DNA coiled around histones

Credit: Eric Smith

Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.

And this finding could have implications for the treatment of leukemias and lymphomas.

Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.

Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.

Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.

Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.

But how the methylase’s activity was directed toward the appropriate targets was unclear.

Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.

The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.

The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.

“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”

Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.

The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.

This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.

But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.

The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.

Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.

In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.

The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.

The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.

The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.

DNA coiled around histones

Credit: Eric Smith

Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.

And this finding could have implications for the treatment of leukemias and lymphomas.

Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.

Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.

Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.

Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.

But how the methylase’s activity was directed toward the appropriate targets was unclear.

Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.

The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.

The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.

“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”

Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.

The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.

This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.

But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.

The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.

Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.

In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.

The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.

The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.

The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.

DNA coiled around histones

Credit: Eric Smith

Investigators have uncovered an unanticipated mechanism underlying trimethylation of a histone that activates gene expression.

And this finding could have implications for the treatment of leukemias and lymphomas.

Ali Shilatifard, PhD, of the Stowers Institute for Medical Research in Kansas City, Missouri, and his colleagues described the discovery in Genes & Development.

Histones, which come in 4 subtypes—H2A, H2B, H3, and H4—can either coil DNA into inaccessible, silent regions or untwist it to allow gene expression. And small chemical flags, such as methyl groups, affect whether histones silence or activate genes.

Among activator histones is a form of H3 decorated at a precise location with 3 methyl groups, known as H3K4me3.

Previous research showed that the presence of H2B exhibiting a single ubiquitin molecule stimulated the methylase that modifies H3K4, thereby increasing H3K4me3 levels.

But how the methylase’s activity was directed toward the appropriate targets was unclear.

Now, Dr Shilatifard and his colleagues have discovered a mechanism underlying H3K4 trimethylation. Their research explains why H3K4me3 is deposited adjacent to a target gene promoter rather than haphazardly across the entire gene.

The team said this finding is significant because mutations in the human gene encoding the methylase responsible for H3K4me3 are associated with leukemias, lymphomas, and other malignancies.

The methylase in question, named SET1 in yeast and MLL in mammals, is part of a protein aggregate called COMPASS (COMplex of Proteins ASsociated with Set1). Dr Shilatifard was the first to define the role of COMPASS in chromatin modification.

“Over a decade ago, our lab used yeast to show that COMPASS was an H3 methylase,” he said. “Since these fundamental systems are highly conserved from yeast to Drosophila to humans, we took advantage of the awesome power of yeast genetics to identify what regulates H3K4 methylation activity.”

Part of his group’s latest paper addresses SET1/MLL regulation by different proteins within yeast COMPASS.

The investigators knew that if more than half of SET1’s front end was removed, levels of DNA-bound trimethylated H3K4 in cells harboring the remaining “stub” were equal to those in cells containing the full-length protein when analyzed in bulk.

This finding led some researchers to presume that the entire front end of SET1/MLL, as well as factors that interact with it, must not be needed to regulate H3K4me3 activity.

But Dr Shilatifard and his colleagues found evidence suggesting this presumption is incorrect.

The team first employed biochemical methods to capture every piece of DNA bound to H3K4me3 in the genome of yeast harboring either full-length SET1 or the stub missing the front end. They then sequenced all of those DNA fragments and mapped their position in the yeast genome.

Results showed that even though H3K4me3 levels in bulk were equivalent in normal and mutant cells, H3K4me3 was differentially distributed throughout the genome.

In normal cells, H3K4me3 complexes sat primarily on DNA promoter regions. By contrast, the DNA of cells harboring the stub exhibited DNA-binding H3K4me3 complexes in the middle of or between genes.

The work shows that COMPASS factors that bind to the SET1/MLL front end limit H3K4me3 deposition to the correct genomic sites (the promoter regions), while factors that bind the SET1/MLL stub increase the protein’s half-life.

The investigators also discovered how H2B ubiquitin modification machineries stimulate the entire process.

The team said understanding COMPASS regulation is essential, as genes encoding factors in the complex are mutant in numerous cancers.

Thrombus

Credit: Andre E.X. Brown

An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.

The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.

The FDA will take this opinion into account when deciding whether or not to approve the drug.

The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.

In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.

The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).

The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).

However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.

And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.

These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.

The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.

The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.

Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.

For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.

Thrombus

Credit: Andre E.X. Brown

An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.

The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.

The FDA will take this opinion into account when deciding whether or not to approve the drug.

The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.

In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.

The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).

The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).

However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.

And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.

These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.

The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.

The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.

Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.

For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.

Thrombus

Credit: Andre E.X. Brown

An advisory committee is recommending that the US Food and Drug Administration (FDA) approve the antiplatelet agent vorapaxar as prophylaxis for atherothrombotic events in patients with a history of myocardial infarction.

The committee voted 10-1 in favor of vorapaxar, saying trial data suggest the drug’s potential benefits outweigh the risks for this patient population.

The FDA will take this opinion into account when deciding whether or not to approve the drug.

The committee evaluated data from the TRA 2P-TIMI 50 and TRACER trials.

In the TRACER study, researchers compared vorapaxar to placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation.

The trial was terminated early due to a significantly increased risk of bleeding in patients receiving vorapaxar. Rates of moderate and severe bleeding were 7.2% in the vorapaxar arm and 5.2% in the placebo arm (P<0.001). And the rates of intracranial hemorrhage were 1.1% and 0.2%, respectively (P<0.001).

The TRA 2P-TIMI 50 trial also showed an increased risk of bleeding with vorapaxar. In that study, investigators compared the drug to placebo in 26,449 patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

Moderate or severe bleeding occurred in 4.2% of vorapaxar-treated patients and 2.5% of patients in the placebo arm (P<0.001). The rates of intracranial hemorrhage were 1.0% and 0.5%, respectively (P<0.001).

However, data from this trial also showed that vorapaxar can prevent thrombosis and decrease the likelihood of cardiac events.

And a subgroup analysis of patients with a history of myocardial infarction suggested the drug can reduce vascular events in these patients without increasing the risk of intracranial hemorrhage, although it did increase the risk of moderate or severe bleeding.

These results prompted the drug’s developer, Merck, to file a New Drug Application for vorapaxar to treat patients with a history of myocardial infarction, and not those with a history of ischemic stroke or peripheral arterial disease.

The FDA advisory committee agreed with the company’s decision to exclude patients with a history of ischemic stroke, but not those with peripheral arterial disease, as there were no significant safety issues in this population.

The committee also expressed concerns about some of the trial data, including analyses suggesting worse outcomes with vorapaxar in patients weighing less than 60 kg.

Nevertheless, the committee concluded that, overall, the benefits of vorapaxar outweigh the risks.

For more details and vorapaxar data, see the briefing information compiled for the advisory committee’s meeting.

Salvador Macip, MD, PhD

Credit: University of Leicester

Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.

The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.

Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).

But new results in a patient with HCL suggest otherwise.

Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.

The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.

They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.

But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.

“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”

The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.

A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.

“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.

Salvador Macip, MD, PhD

Credit: University of Leicester

Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.

The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.

Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).

But new results in a patient with HCL suggest otherwise.

Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.

The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.

They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.

But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.

“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”

The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.

A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.

