 in OMT with TEVAR. In patients treated with TEVAR there was 90.6% complete FL thrombosis with a maximum true lumen diameter of 32.6 mm as compared to 22% and 18.7 mm in those treated with medical therapy alone. Furthermore, there was a 12.4% absolute risk reduction in aortic specific mortality and a 19.1% absolute risk reduction in disease progression in patients treated with TEVAR.

It is clear that patients that present with complicated type B aortic dissections mandate intervention with TEVAR and potentially other interventions to alleviate the complications at presentation. INSTEAD demonstrates that elective TEVAR results in favorable aortic remodeling and long-term survival, reinterventions were low, and it prevents late expansion and malperfusion. TEVAR was also associated with improved 5-year aortic-specific survival. TEVAR appears to be beneficial in those patients who present initially with a false lumen diameter of greater than 22 mm and an aortic diameter of greater than 40 mm with a patent false lumen.

References

1. Circ. Cardiovasc. Interv. 2013;4:407-16.

2. J. Vasc. Surg. 2012;55:641-51.

3. J. Vasc. Surg. 2011;54:985-92

4. Ann. Thorac. Surg. 2004;78:1268-73.

5. Ann. Thorac. Surg. 2007;83:1059-66.

6. J. Vasc. Surg. 2009;50:510-17.

7. Circulation 2009;120:2519-28.

Dr. Arko is with the Aortic Institute, Sanger Heart & Vascular Institute, Charlotte, N.C. He reported no relevant conflicts.

No, evidence supports careful choice of patients.

While the role of TEVAR has been proven to treat complications of acute type B dissections,¹ its value as a prophylactic treatment in uncomplicated cases remains controversial. Optimal medical treatment (OMT) with strict blood pressure (SBP less than 120 mm Hg) and heart rate control is associated with a low morbidity and mortality, despite the risk of progressive aortic dilation. On the other hand TEVAR can result in early death and significant neurologic complications; other devastating complications of TEVAR include retrograde aortic dissection and access vessel rupture with a high associated mortality.

A meta-analysis of the published literature reported a high technical success of TEVAR for uncomplicated type B dissection and a relatively high conversion rate (20%) for patient treated with OMT, however the results did not identify an advantage for TEVAR with respect to 30-day and 2-year mortality.²

An expert panel review of the world literature also did not find significant data to support use of TEVAR for uncomplicated type B dissection.³ In the only randomized prospective trial to examine the role of TEVAR for uncomplicated type B dissection, the INSTEAD trial randomized 140 patients to OMT vs. OMT and TEVAR.⁴ The study results also did not support the use of TEVAR for the treatment of uncomplicated type B dissection, there was no survival advantage at 2 years, while TEVAR was associated with a 11.1% overall mortality and 4.3% neurologic complication rate, compared with 4.4% and 1.4% in the OMT group. The initial study did however report improved aortic remodeling at 2 years with TEVAR. The results of INSTEAD have been challenged because critical analysis of the INSTEAD trial has determined that the results were underpowered and that there was a 21% crossover in the OMT group and four patients received TEVAR that should have been excluded.⁵

Subsequent long-term analysis of the INSTEAD XL data do demonstrate a significant survival benefit and freedom from aortic adverse events in the TEVAR group after the initial 2-year analysis.⁶ At the 5-year follow up only 27 patients remained without a TEVAR. Fortunately there were no adverse events in the patients that crossed over to TEVAR from the OMT group demonstrating the safety of delayed TEVAR in this group. The high rate of aortic associated adverse events may favor early TEVAR. The INSTEAD XL study did identify a large primary tear (more than 10 mm) and an initial aortic diameter of 40 mm as risk factors to crossover suggesting a more aggressive approach in this subset of patients.

So while the INSTEAD XL trial now supports the use of TEVAR for uncomplicated type B dissections this was a relatively small trial that was underpowered in its initial analysis. Expert review of the world literature still supports medical management in the initial phase of treatment. Obviously in cases of failure of medical management TEVAR provides an effective treatment to restore the true lumen and visceral perfusion with possible sustained remodeling of the false lumen.

