In the wake of the actor Philip Seymour Hoffman’s death, I’ve been thinking a lot about the movie Doubt. In it, Hoffman plays Father Brendan Flynn, a Catholic priest newly assigned to a parish in the Bronx. The school attached to the parish is run by the strict Sister Aloysius Beauvier, played by Meryl Streep. She is suspicious of the priest’s motives behind his befriending a boy, who happens to be the school’s only black student. The boy’s mother welcomes the friendship, as it provides shelter from his abusive father, and begs Sister Beauvier to leave things alone. But the nun doggedly pursues the issue, and in the end she succeeds in getting the priest removed from the parish.

Being relatively new to private practice, I constantly reflect on my methods. I have gotten the diagnosis wrong sometimes, and while I understand that this happens to even the most seasoned among us, when it happens to me, I cannot help but feel like an impostor, unqualified and incompetent. When I risk doing harm to a patient by giving them medications that may not work, I feel like curling up under the covers and not ever coming out. Steroids and chronic immunosuppression don’t exactly inspire confidence. It does not help that rheumatology isn’t the most exact of specialties and the diseases that we diagnose and treat are nebulous by nature.

Therefore, I would venture to say that rheumatologists are probably more comfortable with ambiguity than most other specialists. That’s not easy for a scientist to say; the object of science, after all, is to find answers. Certitude is comforting. Patients expect that from us, and we do our best to provide it. But it is not always possible through no fault of our own, but as a limitation of the field itself. In such situations, it can be very humbling to acknowledge that there are gaps in our knowledge.

I am learning to be comfortable with saying, "I don’t know. I need help. I cannot figure this out on my own." If I do not allow myself to question my judgment, I run the risk of harming this person who trusts me implicitly. Humility and certitude are, in our imperfect science, two sides of the same patient care coin that can spell the difference in a patient’s outcome.

After all, questioning is integral to the pursuit of knowledge. Great science is not possible without curiosity. The philosopher Simon Critchley says that "knowledge is precise, but that precision is confined within a certain toleration of uncertainty." Therefore, just as there is comfort in certitude, there is also some comfort in doubt.

At the end of the movie, we are left wondering if Father Flynn is guilty of abusing the young boy. But we’re not meant to know. In fact, the cast, except for Hoffman, did not know either. Not knowing is the point. We are meant to examine our attitudes toward conviction, toward truth, to the extent that it is limited by what is knowable. As Father Flynn in the movie says: "Doubt can be a bond as powerful and sustaining as certainty. When you are lost, you are not alone."

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

In the wake of the actor Philip Seymour Hoffman’s death, I’ve been thinking a lot about the movie Doubt. In it, Hoffman plays Father Brendan Flynn, a Catholic priest newly assigned to a parish in the Bronx. The school attached to the parish is run by the strict Sister Aloysius Beauvier, played by Meryl Streep. She is suspicious of the priest’s motives behind his befriending a boy, who happens to be the school’s only black student. The boy’s mother welcomes the friendship, as it provides shelter from his abusive father, and begs Sister Beauvier to leave things alone. But the nun doggedly pursues the issue, and in the end she succeeds in getting the priest removed from the parish.

Being relatively new to private practice, I constantly reflect on my methods. I have gotten the diagnosis wrong sometimes, and while I understand that this happens to even the most seasoned among us, when it happens to me, I cannot help but feel like an impostor, unqualified and incompetent. When I risk doing harm to a patient by giving them medications that may not work, I feel like curling up under the covers and not ever coming out. Steroids and chronic immunosuppression don’t exactly inspire confidence. It does not help that rheumatology isn’t the most exact of specialties and the diseases that we diagnose and treat are nebulous by nature.

Therefore, I would venture to say that rheumatologists are probably more comfortable with ambiguity than most other specialists. That’s not easy for a scientist to say; the object of science, after all, is to find answers. Certitude is comforting. Patients expect that from us, and we do our best to provide it. But it is not always possible through no fault of our own, but as a limitation of the field itself. In such situations, it can be very humbling to acknowledge that there are gaps in our knowledge.

I am learning to be comfortable with saying, "I don’t know. I need help. I cannot figure this out on my own." If I do not allow myself to question my judgment, I run the risk of harming this person who trusts me implicitly. Humility and certitude are, in our imperfect science, two sides of the same patient care coin that can spell the difference in a patient’s outcome.