“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.

Salvador Macip, MD, PhD

Credit: University of Leicester

Results of a case study suggest the BRAF inhibitor vemurafenib does not treat hairy cell leukemia (HCL) in the way researchers thought.

The BRAF V600E mutation is present in nearly all cases of HCL, so it’s not surprising that vemurafenib has elicited responses in patients with the disease.

Researchers thought the drug did this by inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein–ERK kinase (MEK).

But new results in a patient with HCL suggest otherwise.

Salvador Macip, MD, PhD, of the University of Leicester in the UK, and his colleagues described this case in a letter to NEJM.

The patient had purine analogue-refractory disease, biallelic BRAF V600E mutations, and a high leukemic burden. Because the patient had such high numbers of circulating HCL cells, the researchers were able to study the effects of vemurafenib in vivo.

They found that vemurafenib cleared malignant cells from the patient’s blood and led to a complete clinical recovery within days of treatment initiation.

But BRAF inhibition was not associated with major changes in phosphorylation of MEK or ERK.

“[T]he drug did not work in the way we expected it to,” Dr Macip said. “Whilst it successfully blocked BRAF and killed the cancerous cells, there was no ability to block the downstream cascade of signals.”

The researchers said they could not rule out the possibility that BRAF inhibition eventually resulted in suppression of ERK activation in some anatomical compartment other than the blood. But they believe this is unlikely.

A more plausible explanation is that an alternative signaling pathway may be affected by vemurafenib, either directly or through BRAF inhibition.

“[M]ore research is required to better understand how this drug works, to ensure we are able to use it in the best possible way,” Dr Macip concluded.

Clinical question

As compared with crystalloid therapy, does the use of colloid solutions for fluid resuscitation in the intensive care unit improve mortality in critically ill patients with hypovolemic shock?

Bottom line

For critically ill patients with acute hypovolemic shock, the use of colloid solutions for fluid resuscitation does not significantly affect short-term mortality as compared with the use of crystalloid solutions. However, the data suggest that deaths over 90 days may be reduced with colloids. More research is needed to confirm these findings. (LOE = 1b-)

Reference

Annane D, Siami S, Jaber S, et al, for the CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. JAMA 2013:310(17);1809-1817.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Critically ill patients with acute hypovolemia were randomized, using concealed allocation, to receive fluid resuscitation with crystalloids or colloids. Patients who had already received fluid resuscitation while in the intensive care unit (ICU) were excluded from the study. Randomization was stratified according to diagnosis: sepsis, trauma, or other causes of hypovolemic shock. In the crystalloid group, patients received isotonic or hypertonic saline or other buffered solutions; patients in the colloid group received hypo- or hyper-oncotic solutions such as gelatins, dextrans, hydroxyethyl starches, or albumin. The amount and duration of fluid resuscitation was left to the discretion of the clinicians. Clinicians were not masked as it was considered infeasible to stock the units with adequately masked fluid solutions, especially for the use in emergencies. Analysis was by intention to treat. Baseline characteristics in the 2 groups were similar. The median age was 63 years and the majority of patients had hypovolemia due to sepsis. The median volume of fluid administered (excluding maintenance therapy) during the first 7 days in the ICU was higher in the crystalloid group (3 L vs 2 L; P < .001). For the primary outcome of mortality at 28 days, there was no significant difference detected between the 2 groups. Although there were fewer deaths in the colloid group at 90 days, this was a secondary outcome and the confidence interval approached 1 (31% vs. 34%; relative risk = 0.92; 95% CI, 0.86-0.99; P = .03). At the 28-day mark, patients in the colloid group were more likely to be alive without the need for mechanical ventilation (14.6 days vs 13.5 days; P = .01) or vasopressor therapy (16.2 days vs 15.2 days; P = .03).

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

Clinical question

As compared with crystalloid therapy, does the use of colloid solutions for fluid resuscitation in the intensive care unit improve mortality in critically ill patients with hypovolemic shock?

Bottom line

For critically ill patients with acute hypovolemic shock, the use of colloid solutions for fluid resuscitation does not significantly affect short-term mortality as compared with the use of crystalloid solutions. However, the data suggest that deaths over 90 days may be reduced with colloids. More research is needed to confirm these findings. (LOE = 1b-)

Reference

Annane D, Siami S, Jaber S, et al, for the CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. JAMA 2013:310(17);1809-1817.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Critically ill patients with acute hypovolemia were randomized, using concealed allocation, to receive fluid resuscitation with crystalloids or colloids. Patients who had already received fluid resuscitation while in the intensive care unit (ICU) were excluded from the study. Randomization was stratified according to diagnosis: sepsis, trauma, or other causes of hypovolemic shock. In the crystalloid group, patients received isotonic or hypertonic saline or other buffered solutions; patients in the colloid group received hypo- or hyper-oncotic solutions such as gelatins, dextrans, hydroxyethyl starches, or albumin. The amount and duration of fluid resuscitation was left to the discretion of the clinicians. Clinicians were not masked as it was considered infeasible to stock the units with adequately masked fluid solutions, especially for the use in emergencies. Analysis was by intention to treat. Baseline characteristics in the 2 groups were similar. The median age was 63 years and the majority of patients had hypovolemia due to sepsis. The median volume of fluid administered (excluding maintenance therapy) during the first 7 days in the ICU was higher in the crystalloid group (3 L vs 2 L; P < .001). For the primary outcome of mortality at 28 days, there was no significant difference detected between the 2 groups. Although there were fewer deaths in the colloid group at 90 days, this was a secondary outcome and the confidence interval approached 1 (31% vs. 34%; relative risk = 0.92; 95% CI, 0.86-0.99; P = .03). At the 28-day mark, patients in the colloid group were more likely to be alive without the need for mechanical ventilation (14.6 days vs 13.5 days; P = .01) or vasopressor therapy (16.2 days vs 15.2 days; P = .03).

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

Clinical question

As compared with crystalloid therapy, does the use of colloid solutions for fluid resuscitation in the intensive care unit improve mortality in critically ill patients with hypovolemic shock?

Bottom line

For critically ill patients with acute hypovolemic shock, the use of colloid solutions for fluid resuscitation does not significantly affect short-term mortality as compared with the use of crystalloid solutions. However, the data suggest that deaths over 90 days may be reduced with colloids. More research is needed to confirm these findings. (LOE = 1b-)

Reference

Annane D, Siami S, Jaber S, et al, for the CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. JAMA 2013:310(17);1809-1817.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Critically ill patients with acute hypovolemia were randomized, using concealed allocation, to receive fluid resuscitation with crystalloids or colloids. Patients who had already received fluid resuscitation while in the intensive care unit (ICU) were excluded from the study. Randomization was stratified according to diagnosis: sepsis, trauma, or other causes of hypovolemic shock. In the crystalloid group, patients received isotonic or hypertonic saline or other buffered solutions; patients in the colloid group received hypo- or hyper-oncotic solutions such as gelatins, dextrans, hydroxyethyl starches, or albumin. The amount and duration of fluid resuscitation was left to the discretion of the clinicians. Clinicians were not masked as it was considered infeasible to stock the units with adequately masked fluid solutions, especially for the use in emergencies. Analysis was by intention to treat. Baseline characteristics in the 2 groups were similar. The median age was 63 years and the majority of patients had hypovolemia due to sepsis. The median volume of fluid administered (excluding maintenance therapy) during the first 7 days in the ICU was higher in the crystalloid group (3 L vs 2 L; P < .001). For the primary outcome of mortality at 28 days, there was no significant difference detected between the 2 groups. Although there were fewer deaths in the colloid group at 90 days, this was a secondary outcome and the confidence interval approached 1 (31% vs. 34%; relative risk = 0.92; 95% CI, 0.86-0.99; P = .03). At the 28-day mark, patients in the colloid group were more likely to be alive without the need for mechanical ventilation (14.6 days vs 13.5 days; P = .01) or vasopressor therapy (16.2 days vs 15.2 days; P = .03).