Given the not insignificant morbidity associated with TEVAR placement, routine treatment of all acute, uncomplicated type B dissections cannot be supported with the current evidence. However, a strategy of selective treatment based on size of the entry tear, extent of dissection, false lumen diameter and extent of thrombosis, effectiveness of antihypertension medications, ability to comply with medical therapy, and surveillance may be implemented. Furthermore treatment at centers of excellence with extensive TEVAR experience based on established protocols favor improved patient outcomes.

References

1. N. Engl. J. Med. 199;340:1546-52

2. Vasc. Endovascular. Surg. 2013 Oct 12;47(7):497-501. Epub 2013 Jul 12.

3. J. Am. Coll. Cardiol. 2013;61(16):1661-78.

4. Circulation 2009;120:2519-28.

5. Circulation 2009;120:2513-14.

6. Circ. Cardiovasc. Interv. 2013;6:407-16.

Dr. Shames is professor of surgery and radiology and program director of vascular surgery at the University of South Florida, Tampa. He reported no relevant conflicts.

Yes, TEVAR is clearly indicated.

Aortic dissection is a devastating condition afflicting an estimated two to eight per 100,000 people annually and comprises a large portion of the clinical entity known as the acute aortic syndromes. Patients presenting with an uncomplicated type B acute aortic dissection (TBAD) generally have low in-hospital mortality rates (2.4%-9%) when managed appropriately with anti-impulse therapy. However, survival continues to decrease with follow-up, with survival ranging between 80% and more than 95% at 1 year, progressing to approximately 75% at 3-4 years, and 48%-65% at 10 years. In late follow-up, the development of a new dissection with complications is estimated to occur in 20%-50% of patients. Complicated aortic dissections affect between 22% and 47%, and when present, mortality reaches more than 50% within the first week. TEVAR in these patients has been shown to be clearly indicated in a variety of studies with marked improvements in early mortality and late survival. Thus, one can see that aortic dissection is a disease that needs to be managed lifelong, and is associated with a high risk of mortality for the next 10 years after the initial presentation.^1,2,3

The long-term effects of a patent false lumen have been well documented. Several studies following patients with chronic TBAD have documented progressive enlargement in aortic diameter with a patent false lumen. The mean increase in maximum aortic diameter ranges from 3.8 to 7.1 mm annually with any flow in the false lumen (FL) versus 1-2 mm per year with a thrombosed FL. Patients with a patent FL had 7.5 times increased risk of a dissection-related death or need for surgery as compared to patients with thrombosis of the FL. Dissection-related death or need for surgery occurred at a significantly earlier follow-up period in the patients with a patent FL.^1,2,3

The aortic diameter may also influence the patency of the FL at presentation. In a review of 110 patients presenting with acute uncomplicated TBAD, 44% were identified to have a patent FL on initial imaging. Thirty-one percent of these patients had a maximum aortic diameter of 45 mm or more versus 14% of patients with a thrombosed FL (P = .053). Incidentally, patients with FL patency were on average 4 years younger than their thrombosed counterparts (62 vs. 66 years, P = .009).

Moreover, it appears that the long-term risks associated with a patent FL are further augmented by aortic dilatation at presentation. When combining both risk factors (FL patency and aortic diameter of 40 mm or more), only 22% of patients are dissection-related event–free at 5-year follow-up.Onitsuka et al.⁴ substantiated this finding on multivariate analysis. Interestingly, 10 of the 76 patients included in that study met both conditions, and seven of those patients (70%) experienced a dissection-related death or surgical conversion. Certainly patients meeting both criteria merit close follow-up for the development of aortic enlargement or symptoms of impending rupture.

The natural history of TBAD lends itself to at least some thrombus formation within the FL and is a common finding as the dissection becomes chronic. But in fact, partial thrombosis of the FL is associated with higher mortality in patients discharged from the hospital with stable TBAD at 1- and 3-year follow-up (15.4% and 31.6%, respectively). Matched patients with a patent FL had a 5.4% and 13.7% rate of mortality at 1 and 3 years, and patients with complete FL thrombosis were found to have mortality rates of 0% and 22.6% at the same follow-up.