After all, questioning is integral to the pursuit of knowledge. Great science is not possible without curiosity. The philosopher Simon Critchley says that "knowledge is precise, but that precision is confined within a certain toleration of uncertainty." Therefore, just as there is comfort in certitude, there is also some comfort in doubt.

At the end of the movie, we are left wondering if Father Flynn is guilty of abusing the young boy. But we’re not meant to know. In fact, the cast, except for Hoffman, did not know either. Not knowing is the point. We are meant to examine our attitudes toward conviction, toward truth, to the extent that it is limited by what is knowable. As Father Flynn in the movie says: "Doubt can be a bond as powerful and sustaining as certainty. When you are lost, you are not alone."

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

In the wake of the actor Philip Seymour Hoffman’s death, I’ve been thinking a lot about the movie Doubt. In it, Hoffman plays Father Brendan Flynn, a Catholic priest newly assigned to a parish in the Bronx. The school attached to the parish is run by the strict Sister Aloysius Beauvier, played by Meryl Streep. She is suspicious of the priest’s motives behind his befriending a boy, who happens to be the school’s only black student. The boy’s mother welcomes the friendship, as it provides shelter from his abusive father, and begs Sister Beauvier to leave things alone. But the nun doggedly pursues the issue, and in the end she succeeds in getting the priest removed from the parish.

Being relatively new to private practice, I constantly reflect on my methods. I have gotten the diagnosis wrong sometimes, and while I understand that this happens to even the most seasoned among us, when it happens to me, I cannot help but feel like an impostor, unqualified and incompetent. When I risk doing harm to a patient by giving them medications that may not work, I feel like curling up under the covers and not ever coming out. Steroids and chronic immunosuppression don’t exactly inspire confidence. It does not help that rheumatology isn’t the most exact of specialties and the diseases that we diagnose and treat are nebulous by nature.

Therefore, I would venture to say that rheumatologists are probably more comfortable with ambiguity than most other specialists. That’s not easy for a scientist to say; the object of science, after all, is to find answers. Certitude is comforting. Patients expect that from us, and we do our best to provide it. But it is not always possible through no fault of our own, but as a limitation of the field itself. In such situations, it can be very humbling to acknowledge that there are gaps in our knowledge.

I am learning to be comfortable with saying, "I don’t know. I need help. I cannot figure this out on my own." If I do not allow myself to question my judgment, I run the risk of harming this person who trusts me implicitly. Humility and certitude are, in our imperfect science, two sides of the same patient care coin that can spell the difference in a patient’s outcome.

After all, questioning is integral to the pursuit of knowledge. Great science is not possible without curiosity. The philosopher Simon Critchley says that "knowledge is precise, but that precision is confined within a certain toleration of uncertainty." Therefore, just as there is comfort in certitude, there is also some comfort in doubt.

At the end of the movie, we are left wondering if Father Flynn is guilty of abusing the young boy. But we’re not meant to know. In fact, the cast, except for Hoffman, did not know either. Not knowing is the point. We are meant to examine our attitudes toward conviction, toward truth, to the extent that it is limited by what is knowable. As Father Flynn in the movie says: "Doubt can be a bond as powerful and sustaining as certainty. When you are lost, you are not alone."

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

1. Which of the following suture properties is most responsible for accommodation of edema postoperatively?

a. memory
b. plasticity
c. pliability
d. size
e. stretching

2. Which of the following has the highest memory?

a. coated polyester (Ethibond Excel)
b. poliglecaprone 25 (Monocryl)
c. polyglactin 910 (Vicryl)
d. silk
e. stainless steel

3. The most worrisome consequence of capillarity is:

a. increased potential of translocation of bacterium in a wound
b. increased reactivity
c. increased spitting of suture
d. increased wound edema
e. decreased tensile strength

4. Which of the following would be an excellent choice for closing the mucosal surface on an Abbe flap repair?

a. 2-octyl cyanoacrylate (Dermabond Advanced)
b. 5-0 chromic gut
c. 5-0 coated polyester (Ethibond Excel)
d. 5-0 polybutester (Novafil)
e. polypropylene (Prolene)

5. Knot security is thought to be most directly related to which property of suture:

a. coefficient of friction
b. configuration
c. memory
d. size
e. tensile strength