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

Clinical question

Does the use of renal artery stenting combined with aggressive medical therapy improve outcomes in patients with severe atherosclerotic renal artery stenosis?

Bottom line

In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting does not provide an additional benefit when added to comprehensive medical therapy that includes blood pressure and diabetes management and antiplatelet and lipid therapies. (LOE = 1b)

Reference

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013 Nov 13 [Epub ahead of print].

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Outpatient (any)

Synopsis

These investigators enrolled 947 patients with severe atherosclerotic renal artery stenosis (60% stenosis or more). Eligible patients also had either systolic hypertension while taking 2 or more antihypertensive medications or chronic kidney disease. Using concealed allocation, patients were randomized to receive either stenting plus medical therapy or medical therapy alone. Medical management included antiplatelet agents, antihypertensives, and lipid-lowering therapies. Specifically, all patients received candesartan with or without hydrochorthiazide, as well as the combination pill amlodipine-atorvastatin. Diabetes was managed according to clinical practice guidelines. The 2 groups had similar comorbidities at baseline. Overall, 90% of patients in each group had hyperlipidemia and approximately 30% had diabetes. The primary outcome was a composite of death from cardiovascular or renal causes, stroke, myocardial infarction, hospitalization for acute heart failure, worsening renal insufficiency, or the need for permanent dialysis. At a median follow-up of 43 months, there was no significant difference detected between the 2 groups in either the composite outcome (hazard ratio [HR] = 0.95; 95% CI, 0.76-1.17) or its individual components. All-cause mortality was also similar (HR = 0.80; 0.58-1.12).

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

Clinical question

Does the use of renal artery stenting combined with aggressive medical therapy improve outcomes in patients with severe atherosclerotic renal artery stenosis?

Bottom line

In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting does not provide an additional benefit when added to comprehensive medical therapy that includes blood pressure and diabetes management and antiplatelet and lipid therapies. (LOE = 1b)

Reference

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013 Nov 13 [Epub ahead of print].

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Outpatient (any)

Synopsis

These investigators enrolled 947 patients with severe atherosclerotic renal artery stenosis (60% stenosis or more). Eligible patients also had either systolic hypertension while taking 2 or more antihypertensive medications or chronic kidney disease. Using concealed allocation, patients were randomized to receive either stenting plus medical therapy or medical therapy alone. Medical management included antiplatelet agents, antihypertensives, and lipid-lowering therapies. Specifically, all patients received candesartan with or without hydrochorthiazide, as well as the combination pill amlodipine-atorvastatin. Diabetes was managed according to clinical practice guidelines. The 2 groups had similar comorbidities at baseline. Overall, 90% of patients in each group had hyperlipidemia and approximately 30% had diabetes. The primary outcome was a composite of death from cardiovascular or renal causes, stroke, myocardial infarction, hospitalization for acute heart failure, worsening renal insufficiency, or the need for permanent dialysis. At a median follow-up of 43 months, there was no significant difference detected between the 2 groups in either the composite outcome (hazard ratio [HR] = 0.95; 95% CI, 0.76-1.17) or its individual components. All-cause mortality was also similar (HR = 0.80; 0.58-1.12).

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

Clinical question

Does the use of renal artery stenting combined with aggressive medical therapy improve outcomes in patients with severe atherosclerotic renal artery stenosis?

Bottom line

In patients with severe atherosclerotic renal artery stenosis and hypertension or chronic kidney disease, renal artery stenting does not provide an additional benefit when added to comprehensive medical therapy that includes blood pressure and diabetes management and antiplatelet and lipid therapies. (LOE = 1b)

Reference

Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013 Nov 13 [Epub ahead of print].

Study design

Randomized controlled trial (nonblinded)

Funding source

Industry + govt

Allocation

Concealed

Setting

Outpatient (any)

Synopsis

These investigators enrolled 947 patients with severe atherosclerotic renal artery stenosis (60% stenosis or more). Eligible patients also had either systolic hypertension while taking 2 or more antihypertensive medications or chronic kidney disease. Using concealed allocation, patients were randomized to receive either stenting plus medical therapy or medical therapy alone. Medical management included antiplatelet agents, antihypertensives, and lipid-lowering therapies. Specifically, all patients received candesartan with or without hydrochorthiazide, as well as the combination pill amlodipine-atorvastatin. Diabetes was managed according to clinical practice guidelines. The 2 groups had similar comorbidities at baseline. Overall, 90% of patients in each group had hyperlipidemia and approximately 30% had diabetes. The primary outcome was a composite of death from cardiovascular or renal causes, stroke, myocardial infarction, hospitalization for acute heart failure, worsening renal insufficiency, or the need for permanent dialysis. At a median follow-up of 43 months, there was no significant difference detected between the 2 groups in either the composite outcome (hazard ratio [HR] = 0.95; 95% CI, 0.76-1.17) or its individual components. All-cause mortality was also similar (HR = 0.80; 0.58-1.12).

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

I’ve just come across a really interesting project that I think we can all get behind: tuberculosis-sniffing rats.

It started with land mines. In many war-torn regions in Africa, people cannot access their land for agriculture because it is riddled with mines left over from previous conflicts. Bart Weetjens, a Belgian product development engineer with some experience of the difficulties of living in rural Africa, came across American experiments from the 1970s using gerbils to sniff out explosives. This inspired him to look into using rats to sniff out land mines. In 1997, he founded a nonprofit called Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) and received funding from the Belgian government to pursue his research.

Weetjens settled on using African giant pouch rats to sniff out land mines. The rats were inexpensive, intelligent, plentiful, sociable, trainable, and, most importantly, light enough to not set the land mines off. In 2003, they first tested the rats on real fields with real land mines in Mozambique. Now, they’ve received the backing of international peace agencies and have, to date, rendered safe 2.5 million square-meters of land area in Mozambique, effectively returning 100,000 people to their lands.

Given the success of this project, and the prevalence of pulmonary tuberculosis (TB) in the same communities affected by land mines, Weetjens thought of expanding the project into detection of tuberculosis from sputum samples. The premise is that Mycobacterium tuberculosis emits volatile organic compounds that the rats, with more genetic material dedicated to olfaction than any other mammal, might be able to detect.