Aortic remodeling after TEVAR

Placement of a thoracic endograft under these acute circumstances can often significantly alter the preoperative morphology of the true and false lumen. Schoder and colleagues⁵ followed changes in the TL and FL diameter in 20 patients after TEVAR for acute complicated dissection. Ninety percent of patients were found to have complete FL thrombosis of the thoracic aorta at 1 year, with a mean decrease in FL diameter of 11.6 mm. Two patients with a patent FL showed a mean increase in the maximal aortic diameter of 4.5 mm. In a similar study, Conrad et al.⁶ documented aortic remodeling of 21 patients in the year following TEVAR, 88% of whom had thrombosis of the FL. Most often the mobile septum is easily displaced by the radial force of the stent graft, with minimal limitation of expansion to the design diameter. Thus, endograft selection should be directed by the diameter of the normal unaffected aorta with minimal oversizing commonly limited to 5%-10%. Balloon profiling is not typically necessary.

The INSTEAD trial⁷ evaluated the management of uncomplicated type B aortic dissection and compared optimum medical therapy (OMT) to OMT with TEVAR. A total of 140 subjects were enrolled at seven European sites with 68 patients enrolled in OMT and 72 in OMT with TEVAR. In patients treated with TEVAR there was 90.6% complete FL thrombosis with a maximum true lumen diameter of 32.6 mm as compared to 22% and 18.7 mm in those treated with medical therapy alone. Furthermore, there was a 12.4% absolute risk reduction in aortic specific mortality and a 19.1% absolute risk reduction in disease progression in patients treated with TEVAR.

It is clear that patients that present with complicated type B aortic dissections mandate intervention with TEVAR and potentially other interventions to alleviate the complications at presentation. INSTEAD demonstrates that elective TEVAR results in favorable aortic remodeling and long-term survival, reinterventions were low, and it prevents late expansion and malperfusion. TEVAR was also associated with improved 5-year aortic-specific survival. TEVAR appears to be beneficial in those patients who present initially with a false lumen diameter of greater than 22 mm and an aortic diameter of greater than 40 mm with a patent false lumen.

References

1. Circ. Cardiovasc. Interv. 2013;4:407-16.

2. J. Vasc. Surg. 2012;55:641-51.

3. J. Vasc. Surg. 2011;54:985-92

4. Ann. Thorac. Surg. 2004;78:1268-73.

5. Ann. Thorac. Surg. 2007;83:1059-66.

6. J. Vasc. Surg. 2009;50:510-17.

7. Circulation 2009;120:2519-28.

Dr. Arko is with the Aortic Institute, Sanger Heart & Vascular Institute, Charlotte, N.C. He reported no relevant conflicts.

No, evidence supports careful choice of patients.

While the role of TEVAR has been proven to treat complications of acute type B dissections,¹ its value as a prophylactic treatment in uncomplicated cases remains controversial. Optimal medical treatment (OMT) with strict blood pressure (SBP less than 120 mm Hg) and heart rate control is associated with a low morbidity and mortality, despite the risk of progressive aortic dilation. On the other hand TEVAR can result in early death and significant neurologic complications; other devastating complications of TEVAR include retrograde aortic dissection and access vessel rupture with a high associated mortality.