1. Which of the following suture properties is most responsible for accommodation of edema postoperatively?

a. memory
b. plasticity
c. pliability
d. size
e. stretching

2. Which of the following has the highest memory?

a. coated polyester (Ethibond Excel)
b. poliglecaprone 25 (Monocryl)
c. polyglactin 910 (Vicryl)
d. silk
e. stainless steel

3. The most worrisome consequence of capillarity is:

a. increased potential of translocation of bacterium in a wound
b. increased reactivity
c. increased spitting of suture
d. increased wound edema
e. decreased tensile strength

4. Which of the following would be an excellent choice for closing the mucosal surface on an Abbe flap repair?

a. 2-octyl cyanoacrylate (Dermabond Advanced)
b. 5-0 chromic gut
c. 5-0 coated polyester (Ethibond Excel)
d. 5-0 polybutester (Novafil)
e. polypropylene (Prolene)

5. Knot security is thought to be most directly related to which property of suture:

a. coefficient of friction
b. configuration
c. memory
d. size
e. tensile strength

1. Which of the following suture properties is most responsible for accommodation of edema postoperatively?

a. memory
b. plasticity
c. pliability
d. size
e. stretching

2. Which of the following has the highest memory?

a. coated polyester (Ethibond Excel)
b. poliglecaprone 25 (Monocryl)
c. polyglactin 910 (Vicryl)
d. silk
e. stainless steel

3. The most worrisome consequence of capillarity is:

a. increased potential of translocation of bacterium in a wound
b. increased reactivity
c. increased spitting of suture
d. increased wound edema
e. decreased tensile strength

4. Which of the following would be an excellent choice for closing the mucosal surface on an Abbe flap repair?

a. 2-octyl cyanoacrylate (Dermabond Advanced)
b. 5-0 chromic gut
c. 5-0 coated polyester (Ethibond Excel)
d. 5-0 polybutester (Novafil)
e. polypropylene (Prolene)

5. Knot security is thought to be most directly related to which property of suture:

a. coefficient of friction
b. configuration
c. memory
d. size
e. tensile strength

The risk of amputation and death appears to increase as the number of revascularization procedures increases, according to findings from a retrospective analysis of data.

The amputation risk was present among patients who underwent percutaneous transluminal angioplasty (PTA) only, as well as among subsets of patients who underwent lower extremity bypass (LEB) only, reported Dr. Alexander T. Hawkins of the Center for Surgery and Public Health, Boston, and his colleagues.

Among 11,190 patients with critical limb ischemia who underwent one, two, three, four, or five or more revascularization procedures, the 1-year estimated amputation rates were 23.3%, 27.1%, 30.3%, 26.7%, and 28.6%, and the 1-year estimated mortality rates were 18.7%, 21.1%, 26.3%, 23.6%, and 32.1%, respectively, the investigators reported. The findings were published in the January issue of Annals of Vascular Surgery.

The risk of amputation increased significantly for those with two vs. one revascularization procedure (hazard ratio, 1.22) and for those with three vs. two procedures (HR, 1.33). The risk for death at one year also increased significantly among those with two vs. one procedure (HR, 1.18) (Ann. Vasc. Surg. 2014;28:35-47).

Similar trends for amputation were seen in the PTA-only (1: 24.5%; 2: 26.1%; 3: 27.9%; 4: 31.3%; 5+: 26.8%), and LEB-only (1: 26.0%; 2: 32.5%; 3+: 45.5%) groups. "The increases did not appear to be exponential," they noted.

No changes were seen in the PTA-only and LEB-only groups with respect to 1-year estimates of in-hospital death.

A subgroup analysis further showed that timing between procedures was significantly associated with 1-year amputation risk; the risk was 27.2% for a 1-7 day interval, 36.4% for 8 days to 1 month, 19.4% for 1-6 months; and 22.2% for 6 months or more.

"There was also a difference in 1-year amputation rates between bypass patients who underwent bypass first and who underwent PTA followed by bypass" (21.8% vs. 30.7%), the researchers wrote.

Study subjects were adult patients with a mean age of 71 years who underwent revascularization between July 2007 and December 2009. The patients, including 6,225 men (55.9%), were identified from the California State Inpatient Database and had a high burden of comorbidities; 55.2% abused tobacco, 64.9% had coronary artery disease, 51.3% had hypertension, and 68% had diabetes.