It’s a fascinating demonstration of the intersection between science fiction and reality. You have to watch the videos to believe it, but the organization has trained several dozen rats in Tanzania and Mozambique to sniff out TB. It takes the rats 20 msec to sniff out and correctly identify a sample. The rats are able to process in 7 minutes the number of samples that a lab technician (or a lab "rat," if you will) would take a day to process using conventional light microscopy methods. In Dar es Salaam, using samples from more than 10,500 people from five hospitals, they increased the case detection rate by 44% over that of conventional microscopy. This method has a sensitivity of about 85% and a specificity of 90% – about the same rates as a 10-mm positive tuberculin test (Am. J. Trop. Med. Hyg. 2010;83:1308-10). It is even able to distinguish between M. tuberculosis and other mycobacterial species.

According to the World Health Organization, people with active tuberculosis can spread the disease to 10-15 close contacts in a year. WHO also says that TB is the second biggest infectious killer (behind HIV) worldwide, with over 1.3 million deaths in 2012. If these rats can really detect patients with TB at a much higher rate and with a greater sensitivity than standard microscopy, imagine the impact they would have on reducing the number of deaths worldwide from TB, especially in African nations where TB and HIV often co-occur, and access to health care is difficult.

APOPO’s project is a wonderful example of how simple innovations in science can have such a large footprint on global health. If you’re interested in learning more about APOPO, visit their website. You’ll find interesting videos and links to publications, plus ways to donate.

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

I’ve just come across a really interesting project that I think we can all get behind: tuberculosis-sniffing rats.

It started with land mines. In many war-torn regions in Africa, people cannot access their land for agriculture because it is riddled with mines left over from previous conflicts. Bart Weetjens, a Belgian product development engineer with some experience of the difficulties of living in rural Africa, came across American experiments from the 1970s using gerbils to sniff out explosives. This inspired him to look into using rats to sniff out land mines. In 1997, he founded a nonprofit called Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) and received funding from the Belgian government to pursue his research.

Weetjens settled on using African giant pouch rats to sniff out land mines. The rats were inexpensive, intelligent, plentiful, sociable, trainable, and, most importantly, light enough to not set the land mines off. In 2003, they first tested the rats on real fields with real land mines in Mozambique. Now, they’ve received the backing of international peace agencies and have, to date, rendered safe 2.5 million square-meters of land area in Mozambique, effectively returning 100,000 people to their lands.

Given the success of this project, and the prevalence of pulmonary tuberculosis (TB) in the same communities affected by land mines, Weetjens thought of expanding the project into detection of tuberculosis from sputum samples. The premise is that Mycobacterium tuberculosis emits volatile organic compounds that the rats, with more genetic material dedicated to olfaction than any other mammal, might be able to detect.

It’s a fascinating demonstration of the intersection between science fiction and reality. You have to watch the videos to believe it, but the organization has trained several dozen rats in Tanzania and Mozambique to sniff out TB. It takes the rats 20 msec to sniff out and correctly identify a sample. The rats are able to process in 7 minutes the number of samples that a lab technician (or a lab "rat," if you will) would take a day to process using conventional light microscopy methods. In Dar es Salaam, using samples from more than 10,500 people from five hospitals, they increased the case detection rate by 44% over that of conventional microscopy. This method has a sensitivity of about 85% and a specificity of 90% – about the same rates as a 10-mm positive tuberculin test (Am. J. Trop. Med. Hyg. 2010;83:1308-10). It is even able to distinguish between M. tuberculosis and other mycobacterial species.

According to the World Health Organization, people with active tuberculosis can spread the disease to 10-15 close contacts in a year. WHO also says that TB is the second biggest infectious killer (behind HIV) worldwide, with over 1.3 million deaths in 2012. If these rats can really detect patients with TB at a much higher rate and with a greater sensitivity than standard microscopy, imagine the impact they would have on reducing the number of deaths worldwide from TB, especially in African nations where TB and HIV often co-occur, and access to health care is difficult.

APOPO’s project is a wonderful example of how simple innovations in science can have such a large footprint on global health. If you’re interested in learning more about APOPO, visit their website. You’ll find interesting videos and links to publications, plus ways to donate.

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

I’ve just come across a really interesting project that I think we can all get behind: tuberculosis-sniffing rats.

It started with land mines. In many war-torn regions in Africa, people cannot access their land for agriculture because it is riddled with mines left over from previous conflicts. Bart Weetjens, a Belgian product development engineer with some experience of the difficulties of living in rural Africa, came across American experiments from the 1970s using gerbils to sniff out explosives. This inspired him to look into using rats to sniff out land mines. In 1997, he founded a nonprofit called Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) and received funding from the Belgian government to pursue his research.

Weetjens settled on using African giant pouch rats to sniff out land mines. The rats were inexpensive, intelligent, plentiful, sociable, trainable, and, most importantly, light enough to not set the land mines off. In 2003, they first tested the rats on real fields with real land mines in Mozambique. Now, they’ve received the backing of international peace agencies and have, to date, rendered safe 2.5 million square-meters of land area in Mozambique, effectively returning 100,000 people to their lands.

Given the success of this project, and the prevalence of pulmonary tuberculosis (TB) in the same communities affected by land mines, Weetjens thought of expanding the project into detection of tuberculosis from sputum samples. The premise is that Mycobacterium tuberculosis emits volatile organic compounds that the rats, with more genetic material dedicated to olfaction than any other mammal, might be able to detect.

It’s a fascinating demonstration of the intersection between science fiction and reality. You have to watch the videos to believe it, but the organization has trained several dozen rats in Tanzania and Mozambique to sniff out TB. It takes the rats 20 msec to sniff out and correctly identify a sample. The rats are able to process in 7 minutes the number of samples that a lab technician (or a lab "rat," if you will) would take a day to process using conventional light microscopy methods. In Dar es Salaam, using samples from more than 10,500 people from five hospitals, they increased the case detection rate by 44% over that of conventional microscopy. This method has a sensitivity of about 85% and a specificity of 90% – about the same rates as a 10-mm positive tuberculin test (Am. J. Trop. Med. Hyg. 2010;83:1308-10). It is even able to distinguish between M. tuberculosis and other mycobacterial species.

According to the World Health Organization, people with active tuberculosis can spread the disease to 10-15 close contacts in a year. WHO also says that TB is the second biggest infectious killer (behind HIV) worldwide, with over 1.3 million deaths in 2012. If these rats can really detect patients with TB at a much higher rate and with a greater sensitivity than standard microscopy, imagine the impact they would have on reducing the number of deaths worldwide from TB, especially in African nations where TB and HIV often co-occur, and access to health care is difficult.

APOPO’s project is a wonderful example of how simple innovations in science can have such a large footprint on global health. If you’re interested in learning more about APOPO, visit their website. You’ll find interesting videos and links to publications, plus ways to donate.

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

The Town Hall Meeting held at the Annual Meeting of the American College of Surgeons in Washington, DC, on Oct. 8, entitled, "Introspection – the Next Surgical Time-Out," was cochaired by Geoffrey Dunn, M.D., FACS, and Ann Mosenthal, M.D., FACS, with panelists Dan Hinshaw, M.D., FACS, and David Page, M.D., FACS.