A meta-analysis of the published literature reported a high technical success of TEVAR for uncomplicated type B dissection and a relatively high conversion rate (20%) for patient treated with OMT, however the results did not identify an advantage for TEVAR with respect to 30-day and 2-year mortality.²

An expert panel review of the world literature also did not find significant data to support use of TEVAR for uncomplicated type B dissection.³ In the only randomized prospective trial to examine the role of TEVAR for uncomplicated type B dissection, the INSTEAD trial randomized 140 patients to OMT vs. OMT and TEVAR.⁴ The study results also did not support the use of TEVAR for the treatment of uncomplicated type B dissection, there was no survival advantage at 2 years, while TEVAR was associated with a 11.1% overall mortality and 4.3% neurologic complication rate, compared with 4.4% and 1.4% in the OMT group. The initial study did however report improved aortic remodeling at 2 years with TEVAR. The results of INSTEAD have been challenged because critical analysis of the INSTEAD trial has determined that the results were underpowered and that there was a 21% crossover in the OMT group and four patients received TEVAR that should have been excluded.⁵

Subsequent long-term analysis of the INSTEAD XL data do demonstrate a significant survival benefit and freedom from aortic adverse events in the TEVAR group after the initial 2-year analysis.⁶ At the 5-year follow up only 27 patients remained without a TEVAR. Fortunately there were no adverse events in the patients that crossed over to TEVAR from the OMT group demonstrating the safety of delayed TEVAR in this group. The high rate of aortic associated adverse events may favor early TEVAR. The INSTEAD XL study did identify a large primary tear (more than 10 mm) and an initial aortic diameter of 40 mm as risk factors to crossover suggesting a more aggressive approach in this subset of patients.

So while the INSTEAD XL trial now supports the use of TEVAR for uncomplicated type B dissections this was a relatively small trial that was underpowered in its initial analysis. Expert review of the world literature still supports medical management in the initial phase of treatment. Obviously in cases of failure of medical management TEVAR provides an effective treatment to restore the true lumen and visceral perfusion with possible sustained remodeling of the false lumen.

Given the not insignificant morbidity associated with TEVAR placement, routine treatment of all acute, uncomplicated type B dissections cannot be supported with the current evidence. However, a strategy of selective treatment based on size of the entry tear, extent of dissection, false lumen diameter and extent of thrombosis, effectiveness of antihypertension medications, ability to comply with medical therapy, and surveillance may be implemented. Furthermore treatment at centers of excellence with extensive TEVAR experience based on established protocols favor improved patient outcomes.

References

1. N. Engl. J. Med. 199;340:1546-52

2. Vasc. Endovascular. Surg. 2013 Oct 12;47(7):497-501. Epub 2013 Jul 12.

3. J. Am. Coll. Cardiol. 2013;61(16):1661-78.

4. Circulation 2009;120:2519-28.

5. Circulation 2009;120:2513-14.

6. Circ. Cardiovasc. Interv. 2013;6:407-16.

Dr. Shames is professor of surgery and radiology and program director of vascular surgery at the University of South Florida, Tampa. He reported no relevant conflicts.

Yes, TEVAR is clearly indicated.

Aortic dissection is a devastating condition afflicting an estimated two to eight per 100,000 people annually and comprises a large portion of the clinical entity known as the acute aortic syndromes. Patients presenting with an uncomplicated type B acute aortic dissection (TBAD) generally have low in-hospital mortality rates (2.4%-9%) when managed appropriately with anti-impulse therapy. However, survival continues to decrease with follow-up, with survival ranging between 80% and more than 95% at 1 year, progressing to approximately 75% at 3-4 years, and 48%-65% at 10 years. In late follow-up, the development of a new dissection with complications is estimated to occur in 20%-50% of patients. Complicated aortic dissections affect between 22% and 47%, and when present, mortality reaches more than 50% within the first week. TEVAR in these patients has been shown to be clearly indicated in a variety of studies with marked improvements in early mortality and late survival. Thus, one can see that aortic dissection is a disease that needs to be managed lifelong, and is associated with a high risk of mortality for the next 10 years after the initial presentation.^1,2,3

The long-term effects of a patent false lumen have been well documented. Several studies following patients with chronic TBAD have documented progressive enlargement in aortic diameter with a patent false lumen. The mean increase in maximum aortic diameter ranges from 3.8 to 7.1 mm annually with any flow in the false lumen (FL) versus 1-2 mm per year with a thrombosed FL. Patients with a patent FL had 7.5 times increased risk of a dissection-related death or need for surgery as compared to patients with thrombosis of the FL. Dissection-related death or need for surgery occurred at a significantly earlier follow-up period in the patients with a patent FL.^1,2,3

The aortic diameter may also influence the patency of the FL at presentation. In a review of 110 patients presenting with acute uncomplicated TBAD, 44% were identified to have a patent FL on initial imaging. Thirty-one percent of these patients had a maximum aortic diameter of 45 mm or more versus 14% of patients with a thrombosed FL (P = .053). Incidentally, patients with FL patency were on average 4 years younger than their thrombosed counterparts (62 vs. 66 years, P = .009).