Though limited by factors inherent in the use of an administrative database (such as potential inconsistencies in coding accuracy) and in a nonrandomized study (subject to confounding), the findings nonetheless provide "novel and useful information on the increasing risk of amputation and death in patients undergoing multiple revascularization procedures," the investigators said.

They stressed that they are "by no means making the claim that secondary revascularization is inappropriate," but rather, that they are presenting the risks associated with further procedures in an effort to inform the decision-making process.

Critical limb ischemia confers a high risk of limb loss without treatment, they said, noting that 16%-50% of revascularized patients require secondary revascularization. A "major proportion" of these patients will require further procedures, they noted.

"We emphasize continued communication between clinicians and patients on the true risks and benefits of these procedures," they concluded.

Dr. Hawkins and his coauthor, Dr. Stuart Lipsitz, are supported by a grant from the Brigham and Women's Center for Surgery and Public Health Arthur Tracy Cabot Fellowship. Dr. Hawkins is also supported by the NIH NHLBI T32 Harvard/Longwood Vascular Surgery Training Program. Another author, Dr. Maria J. Schaumeier, is supported by a grant from the Freiwillige Akademische Gesellschaft, Basel, Switzerland.

The risk of amputation and death appears to increase as the number of revascularization procedures increases, according to findings from a retrospective analysis of data.

The amputation risk was present among patients who underwent percutaneous transluminal angioplasty (PTA) only, as well as among subsets of patients who underwent lower extremity bypass (LEB) only, reported Dr. Alexander T. Hawkins of the Center for Surgery and Public Health, Boston, and his colleagues.

Among 11,190 patients with critical limb ischemia who underwent one, two, three, four, or five or more revascularization procedures, the 1-year estimated amputation rates were 23.3%, 27.1%, 30.3%, 26.7%, and 28.6%, and the 1-year estimated mortality rates were 18.7%, 21.1%, 26.3%, 23.6%, and 32.1%, respectively, the investigators reported. The findings were published in the January issue of Annals of Vascular Surgery.

The risk of amputation increased significantly for those with two vs. one revascularization procedure (hazard ratio, 1.22) and for those with three vs. two procedures (HR, 1.33). The risk for death at one year also increased significantly among those with two vs. one procedure (HR, 1.18) (Ann. Vasc. Surg. 2014;28:35-47).

Similar trends for amputation were seen in the PTA-only (1: 24.5%; 2: 26.1%; 3: 27.9%; 4: 31.3%; 5+: 26.8%), and LEB-only (1: 26.0%; 2: 32.5%; 3+: 45.5%) groups. "The increases did not appear to be exponential," they noted.

No changes were seen in the PTA-only and LEB-only groups with respect to 1-year estimates of in-hospital death.

A subgroup analysis further showed that timing between procedures was significantly associated with 1-year amputation risk; the risk was 27.2% for a 1-7 day interval, 36.4% for 8 days to 1 month, 19.4% for 1-6 months; and 22.2% for 6 months or more.

"There was also a difference in 1-year amputation rates between bypass patients who underwent bypass first and who underwent PTA followed by bypass" (21.8% vs. 30.7%), the researchers wrote.

Study subjects were adult patients with a mean age of 71 years who underwent revascularization between July 2007 and December 2009. The patients, including 6,225 men (55.9%), were identified from the California State Inpatient Database and had a high burden of comorbidities; 55.2% abused tobacco, 64.9% had coronary artery disease, 51.3% had hypertension, and 68% had diabetes.

Though limited by factors inherent in the use of an administrative database (such as potential inconsistencies in coding accuracy) and in a nonrandomized study (subject to confounding), the findings nonetheless provide "novel and useful information on the increasing risk of amputation and death in patients undergoing multiple revascularization procedures," the investigators said.

They stressed that they are "by no means making the claim that secondary revascularization is inappropriate," but rather, that they are presenting the risks associated with further procedures in an effort to inform the decision-making process.

Critical limb ischemia confers a high risk of limb loss without treatment, they said, noting that 16%-50% of revascularized patients require secondary revascularization. A "major proportion" of these patients will require further procedures, they noted.

"We emphasize continued communication between clinicians and patients on the true risks and benefits of these procedures," they concluded.