Well-attended, the discussion raised specific issues that addressed the growing need for surgeons to care for themselves in a sometimes chaotic and hostile practice environment. Given a reported 30%-40% burnout rate among surgeons, it was felt prudent to explore a side of the surgical personality too often resistant to self-examination. And like scheduled time-outs before starting a case in the OR, it was felt that a personal time-out before diving into the next procedure or busy office session might blunt the frustration born of time constraints and excessive documentation demands piling up on surgical practitioners of all stripes.

For example, an attendee raised the issue of humanizing the otherwise sterile EHR with personal patient information, perhaps insights about the interior life of the patient unrelated to the diagnosis. Another attendee addressed the need for surgeons to model compassion as well as their reactions to grief for learners at all levels. The notion of using videos to teach introspection was raised and discussed, as was the technique of "reflective" or free (uninhibited) writing and journaling as methods for probing one’s inner landscape and deeper feelings and emotions.

The panel addressed the paradox all surgeons face: the need to confront with objectivity organic surgical disease in all of its anatomic-pathologic complexity, employ technical skills in a time-compressed stressful operating room, interact with other caregivers involved in employing complex technology, and then step away from the operative field and become transformed into a compassionate physician. It is fitting that surgeons understand that draping a patient is both a requirement of sterile technique as well as a metaphorical "hiding of the humanity on the table" in order to shift gears and become engrossed "in the moment," to become focused on the mechanical tasks of cure and not distracted by emotional issues.

What challenges the surgeon in ways he or she may not have anticipated is the act of undraping a wounded human who now needs the surgeon’s empathetic attention as the blood stops flowing. Only self-reflection and a consideration of the profound challenges of these diametrically opposed sides of the surgical personality will sustain surgeons through endless daily lists of complex operations and their associated political, cultural, and psychological burdens. And when cure is no longer possible, confrontation with the patient’s imminent demise too often echoes the confrontation between the surgeon and his or her self-image of invincibility.

Also discussed were two recent changes in the matrix of modern surgical practice that were thought to positively shift the traditional image of surgeons as action hero with relative insensitivity to their patients’ suffering. These features include the minimally invasive surgery revolution which transformed the surgeon from blood-splattered aggressor to a delicate-handed laparoscopic wizard capable of heretofore unseen indirect motor skills maneuvers, a quiet ectomorphic individual rather than the traditional mesomorphic "linebacker" persona. The second change is the rise of women in surgery. Once derided, discouraged, and humiliated at every turn, women are now a valued cohort of colleagues whose innate caregiving skills are matched by an admirable and unflinching work ethic. Introspection seems more natural for women, something the macho surgical male ought to learn from.

Finally, introspection was seen to be somewhat like the "second effect" in opioid administration (hastening death is justifiable if the intent is to reduce suffering, not to cause death). Because although the intent of introspection is ultimately to improve the care of our patients, an unforeseen consequence of introspection may center on the arrival of profound insight into the meaning of the surgeon’s own life.

The potential role of artistic expression by surgeons such as painting or creative writing was entertained and will be further explored in a similar format at next year’s ACS meeting in San Francisco.

Dr. Page is professor of surgery at Tufts University School of Medicine, Boston, and director of Undergraduate Programs in the department of surgery, Baystate Medical Center, Springfield, Mass.

The Town Hall Meeting held at the Annual Meeting of the American College of Surgeons in Washington, DC, on Oct. 8, entitled, "Introspection – the Next Surgical Time-Out," was cochaired by Geoffrey Dunn, M.D., FACS, and Ann Mosenthal, M.D., FACS, with panelists Dan Hinshaw, M.D., FACS, and David Page, M.D., FACS.

Well-attended, the discussion raised specific issues that addressed the growing need for surgeons to care for themselves in a sometimes chaotic and hostile practice environment. Given a reported 30%-40% burnout rate among surgeons, it was felt prudent to explore a side of the surgical personality too often resistant to self-examination. And like scheduled time-outs before starting a case in the OR, it was felt that a personal time-out before diving into the next procedure or busy office session might blunt the frustration born of time constraints and excessive documentation demands piling up on surgical practitioners of all stripes.

For example, an attendee raised the issue of humanizing the otherwise sterile EHR with personal patient information, perhaps insights about the interior life of the patient unrelated to the diagnosis. Another attendee addressed the need for surgeons to model compassion as well as their reactions to grief for learners at all levels. The notion of using videos to teach introspection was raised and discussed, as was the technique of "reflective" or free (uninhibited) writing and journaling as methods for probing one’s inner landscape and deeper feelings and emotions.

The panel addressed the paradox all surgeons face: the need to confront with objectivity organic surgical disease in all of its anatomic-pathologic complexity, employ technical skills in a time-compressed stressful operating room, interact with other caregivers involved in employing complex technology, and then step away from the operative field and become transformed into a compassionate physician. It is fitting that surgeons understand that draping a patient is both a requirement of sterile technique as well as a metaphorical "hiding of the humanity on the table" in order to shift gears and become engrossed "in the moment," to become focused on the mechanical tasks of cure and not distracted by emotional issues.

What challenges the surgeon in ways he or she may not have anticipated is the act of undraping a wounded human who now needs the surgeon’s empathetic attention as the blood stops flowing. Only self-reflection and a consideration of the profound challenges of these diametrically opposed sides of the surgical personality will sustain surgeons through endless daily lists of complex operations and their associated political, cultural, and psychological burdens. And when cure is no longer possible, confrontation with the patient’s imminent demise too often echoes the confrontation between the surgeon and his or her self-image of invincibility.

Also discussed were two recent changes in the matrix of modern surgical practice that were thought to positively shift the traditional image of surgeons as action hero with relative insensitivity to their patients’ suffering. These features include the minimally invasive surgery revolution which transformed the surgeon from blood-splattered aggressor to a delicate-handed laparoscopic wizard capable of heretofore unseen indirect motor skills maneuvers, a quiet ectomorphic individual rather than the traditional mesomorphic "linebacker" persona. The second change is the rise of women in surgery. Once derided, discouraged, and humiliated at every turn, women are now a valued cohort of colleagues whose innate caregiving skills are matched by an admirable and unflinching work ethic. Introspection seems more natural for women, something the macho surgical male ought to learn from.

Finally, introspection was seen to be somewhat like the "second effect" in opioid administration (hastening death is justifiable if the intent is to reduce suffering, not to cause death). Because although the intent of introspection is ultimately to improve the care of our patients, an unforeseen consequence of introspection may center on the arrival of profound insight into the meaning of the surgeon’s own life.

The potential role of artistic expression by surgeons such as painting or creative writing was entertained and will be further explored in a similar format at next year’s ACS meeting in San Francisco.

Dr. Page is professor of surgery at Tufts University School of Medicine, Boston, and director of Undergraduate Programs in the department of surgery, Baystate Medical Center, Springfield, Mass.

The Town Hall Meeting held at the Annual Meeting of the American College of Surgeons in Washington, DC, on Oct. 8, entitled, "Introspection – the Next Surgical Time-Out," was cochaired by Geoffrey Dunn, M.D., FACS, and Ann Mosenthal, M.D., FACS, with panelists Dan Hinshaw, M.D., FACS, and David Page, M.D., FACS.