Moreover, it appears that the long-term risks associated with a patent FL are further augmented by aortic dilatation at presentation. When combining both risk factors (FL patency and aortic diameter of 40 mm or more), only 22% of patients are dissection-related event–free at 5-year follow-up.Onitsuka et al.⁴ substantiated this finding on multivariate analysis. Interestingly, 10 of the 76 patients included in that study met both conditions, and seven of those patients (70%) experienced a dissection-related death or surgical conversion. Certainly patients meeting both criteria merit close follow-up for the development of aortic enlargement or symptoms of impending rupture.

The natural history of TBAD lends itself to at least some thrombus formation within the FL and is a common finding as the dissection becomes chronic. But in fact, partial thrombosis of the FL is associated with higher mortality in patients discharged from the hospital with stable TBAD at 1- and 3-year follow-up (15.4% and 31.6%, respectively). Matched patients with a patent FL had a 5.4% and 13.7% rate of mortality at 1 and 3 years, and patients with complete FL thrombosis were found to have mortality rates of 0% and 22.6% at the same follow-up.

Aortic remodeling after TEVAR

Placement of a thoracic endograft under these acute circumstances can often significantly alter the preoperative morphology of the true and false lumen. Schoder and colleagues⁵ followed changes in the TL and FL diameter in 20 patients after TEVAR for acute complicated dissection. Ninety percent of patients were found to have complete FL thrombosis of the thoracic aorta at 1 year, with a mean decrease in FL diameter of 11.6 mm. Two patients with a patent FL showed a mean increase in the maximal aortic diameter of 4.5 mm. In a similar study, Conrad et al.⁶ documented aortic remodeling of 21 patients in the year following TEVAR, 88% of whom had thrombosis of the FL. Most often the mobile septum is easily displaced by the radial force of the stent graft, with minimal limitation of expansion to the design diameter. Thus, endograft selection should be directed by the diameter of the normal unaffected aorta with minimal oversizing commonly limited to 5%-10%. Balloon profiling is not typically necessary.

The INSTEAD trial⁷ evaluated the management of uncomplicated type B aortic dissection and compared optimum medical therapy (OMT) to OMT with TEVAR. A total of 140 subjects were enrolled at seven European sites with 68 patients enrolled in OMT and 72 in OMT with TEVAR. In patients treated with TEVAR there was 90.6% complete FL thrombosis with a maximum true lumen diameter of 32.6 mm as compared to 22% and 18.7 mm in those treated with medical therapy alone. Furthermore, there was a 12.4% absolute risk reduction in aortic specific mortality and a 19.1% absolute risk reduction in disease progression in patients treated with TEVAR.

It is clear that patients that present with complicated type B aortic dissections mandate intervention with TEVAR and potentially other interventions to alleviate the complications at presentation. INSTEAD demonstrates that elective TEVAR results in favorable aortic remodeling and long-term survival, reinterventions were low, and it prevents late expansion and malperfusion. TEVAR was also associated with improved 5-year aortic-specific survival. TEVAR appears to be beneficial in those patients who present initially with a false lumen diameter of greater than 22 mm and an aortic diameter of greater than 40 mm with a patent false lumen.