Dr. Hawkins and his coauthor, Dr. Stuart Lipsitz, are supported by a grant from the Brigham and Women's Center for Surgery and Public Health Arthur Tracy Cabot Fellowship. Dr. Hawkins is also supported by the NIH NHLBI T32 Harvard/Longwood Vascular Surgery Training Program. Another author, Dr. Maria J. Schaumeier, is supported by a grant from the Freiwillige Akademische Gesellschaft, Basel, Switzerland.

The risk of amputation and death appears to increase as the number of revascularization procedures increases, according to findings from a retrospective analysis of data.

The amputation risk was present among patients who underwent percutaneous transluminal angioplasty (PTA) only, as well as among subsets of patients who underwent lower extremity bypass (LEB) only, reported Dr. Alexander T. Hawkins of the Center for Surgery and Public Health, Boston, and his colleagues.

Among 11,190 patients with critical limb ischemia who underwent one, two, three, four, or five or more revascularization procedures, the 1-year estimated amputation rates were 23.3%, 27.1%, 30.3%, 26.7%, and 28.6%, and the 1-year estimated mortality rates were 18.7%, 21.1%, 26.3%, 23.6%, and 32.1%, respectively, the investigators reported. The findings were published in the January issue of Annals of Vascular Surgery.

The risk of amputation increased significantly for those with two vs. one revascularization procedure (hazard ratio, 1.22) and for those with three vs. two procedures (HR, 1.33). The risk for death at one year also increased significantly among those with two vs. one procedure (HR, 1.18) (Ann. Vasc. Surg. 2014;28:35-47).

Similar trends for amputation were seen in the PTA-only (1: 24.5%; 2: 26.1%; 3: 27.9%; 4: 31.3%; 5+: 26.8%), and LEB-only (1: 26.0%; 2: 32.5%; 3+: 45.5%) groups. "The increases did not appear to be exponential," they noted.

No changes were seen in the PTA-only and LEB-only groups with respect to 1-year estimates of in-hospital death.

A subgroup analysis further showed that timing between procedures was significantly associated with 1-year amputation risk; the risk was 27.2% for a 1-7 day interval, 36.4% for 8 days to 1 month, 19.4% for 1-6 months; and 22.2% for 6 months or more.

"There was also a difference in 1-year amputation rates between bypass patients who underwent bypass first and who underwent PTA followed by bypass" (21.8% vs. 30.7%), the researchers wrote.

Study subjects were adult patients with a mean age of 71 years who underwent revascularization between July 2007 and December 2009. The patients, including 6,225 men (55.9%), were identified from the California State Inpatient Database and had a high burden of comorbidities; 55.2% abused tobacco, 64.9% had coronary artery disease, 51.3% had hypertension, and 68% had diabetes.

Though limited by factors inherent in the use of an administrative database (such as potential inconsistencies in coding accuracy) and in a nonrandomized study (subject to confounding), the findings nonetheless provide "novel and useful information on the increasing risk of amputation and death in patients undergoing multiple revascularization procedures," the investigators said.

They stressed that they are "by no means making the claim that secondary revascularization is inappropriate," but rather, that they are presenting the risks associated with further procedures in an effort to inform the decision-making process.

Critical limb ischemia confers a high risk of limb loss without treatment, they said, noting that 16%-50% of revascularized patients require secondary revascularization. A "major proportion" of these patients will require further procedures, they noted.

"We emphasize continued communication between clinicians and patients on the true risks and benefits of these procedures," they concluded.

Dr. Hawkins and his coauthor, Dr. Stuart Lipsitz, are supported by a grant from the Brigham and Women's Center for Surgery and Public Health Arthur Tracy Cabot Fellowship. Dr. Hawkins is also supported by the NIH NHLBI T32 Harvard/Longwood Vascular Surgery Training Program. Another author, Dr. Maria J. Schaumeier, is supported by a grant from the Freiwillige Akademische Gesellschaft, Basel, Switzerland.

PALM BEACH, FLA. – The ankle-brachial index value is directly associated with the prevalence of carotid artery stenosis and with a history of coronary artery disease and cerebrovascular disease, according to analysis of more than 3.6 million records obtained from the private health screening company, Life Line Screening.

But what makes the study interesting is the database itself, and not so much the findings, which have been previously shown, commented Dr. Spence M. Taylor, president of the Greenville (S.C.) Health System Clinical University.