Well-attended, the discussion raised specific issues that addressed the growing need for surgeons to care for themselves in a sometimes chaotic and hostile practice environment. Given a reported 30%-40% burnout rate among surgeons, it was felt prudent to explore a side of the surgical personality too often resistant to self-examination. And like scheduled time-outs before starting a case in the OR, it was felt that a personal time-out before diving into the next procedure or busy office session might blunt the frustration born of time constraints and excessive documentation demands piling up on surgical practitioners of all stripes.

For example, an attendee raised the issue of humanizing the otherwise sterile EHR with personal patient information, perhaps insights about the interior life of the patient unrelated to the diagnosis. Another attendee addressed the need for surgeons to model compassion as well as their reactions to grief for learners at all levels. The notion of using videos to teach introspection was raised and discussed, as was the technique of "reflective" or free (uninhibited) writing and journaling as methods for probing one’s inner landscape and deeper feelings and emotions.

The panel addressed the paradox all surgeons face: the need to confront with objectivity organic surgical disease in all of its anatomic-pathologic complexity, employ technical skills in a time-compressed stressful operating room, interact with other caregivers involved in employing complex technology, and then step away from the operative field and become transformed into a compassionate physician. It is fitting that surgeons understand that draping a patient is both a requirement of sterile technique as well as a metaphorical "hiding of the humanity on the table" in order to shift gears and become engrossed "in the moment," to become focused on the mechanical tasks of cure and not distracted by emotional issues.

What challenges the surgeon in ways he or she may not have anticipated is the act of undraping a wounded human who now needs the surgeon’s empathetic attention as the blood stops flowing. Only self-reflection and a consideration of the profound challenges of these diametrically opposed sides of the surgical personality will sustain surgeons through endless daily lists of complex operations and their associated political, cultural, and psychological burdens. And when cure is no longer possible, confrontation with the patient’s imminent demise too often echoes the confrontation between the surgeon and his or her self-image of invincibility.

Also discussed were two recent changes in the matrix of modern surgical practice that were thought to positively shift the traditional image of surgeons as action hero with relative insensitivity to their patients’ suffering. These features include the minimally invasive surgery revolution which transformed the surgeon from blood-splattered aggressor to a delicate-handed laparoscopic wizard capable of heretofore unseen indirect motor skills maneuvers, a quiet ectomorphic individual rather than the traditional mesomorphic "linebacker" persona. The second change is the rise of women in surgery. Once derided, discouraged, and humiliated at every turn, women are now a valued cohort of colleagues whose innate caregiving skills are matched by an admirable and unflinching work ethic. Introspection seems more natural for women, something the macho surgical male ought to learn from.

Finally, introspection was seen to be somewhat like the "second effect" in opioid administration (hastening death is justifiable if the intent is to reduce suffering, not to cause death). Because although the intent of introspection is ultimately to improve the care of our patients, an unforeseen consequence of introspection may center on the arrival of profound insight into the meaning of the surgeon’s own life.

The potential role of artistic expression by surgeons such as painting or creative writing was entertained and will be further explored in a similar format at next year’s ACS meeting in San Francisco.

Dr. Page is professor of surgery at Tufts University School of Medicine, Boston, and director of Undergraduate Programs in the department of surgery, Baystate Medical Center, Springfield, Mass.

Lab mice

Credit: Aaron Logan

A small molecule targeting sphingosine kinase (SPHK) demonstrates considerable activity against virus-associated lymphoma, according to preclinical research published in Molecular Cancer Therapeutics.

The research focused on primary effusion lymphoma (PEL), a variant of diffuse large B-cell lymphoma etiologically linked to Kaposi’s sarcoma-associated herpesvirus (KSHV).

Investigators found that SPHK generates biologically active sphingolipids that keep PEL cells alive.

“It is still early in our understanding of how these special lipids contribute to viral cancers, but this is a major potential advance,” said senior study author Christopher Parsons, MD, of Louisiana State University Health Sciences Center in New Orleans.

“There are no therapies available to fight viral tumors by selectively blocking these pathways, all while not harming normal, uninfected cells.”

So the researchers decided to test ABC294640, a novel small molecule that selectively targets SPHK, in cells from PEL patients and mouse models of PEL.

ABC294640 induced dose-dependent apoptosis in a number of KSHV⁺ PEL cell lines: KSHV⁺/EBV^- BCBL-1 cells, KSHV⁺/EBV⁺ BC-1 cells, KSHV⁺/EBV^- BC-3 cells, and KSHV⁺/EBV^- BCP-1 cells. But the drug showed little to no activity in KSHV^-/EBV^- BL-41 cells.

Further analyses revealed that ABC294640 induces apoptosis through suppression of KSHV-associated signal transduction.

The investigators observed dose-dependent suppression of ERK, Akt, and NF-kB p65 phosphorylation, as well as cleavage of caspase-3 and caspase-9, in BCBL-1 cells exposed to the drug. But the same effects did not occur in drug-resistant BL-41 cells.

Overexpression of either ERK or p65 in BCBL-1 cells partially suppressed apoptosis induced by ABC294640. And when the researchers used RNAi to target SPHK2, PEL cells exhibited reduced activation of ERK, Akt, and p65 phosphorylation, as well as a 5- to 6-fold increase in apoptosis.

Additionally, the team found that ABC294640 suppressed PEL progression and induced regression of PEL tumors in vivo.

The investigators injected BCL-1 cells into NOD/SCID mice and observed PEL expansion within 3 to 4 weeks. However, when they administered ABC294640 within 24 hours of PEL cell injections, they observed significant reductions in tumor expansion.

The researchers also evaluated ABC294640 activity after PEL tumors had been established. And treated mice showed significant tumor regression compared to untreated mice.

The investigators said these results suggest ABC294640 should be evaluated in clinical trials of KSHV-associated lymphoma.

“Our research thus far indicates that this molecule is safe, with the potential to stand alone as a single, orally administered drug,” Dr Parsons said.

Lab mice

Credit: Aaron Logan

A small molecule targeting sphingosine kinase (SPHK) demonstrates considerable activity against virus-associated lymphoma, according to preclinical research published in Molecular Cancer Therapeutics.

The research focused on primary effusion lymphoma (PEL), a variant of diffuse large B-cell lymphoma etiologically linked to Kaposi’s sarcoma-associated herpesvirus (KSHV).

Investigators found that SPHK generates biologically active sphingolipids that keep PEL cells alive.

“It is still early in our understanding of how these special lipids contribute to viral cancers, but this is a major potential advance,” said senior study author Christopher Parsons, MD, of Louisiana State University Health Sciences Center in New Orleans.

“There are no therapies available to fight viral tumors by selectively blocking these pathways, all while not harming normal, uninfected cells.”

So the researchers decided to test ABC294640, a novel small molecule that selectively targets SPHK, in cells from PEL patients and mouse models of PEL.

ABC294640 induced dose-dependent apoptosis in a number of KSHV⁺ PEL cell lines: KSHV⁺/EBV^- BCBL-1 cells, KSHV⁺/EBV⁺ BC-1 cells, KSHV⁺/EBV^- BC-3 cells, and KSHV⁺/EBV^- BCP-1 cells. But the drug showed little to no activity in KSHV^-/EBV^- BL-41 cells.

Further analyses revealed that ABC294640 induces apoptosis through suppression of KSHV-associated signal transduction.