References

1. Circ. Cardiovasc. Interv. 2013;4:407-16.

2. J. Vasc. Surg. 2012;55:641-51.

3. J. Vasc. Surg. 2011;54:985-92

4. Ann. Thorac. Surg. 2004;78:1268-73.

5. Ann. Thorac. Surg. 2007;83:1059-66.

6. J. Vasc. Surg. 2009;50:510-17.

7. Circulation 2009;120:2519-28.

Dr. Arko is with the Aortic Institute, Sanger Heart & Vascular Institute, Charlotte, N.C. He reported no relevant conflicts.

No, evidence supports careful choice of patients.

While the role of TEVAR has been proven to treat complications of acute type B dissections,¹ its value as a prophylactic treatment in uncomplicated cases remains controversial. Optimal medical treatment (OMT) with strict blood pressure (SBP less than 120 mm Hg) and heart rate control is associated with a low morbidity and mortality, despite the risk of progressive aortic dilation. On the other hand TEVAR can result in early death and significant neurologic complications; other devastating complications of TEVAR include retrograde aortic dissection and access vessel rupture with a high associated mortality.

A meta-analysis of the published literature reported a high technical success of TEVAR for uncomplicated type B dissection and a relatively high conversion rate (20%) for patient treated with OMT, however the results did not identify an advantage for TEVAR with respect to 30-day and 2-year mortality.²

An expert panel review of the world literature also did not find significant data to support use of TEVAR for uncomplicated type B dissection.³ In the only randomized prospective trial to examine the role of TEVAR for uncomplicated type B dissection, the INSTEAD trial randomized 140 patients to OMT vs. OMT and TEVAR.⁴ The study results also did not support the use of TEVAR for the treatment of uncomplicated type B dissection, there was no survival advantage at 2 years, while TEVAR was associated with a 11.1% overall mortality and 4.3% neurologic complication rate, compared with 4.4% and 1.4% in the OMT group. The initial study did however report improved aortic remodeling at 2 years with TEVAR. The results of INSTEAD have been challenged because critical analysis of the INSTEAD trial has determined that the results were underpowered and that there was a 21% crossover in the OMT group and four patients received TEVAR that should have been excluded.⁵

Subsequent long-term analysis of the INSTEAD XL data do demonstrate a significant survival benefit and freedom from aortic adverse events in the TEVAR group after the initial 2-year analysis.⁶ At the 5-year follow up only 27 patients remained without a TEVAR. Fortunately there were no adverse events in the patients that crossed over to TEVAR from the OMT group demonstrating the safety of delayed TEVAR in this group. The high rate of aortic associated adverse events may favor early TEVAR. The INSTEAD XL study did identify a large primary tear (more than 10 mm) and an initial aortic diameter of 40 mm as risk factors to crossover suggesting a more aggressive approach in this subset of patients.

So while the INSTEAD XL trial now supports the use of TEVAR for uncomplicated type B dissections this was a relatively small trial that was underpowered in its initial analysis. Expert review of the world literature still supports medical management in the initial phase of treatment. Obviously in cases of failure of medical management TEVAR provides an effective treatment to restore the true lumen and visceral perfusion with possible sustained remodeling of the false lumen.

Given the not insignificant morbidity associated with TEVAR placement, routine treatment of all acute, uncomplicated type B dissections cannot be supported with the current evidence. However, a strategy of selective treatment based on size of the entry tear, extent of dissection, false lumen diameter and extent of thrombosis, effectiveness of antihypertension medications, ability to comply with medical therapy, and surveillance may be implemented. Furthermore treatment at centers of excellence with extensive TEVAR experience based on established protocols favor improved patient outcomes.

References

1. N. Engl. J. Med. 199;340:1546-52

2. Vasc. Endovascular. Surg. 2013 Oct 12;47(7):497-501. Epub 2013 Jul 12.

3. J. Am. Coll. Cardiol. 2013;61(16):1661-78.

4. Circulation 2009;120:2519-28.

5. Circulation 2009;120:2513-14.

6. Circ. Cardiovasc. Interv. 2013;6:407-16.

Dr. Shames is professor of surgery and radiology and program director of vascular surgery at the University of South Florida, Tampa. He reported no relevant conflicts.