Life Line Screening has mobile units, which travel to various locations and for a fee of more than $100, screen individuals, collecting nearly 300 data points per person. Meanwhile, the ankle-brachial index (ABI) costs less than $30 approximately. Yet, the test hasn’t become widely used, despite the evidence. Not much has changed since the 2001 PARTNERS study, which showed that the primary care physicians’ awareness of PAD diagnosis was "relatively low" (JAMA 2001;286:1317-24).

Results using the Life Line Screening’s large database may show the federal government that ABI can be cost effective, and getting them on board would popularize the screening tool, said Dr. Mark A. Adelman of the New York University Langone Medical Center, who presented his study at the Southern Association for Vascular Surgery annual meeting.

"Life Line is a huge paradox," said Dr. Taylor, senior associate dean of academic affairs at University of South Carolina, Greenville. It’s an operation that "we love to hate and hate to love," he added.

Dr. Adelman, the Frank J. Veith, M.D. Professor of Vascular and Endovascular Surgery and chief of vascular surgery at NYU Langone, and his colleagues analyzed data obtained from Life Line Screening, and found that individuals with an ABI between 0.41 and 0.60 had a 26.4% incidence of carotid artery stenosis (CAS), compared with individuals who had a normal ABI. The incidence increased to 35% for patients with ABI of 0.4 or less.

The majority of the abnormal ABI cases were between 0.81 and 0.90.

The analysis by Dr. Adelman and his colleagues also showed that individuals with PAD were more likely to be aged 70 years or older, male, and have modifiable risk factors, such as a history of smoking, hypertension, diabetes, and hypercholesterolemia, compared with non–PAD persons (P less than .001). (A comparison of Life Line’s database to one from the general population showed that the risk factors such as hypertension, hyperlipidemia, diabetes, and smoking were comparable.)

PAD subjects were also more likely to have CAS, prior stroke, prior transient ischemic attack, prior MI, and prior coronary revascularization, compared with those who didn’t have PAD (P less than .001). There was a significant correlation between decreasing ABI value and an increase in the prevalence of CAS, CAD, and cardiovascular disease (P less than .001).

In a separate study analyzing the same database, Dr. Adelman and his colleagues found that modifiable risk factors, such as hypertension and smoking, are associated with increased prevalence of peripheral vascular disease (J. Vasc. Surg. 2013;58:673-81).

Dr. Adelman said that screening for ABI could trigger other screening and lead to modification of risk factors that could affect better patient outcomes, changes in lifestyle, or changes in pharmacological management.

Dr. Adelman and Dr. Taylor had no disclosures.

nmiller@frontlinemedcom.com

On Twitter @naseemsmiller

PALM BEACH, FLA. – The ankle-brachial index value is directly associated with the prevalence of carotid artery stenosis and with a history of coronary artery disease and cerebrovascular disease, according to analysis of more than 3.6 million records obtained from the private health screening company, Life Line Screening.

But what makes the study interesting is the database itself, and not so much the findings, which have been previously shown, commented Dr. Spence M. Taylor, president of the Greenville (S.C.) Health System Clinical University.

Life Line Screening has mobile units, which travel to various locations and for a fee of more than $100, screen individuals, collecting nearly 300 data points per person. Meanwhile, the ankle-brachial index (ABI) costs less than $30 approximately. Yet, the test hasn’t become widely used, despite the evidence. Not much has changed since the 2001 PARTNERS study, which showed that the primary care physicians’ awareness of PAD diagnosis was "relatively low" (JAMA 2001;286:1317-24).

Results using the Life Line Screening’s large database may show the federal government that ABI can be cost effective, and getting them on board would popularize the screening tool, said Dr. Mark A. Adelman of the New York University Langone Medical Center, who presented his study at the Southern Association for Vascular Surgery annual meeting.

"Life Line is a huge paradox," said Dr. Taylor, senior associate dean of academic affairs at University of South Carolina, Greenville. It’s an operation that "we love to hate and hate to love," he added.

Dr. Adelman, the Frank J. Veith, M.D. Professor of Vascular and Endovascular Surgery and chief of vascular surgery at NYU Langone, and his colleagues analyzed data obtained from Life Line Screening, and found that individuals with an ABI between 0.41 and 0.60 had a 26.4% incidence of carotid artery stenosis (CAS), compared with individuals who had a normal ABI. The incidence increased to 35% for patients with ABI of 0.4 or less.