The investigators observed dose-dependent suppression of ERK, Akt, and NF-kB p65 phosphorylation, as well as cleavage of caspase-3 and caspase-9, in BCBL-1 cells exposed to the drug. But the same effects did not occur in drug-resistant BL-41 cells.

Overexpression of either ERK or p65 in BCBL-1 cells partially suppressed apoptosis induced by ABC294640. And when the researchers used RNAi to target SPHK2, PEL cells exhibited reduced activation of ERK, Akt, and p65 phosphorylation, as well as a 5- to 6-fold increase in apoptosis.

Additionally, the team found that ABC294640 suppressed PEL progression and induced regression of PEL tumors in vivo.

The investigators injected BCL-1 cells into NOD/SCID mice and observed PEL expansion within 3 to 4 weeks. However, when they administered ABC294640 within 24 hours of PEL cell injections, they observed significant reductions in tumor expansion.

The researchers also evaluated ABC294640 activity after PEL tumors had been established. And treated mice showed significant tumor regression compared to untreated mice.

The investigators said these results suggest ABC294640 should be evaluated in clinical trials of KSHV-associated lymphoma.

“Our research thus far indicates that this molecule is safe, with the potential to stand alone as a single, orally administered drug,” Dr Parsons said.

Lab mice

Credit: Aaron Logan

A small molecule targeting sphingosine kinase (SPHK) demonstrates considerable activity against virus-associated lymphoma, according to preclinical research published in Molecular Cancer Therapeutics.

The research focused on primary effusion lymphoma (PEL), a variant of diffuse large B-cell lymphoma etiologically linked to Kaposi’s sarcoma-associated herpesvirus (KSHV).

Investigators found that SPHK generates biologically active sphingolipids that keep PEL cells alive.

“It is still early in our understanding of how these special lipids contribute to viral cancers, but this is a major potential advance,” said senior study author Christopher Parsons, MD, of Louisiana State University Health Sciences Center in New Orleans.

“There are no therapies available to fight viral tumors by selectively blocking these pathways, all while not harming normal, uninfected cells.”

So the researchers decided to test ABC294640, a novel small molecule that selectively targets SPHK, in cells from PEL patients and mouse models of PEL.

ABC294640 induced dose-dependent apoptosis in a number of KSHV⁺ PEL cell lines: KSHV⁺/EBV^- BCBL-1 cells, KSHV⁺/EBV⁺ BC-1 cells, KSHV⁺/EBV^- BC-3 cells, and KSHV⁺/EBV^- BCP-1 cells. But the drug showed little to no activity in KSHV^-/EBV^- BL-41 cells.

Further analyses revealed that ABC294640 induces apoptosis through suppression of KSHV-associated signal transduction.

The investigators observed dose-dependent suppression of ERK, Akt, and NF-kB p65 phosphorylation, as well as cleavage of caspase-3 and caspase-9, in BCBL-1 cells exposed to the drug. But the same effects did not occur in drug-resistant BL-41 cells.

Overexpression of either ERK or p65 in BCBL-1 cells partially suppressed apoptosis induced by ABC294640. And when the researchers used RNAi to target SPHK2, PEL cells exhibited reduced activation of ERK, Akt, and p65 phosphorylation, as well as a 5- to 6-fold increase in apoptosis.

Additionally, the team found that ABC294640 suppressed PEL progression and induced regression of PEL tumors in vivo.

The investigators injected BCL-1 cells into NOD/SCID mice and observed PEL expansion within 3 to 4 weeks. However, when they administered ABC294640 within 24 hours of PEL cell injections, they observed significant reductions in tumor expansion.

The researchers also evaluated ABC294640 activity after PEL tumors had been established. And treated mice showed significant tumor regression compared to untreated mice.

The investigators said these results suggest ABC294640 should be evaluated in clinical trials of KSHV-associated lymphoma.

“Our research thus far indicates that this molecule is safe, with the potential to stand alone as a single, orally administered drug,” Dr Parsons said.

APL cells in the bone marrow

Credit: The Armed Forces

Institute of Pathology

Results of a new study appear to explain how retinoic acid and arsenic trioxide work against acute promyelocytic leukemia (APL).

Researchers found that retinoic acid, either alone or in combination with arsenic trioxide, causes a cascade of molecular events that lead to cellular senescence.

And this halts APL-initiating activity in patient samples and mouse models of the disease.

The team said this mechanism could be activated to fight malignancies other than APL as well.

Hugues de Thé, MD, PhD, of Université Paris Diderot in France, and his colleagues described this research in Nature Medicine.

The group knew that APL is driven by the promyelocytic leukemia-retinoic acid receptor fusion protein (PML-RARA), which interferes with nuclear receptor signaling and PML nuclear body assembly.

Furthermore, APL can be cured by retinoic acid and arsenic trioxide (alone or in combination), both of which trigger PML-RARA degradation through non-overlapping pathways.

However, exactly how these treatments work in APL has been unclear. Dr de Thé’s research indicates that both drugs incite a cascade of events leading to senescence.

The researchers found evidence suggesting that a functional PML-transformation-related protein 53 (Trp53) axis is required to halt APL-initiating activity.

When retinoic acid induces PML-RARA degradation, normal PML elicits nuclear body reformation and prompts a Trp53 response that exhibits features of senescence. And this halts APL-initiating activity.

In addition, normal PML seems to play a role in the synergy between retinoic acid and arsenic trioxide. The researchers discovered that arsenic increases retinoic acid-induced PML-RARA degradation.

But arsenic also appears to cooperate with retinoic acid to cure APL by binding PML, accelerating nuclear body reformation, and enhancing downstream TP53 signaling.

The researchers said it seems likely that the same PML/p53 pathway can be activated in cancers other than PML as well.

APL cells in the bone marrow

Credit: The Armed Forces

Institute of Pathology

Results of a new study appear to explain how retinoic acid and arsenic trioxide work against acute promyelocytic leukemia (APL).

Researchers found that retinoic acid, either alone or in combination with arsenic trioxide, causes a cascade of molecular events that lead to cellular senescence.

And this halts APL-initiating activity in patient samples and mouse models of the disease.

The team said this mechanism could be activated to fight malignancies other than APL as well.

Hugues de Thé, MD, PhD, of Université Paris Diderot in France, and his colleagues described this research in Nature Medicine.

The group knew that APL is driven by the promyelocytic leukemia-retinoic acid receptor fusion protein (PML-RARA), which interferes with nuclear receptor signaling and PML nuclear body assembly.

Furthermore, APL can be cured by retinoic acid and arsenic trioxide (alone or in combination), both of which trigger PML-RARA degradation through non-overlapping pathways.

However, exactly how these treatments work in APL has been unclear. Dr de Thé’s research indicates that both drugs incite a cascade of events leading to senescence.

The researchers found evidence suggesting that a functional PML-transformation-related protein 53 (Trp53) axis is required to halt APL-initiating activity.

When retinoic acid induces PML-RARA degradation, normal PML elicits nuclear body reformation and prompts a Trp53 response that exhibits features of senescence. And this halts APL-initiating activity.

In addition, normal PML seems to play a role in the synergy between retinoic acid and arsenic trioxide. The researchers discovered that arsenic increases retinoic acid-induced PML-RARA degradation.