Transplant preparation

Credit: Chad McNeeley

Combining a couple of “promising” treatment approaches can prevent graft-vs-host disease (GVHD) as well as conventional therapy, researchers have reported in the Journal of Clinical Oncology.

They combined a 4-day myeloablative conditioning regimen of busulfan and fludarabine with 2 days of high-dose cyclophosphamide after transplant.

Typically, patients receive 6 months of immunosuppressive therapy to reduce their risk of GVHD.

The conditioning regimen and post-transplant cyclophosphamide have been tested separately in other studies and have good track records in controlling cancer and preventing severe GVHD.

Those successes led Leo Luznik, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues to combine the 2 therapies.

The team tested the combination in 92 patients with high-risk hematologic malignancies. Diagnoses included acute and chronic leukemias, multiple myeloma, non-Hodgkin lymphoma, and myelodysplastic syndromes. Patients had a median age of 49 (range, 21-65).

All patients received 40 mg/m²/day of intravenous (IV) fludarabine immediately before busulfan on all 4 days of conditioning. The busulfan dose of 130 mg/m² IV daily was adjusted based on pharmacokinetics.

One or 2 days of rest were allowed before patients received a T-cell-replete bone marrow allograft. Forty-five patients had a matched, related donor, and 47 had a matched, unrelated donor.

Patients received 50 mg/kg/day of IV cyclophosphamide for 2 days, with the first dose starting 62 to 72 hours after the start of allograft infusion.

At 100 days after transplant, 51% of patients had developed grade 2-4 acute GVHD, and 15% had grade 3-4 acute GVHD. Fourteen percent of patients developed chronic GVHD.

The 2-year overall survival rate was 67%, and 2-year event-free survival was 62%.

Dr Luznik said he was encouraged by the low rate of chronic GVHD with the regimen. And he noted that percentages of acute GVHD are similar to those seen with the standard 6-month regimen of immunosuppressive drugs.

Reducing the post-transplant treatment to 2 days with cyclophosphamide, he said, “also allows for the earlier integration of other treatments.”

For example, immunotherapies used to eradicate any remaining cancer could be started much sooner with this regimen, said study author Christopher Kanakry, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins.

“If you give patients immune cells to eradicate any remaining cancer cells that might be present,” he said, “those immune cells would not be prevented from doing their job by ongoing immune suppression drugs that are being used in patients treated with conventional transplant approaches.”

Dr Luznik said the researchers’ next step will be a phase 3 trial comparing this regimen to another experimental approach to prevent GVHD or to the more traditional 6-month immunosuppressive therapy.

Funding for this study was provided by Otsuka Pharmaceutical Co., Ltd. and the National Institutes of Health.

Transplant preparation

Credit: Chad McNeeley

Combining a couple of “promising” treatment approaches can prevent graft-vs-host disease (GVHD) as well as conventional therapy, researchers have reported in the Journal of Clinical Oncology.

They combined a 4-day myeloablative conditioning regimen of busulfan and fludarabine with 2 days of high-dose cyclophosphamide after transplant.

Typically, patients receive 6 months of immunosuppressive therapy to reduce their risk of GVHD.

The conditioning regimen and post-transplant cyclophosphamide have been tested separately in other studies and have good track records in controlling cancer and preventing severe GVHD.

Those successes led Leo Luznik, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues to combine the 2 therapies.

The team tested the combination in 92 patients with high-risk hematologic malignancies. Diagnoses included acute and chronic leukemias, multiple myeloma, non-Hodgkin lymphoma, and myelodysplastic syndromes. Patients had a median age of 49 (range, 21-65).

All patients received 40 mg/m²/day of intravenous (IV) fludarabine immediately before busulfan on all 4 days of conditioning. The busulfan dose of 130 mg/m² IV daily was adjusted based on pharmacokinetics.

One or 2 days of rest were allowed before patients received a T-cell-replete bone marrow allograft. Forty-five patients had a matched, related donor, and 47 had a matched, unrelated donor.