The majority of the abnormal ABI cases were between 0.81 and 0.90.

The analysis by Dr. Adelman and his colleagues also showed that individuals with PAD were more likely to be aged 70 years or older, male, and have modifiable risk factors, such as a history of smoking, hypertension, diabetes, and hypercholesterolemia, compared with non–PAD persons (P less than .001). (A comparison of Life Line’s database to one from the general population showed that the risk factors such as hypertension, hyperlipidemia, diabetes, and smoking were comparable.)

PAD subjects were also more likely to have CAS, prior stroke, prior transient ischemic attack, prior MI, and prior coronary revascularization, compared with those who didn’t have PAD (P less than .001). There was a significant correlation between decreasing ABI value and an increase in the prevalence of CAS, CAD, and cardiovascular disease (P less than .001).

In a separate study analyzing the same database, Dr. Adelman and his colleagues found that modifiable risk factors, such as hypertension and smoking, are associated with increased prevalence of peripheral vascular disease (J. Vasc. Surg. 2013;58:673-81).

Dr. Adelman said that screening for ABI could trigger other screening and lead to modification of risk factors that could affect better patient outcomes, changes in lifestyle, or changes in pharmacological management.

Dr. Adelman and Dr. Taylor had no disclosures.

nmiller@frontlinemedcom.com

On Twitter @naseemsmiller

PALM BEACH, FLA. – The ankle-brachial index value is directly associated with the prevalence of carotid artery stenosis and with a history of coronary artery disease and cerebrovascular disease, according to analysis of more than 3.6 million records obtained from the private health screening company, Life Line Screening.

But what makes the study interesting is the database itself, and not so much the findings, which have been previously shown, commented Dr. Spence M. Taylor, president of the Greenville (S.C.) Health System Clinical University.

Life Line Screening has mobile units, which travel to various locations and for a fee of more than $100, screen individuals, collecting nearly 300 data points per person. Meanwhile, the ankle-brachial index (ABI) costs less than $30 approximately. Yet, the test hasn’t become widely used, despite the evidence. Not much has changed since the 2001 PARTNERS study, which showed that the primary care physicians’ awareness of PAD diagnosis was "relatively low" (JAMA 2001;286:1317-24).

Results using the Life Line Screening’s large database may show the federal government that ABI can be cost effective, and getting them on board would popularize the screening tool, said Dr. Mark A. Adelman of the New York University Langone Medical Center, who presented his study at the Southern Association for Vascular Surgery annual meeting.

"Life Line is a huge paradox," said Dr. Taylor, senior associate dean of academic affairs at University of South Carolina, Greenville. It’s an operation that "we love to hate and hate to love," he added.

Dr. Adelman, the Frank J. Veith, M.D. Professor of Vascular and Endovascular Surgery and chief of vascular surgery at NYU Langone, and his colleagues analyzed data obtained from Life Line Screening, and found that individuals with an ABI between 0.41 and 0.60 had a 26.4% incidence of carotid artery stenosis (CAS), compared with individuals who had a normal ABI. The incidence increased to 35% for patients with ABI of 0.4 or less.

The majority of the abnormal ABI cases were between 0.81 and 0.90.

The analysis by Dr. Adelman and his colleagues also showed that individuals with PAD were more likely to be aged 70 years or older, male, and have modifiable risk factors, such as a history of smoking, hypertension, diabetes, and hypercholesterolemia, compared with non–PAD persons (P less than .001). (A comparison of Life Line’s database to one from the general population showed that the risk factors such as hypertension, hyperlipidemia, diabetes, and smoking were comparable.)

PAD subjects were also more likely to have CAS, prior stroke, prior transient ischemic attack, prior MI, and prior coronary revascularization, compared with those who didn’t have PAD (P less than .001). There was a significant correlation between decreasing ABI value and an increase in the prevalence of CAS, CAD, and cardiovascular disease (P less than .001).

In a separate study analyzing the same database, Dr. Adelman and his colleagues found that modifiable risk factors, such as hypertension and smoking, are associated with increased prevalence of peripheral vascular disease (J. Vasc. Surg. 2013;58:673-81).

Dr. Adelman said that screening for ABI could trigger other screening and lead to modification of risk factors that could affect better patient outcomes, changes in lifestyle, or changes in pharmacological management.