But arsenic also appears to cooperate with retinoic acid to cure APL by binding PML, accelerating nuclear body reformation, and enhancing downstream TP53 signaling.

The researchers said it seems likely that the same PML/p53 pathway can be activated in cancers other than PML as well.

APL cells in the bone marrow

Credit: The Armed Forces

Institute of Pathology

Results of a new study appear to explain how retinoic acid and arsenic trioxide work against acute promyelocytic leukemia (APL).

Researchers found that retinoic acid, either alone or in combination with arsenic trioxide, causes a cascade of molecular events that lead to cellular senescence.

And this halts APL-initiating activity in patient samples and mouse models of the disease.

The team said this mechanism could be activated to fight malignancies other than APL as well.

Hugues de Thé, MD, PhD, of Université Paris Diderot in France, and his colleagues described this research in Nature Medicine.

The group knew that APL is driven by the promyelocytic leukemia-retinoic acid receptor fusion protein (PML-RARA), which interferes with nuclear receptor signaling and PML nuclear body assembly.

Furthermore, APL can be cured by retinoic acid and arsenic trioxide (alone or in combination), both of which trigger PML-RARA degradation through non-overlapping pathways.

However, exactly how these treatments work in APL has been unclear. Dr de Thé’s research indicates that both drugs incite a cascade of events leading to senescence.

The researchers found evidence suggesting that a functional PML-transformation-related protein 53 (Trp53) axis is required to halt APL-initiating activity.

When retinoic acid induces PML-RARA degradation, normal PML elicits nuclear body reformation and prompts a Trp53 response that exhibits features of senescence. And this halts APL-initiating activity.

In addition, normal PML seems to play a role in the synergy between retinoic acid and arsenic trioxide. The researchers discovered that arsenic increases retinoic acid-induced PML-RARA degradation.

But arsenic also appears to cooperate with retinoic acid to cure APL by binding PML, accelerating nuclear body reformation, and enhancing downstream TP53 signaling.

The researchers said it seems likely that the same PML/p53 pathway can be activated in cancers other than PML as well.

The NCI-60 cell line U251

expressing NFAT3c-GFP

A little-studied chemical compound has “wide and potent” anticancer activity, investigators have reported in Cancer Cell.

The compound, BMH-21, works by inhibiting the RNA polymerase transcription pathway (Pol I), thereby preventing cancer cell communication and replication.

“Without this transcription machinery, cancer cells cannot function,” said study author Marikki Laiho, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

She and her colleagues homed in on BMH-21 by screening a library of chemical compounds thought to have potential for anticancer activity.

Specifically, the team looked at the compounds’ ability to interfere with transcription in the National Cancer Institute’s collection of 60 human tumor cell lines (known as NCI-60).

BMH-21 demonstrated activity against all 9 cancer types studied—leukemia and melanoma, as well as breast, CNS, colon, lung, ovarian, prostate, and renal cancers.

The drug also repressed tumor growth in mouse models of colon cancer and melanoma.

Additional analyses showed that BMH-21 inhibited Pol I transcription and caused disintegration of the nucleolus. The drug activated loss of the Pol I catalytic subunit RPA194, which led to disassembly of the Pol I holocomplex from the ribosomal DNA.

And the loss of RPA194, which was a result of increased proteasome-mediated turnover, was associated with decreased cancer cell viability.

Dr Laiho and her colleagues are continuing studies of BMH-21 in animal models to confirm the drug’s anticancer activity, identify any toxicities associated with the compound, and determine the optimal dose.

And because Pol I activity is frequently deregulated in cancers, the investigators believe BMH-21 could have therapeutic potential for many malignancies.

Dr Laiho is currently collaborating with experts in multiple myeloma, medullary thyroid cancer, and prostate cancer to explore the drug’s activity in these malignancies.

The NCI-60 cell line U251

expressing NFAT3c-GFP

A little-studied chemical compound has “wide and potent” anticancer activity, investigators have reported in Cancer Cell.

The compound, BMH-21, works by inhibiting the RNA polymerase transcription pathway (Pol I), thereby preventing cancer cell communication and replication.

“Without this transcription machinery, cancer cells cannot function,” said study author Marikki Laiho, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

She and her colleagues homed in on BMH-21 by screening a library of chemical compounds thought to have potential for anticancer activity.

Specifically, the team looked at the compounds’ ability to interfere with transcription in the National Cancer Institute’s collection of 60 human tumor cell lines (known as NCI-60).

BMH-21 demonstrated activity against all 9 cancer types studied—leukemia and melanoma, as well as breast, CNS, colon, lung, ovarian, prostate, and renal cancers.

The drug also repressed tumor growth in mouse models of colon cancer and melanoma.

Additional analyses showed that BMH-21 inhibited Pol I transcription and caused disintegration of the nucleolus. The drug activated loss of the Pol I catalytic subunit RPA194, which led to disassembly of the Pol I holocomplex from the ribosomal DNA.

And the loss of RPA194, which was a result of increased proteasome-mediated turnover, was associated with decreased cancer cell viability.

Dr Laiho and her colleagues are continuing studies of BMH-21 in animal models to confirm the drug’s anticancer activity, identify any toxicities associated with the compound, and determine the optimal dose.

And because Pol I activity is frequently deregulated in cancers, the investigators believe BMH-21 could have therapeutic potential for many malignancies.

Dr Laiho is currently collaborating with experts in multiple myeloma, medullary thyroid cancer, and prostate cancer to explore the drug’s activity in these malignancies.

The NCI-60 cell line U251

expressing NFAT3c-GFP

A little-studied chemical compound has “wide and potent” anticancer activity, investigators have reported in Cancer Cell.

The compound, BMH-21, works by inhibiting the RNA polymerase transcription pathway (Pol I), thereby preventing cancer cell communication and replication.

“Without this transcription machinery, cancer cells cannot function,” said study author Marikki Laiho, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

She and her colleagues homed in on BMH-21 by screening a library of chemical compounds thought to have potential for anticancer activity.

Specifically, the team looked at the compounds’ ability to interfere with transcription in the National Cancer Institute’s collection of 60 human tumor cell lines (known as NCI-60).

BMH-21 demonstrated activity against all 9 cancer types studied—leukemia and melanoma, as well as breast, CNS, colon, lung, ovarian, prostate, and renal cancers.

The drug also repressed tumor growth in mouse models of colon cancer and melanoma.

Additional analyses showed that BMH-21 inhibited Pol I transcription and caused disintegration of the nucleolus. The drug activated loss of the Pol I catalytic subunit RPA194, which led to disassembly of the Pol I holocomplex from the ribosomal DNA.

And the loss of RPA194, which was a result of increased proteasome-mediated turnover, was associated with decreased cancer cell viability.

Dr Laiho and her colleagues are continuing studies of BMH-21 in animal models to confirm the drug’s anticancer activity, identify any toxicities associated with the compound, and determine the optimal dose.

And because Pol I activity is frequently deregulated in cancers, the investigators believe BMH-21 could have therapeutic potential for many malignancies.

Dr Laiho is currently collaborating with experts in multiple myeloma, medullary thyroid cancer, and prostate cancer to explore the drug’s activity in these malignancies.