Patients received 50 mg/kg/day of IV cyclophosphamide for 2 days, with the first dose starting 62 to 72 hours after the start of allograft infusion.

At 100 days after transplant, 51% of patients had developed grade 2-4 acute GVHD, and 15% had grade 3-4 acute GVHD. Fourteen percent of patients developed chronic GVHD.

The 2-year overall survival rate was 67%, and 2-year event-free survival was 62%.

Dr Luznik said he was encouraged by the low rate of chronic GVHD with the regimen. And he noted that percentages of acute GVHD are similar to those seen with the standard 6-month regimen of immunosuppressive drugs.

Reducing the post-transplant treatment to 2 days with cyclophosphamide, he said, “also allows for the earlier integration of other treatments.”

For example, immunotherapies used to eradicate any remaining cancer could be started much sooner with this regimen, said study author Christopher Kanakry, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins.

“If you give patients immune cells to eradicate any remaining cancer cells that might be present,” he said, “those immune cells would not be prevented from doing their job by ongoing immune suppression drugs that are being used in patients treated with conventional transplant approaches.”

Dr Luznik said the researchers’ next step will be a phase 3 trial comparing this regimen to another experimental approach to prevent GVHD or to the more traditional 6-month immunosuppressive therapy.

Funding for this study was provided by Otsuka Pharmaceutical Co., Ltd. and the National Institutes of Health.

Transplant preparation

Credit: Chad McNeeley

Combining a couple of “promising” treatment approaches can prevent graft-vs-host disease (GVHD) as well as conventional therapy, researchers have reported in the Journal of Clinical Oncology.

They combined a 4-day myeloablative conditioning regimen of busulfan and fludarabine with 2 days of high-dose cyclophosphamide after transplant.

Typically, patients receive 6 months of immunosuppressive therapy to reduce their risk of GVHD.

The conditioning regimen and post-transplant cyclophosphamide have been tested separately in other studies and have good track records in controlling cancer and preventing severe GVHD.

Those successes led Leo Luznik, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues to combine the 2 therapies.

The team tested the combination in 92 patients with high-risk hematologic malignancies. Diagnoses included acute and chronic leukemias, multiple myeloma, non-Hodgkin lymphoma, and myelodysplastic syndromes. Patients had a median age of 49 (range, 21-65).

All patients received 40 mg/m²/day of intravenous (IV) fludarabine immediately before busulfan on all 4 days of conditioning. The busulfan dose of 130 mg/m² IV daily was adjusted based on pharmacokinetics.

One or 2 days of rest were allowed before patients received a T-cell-replete bone marrow allograft. Forty-five patients had a matched, related donor, and 47 had a matched, unrelated donor.

Patients received 50 mg/kg/day of IV cyclophosphamide for 2 days, with the first dose starting 62 to 72 hours after the start of allograft infusion.

At 100 days after transplant, 51% of patients had developed grade 2-4 acute GVHD, and 15% had grade 3-4 acute GVHD. Fourteen percent of patients developed chronic GVHD.

The 2-year overall survival rate was 67%, and 2-year event-free survival was 62%.

Dr Luznik said he was encouraged by the low rate of chronic GVHD with the regimen. And he noted that percentages of acute GVHD are similar to those seen with the standard 6-month regimen of immunosuppressive drugs.

Reducing the post-transplant treatment to 2 days with cyclophosphamide, he said, “also allows for the earlier integration of other treatments.”

For example, immunotherapies used to eradicate any remaining cancer could be started much sooner with this regimen, said study author Christopher Kanakry, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins.

“If you give patients immune cells to eradicate any remaining cancer cells that might be present,” he said, “those immune cells would not be prevented from doing their job by ongoing immune suppression drugs that are being used in patients treated with conventional transplant approaches.”

Dr Luznik said the researchers’ next step will be a phase 3 trial comparing this regimen to another experimental approach to prevent GVHD or to the more traditional 6-month immunosuppressive therapy.

Funding for this study was provided by Otsuka Pharmaceutical Co., Ltd. and the National Institutes of Health.