Dr. Adelman and Dr. Taylor had no disclosures.

nmiller@frontlinemedcom.com

On Twitter @naseemsmiller

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

New research suggests patients with hereditary hemorrhagic telangiectasia (HHT) have an increased risk of ischemic stroke if they are iron deficient, and this may be due to enhanced platelet aggregation.

In the last few years, several studies have shown that iron deficiency may be a risk factor for ischemic stroke, but exactly how this occurs has been unclear.

Previous research also revealed a possible link between iron deficiency and platelet aggregation, but it has been largely overlooked, until now.

Claire Shovlin, PhD, of Imperial College London in the UK, and her colleagues found that HHT patients who are iron deficient have both an increased risk of stroke and enhanced aggregation of circulating platelets.

The researchers reported these findings in PLOS ONE.

The team had studied 497 HHT patients who had enlarged blood vessels in the lungs known as pulmonary arteriovenous malformations.

Normally, the lungs’ blood vessels act as a filter to remove small clots before blood enters arteries. In patients with pulmonary arteriovenous malformations, blood is able to bypass the filter, so small blood clots can travel to the brain.

Dr Shovlin and her colleagues found that patients with iron deficiency had a greater risk of stroke than patients with normal iron levels. Even moderately low iron levels, around 6 μmol/L, approximately doubled the risk of stroke when compared with levels in the middle of the normal range (7 to 27 μmol/L).

The researchers evaluated platelet activity in 15 patients, dividing them into 2 groups according to serum ferritin. Iron-deficient patients (n=7) had ferritin levels ranging from 2 μg/L to 17 μg/L. Control subjects (n=8) had ferritin levels of 24 μg/L to 98 μg/L. (None of the patients had levels between 17μg/L and 24 μg/L.)

The team found that ADP induced similar, dose-dependent platelet aggregation in iron-deficient patients and control subjects. But iron-deficient patients exhibited enhanced total aggregation to 5HT over a 5-minute period. And the iron-deficient group displayed faster rates of aggregation in response to 5HT.

“Since platelets in the blood stick together more if you are short of iron, we think this may explain why being short of iron can lead to strokes, though much more research will be needed to prove this link,” Dr Shovlin said.

“The next step is to test whether we can reduce high-risk patients’ chances of having a stroke by treating their iron deficiency. We will be able to look at whether their platelets become less sticky.”

“There are many additional steps from a clot blocking a blood vessel to the final stroke developing, so it is still unclear just how important sticky platelets are to the overall process. We would certainly encourage more studies to investigate this link.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

New research suggests patients with hereditary hemorrhagic telangiectasia (HHT) have an increased risk of ischemic stroke if they are iron deficient, and this may be due to enhanced platelet aggregation.

In the last few years, several studies have shown that iron deficiency may be a risk factor for ischemic stroke, but exactly how this occurs has been unclear.

Previous research also revealed a possible link between iron deficiency and platelet aggregation, but it has been largely overlooked, until now.

Claire Shovlin, PhD, of Imperial College London in the UK, and her colleagues found that HHT patients who are iron deficient have both an increased risk of stroke and enhanced aggregation of circulating platelets.

The researchers reported these findings in PLOS ONE.

The team had studied 497 HHT patients who had enlarged blood vessels in the lungs known as pulmonary arteriovenous malformations.

Normally, the lungs’ blood vessels act as a filter to remove small clots before blood enters arteries. In patients with pulmonary arteriovenous malformations, blood is able to bypass the filter, so small blood clots can travel to the brain.

Dr Shovlin and her colleagues found that patients with iron deficiency had a greater risk of stroke than patients with normal iron levels. Even moderately low iron levels, around 6 μmol/L, approximately doubled the risk of stroke when compared with levels in the middle of the normal range (7 to 27 μmol/L).

The researchers evaluated platelet activity in 15 patients, dividing them into 2 groups according to serum ferritin. Iron-deficient patients (n=7) had ferritin levels ranging from 2 μg/L to 17 μg/L. Control subjects (n=8) had ferritin levels of 24 μg/L to 98 μg/L. (None of the patients had levels between 17μg/L and 24 μg/L.)

The team found that ADP induced similar, dose-dependent platelet aggregation in iron-deficient patients and control subjects. But iron-deficient patients exhibited enhanced total aggregation to 5HT over a 5-minute period. And the iron-deficient group displayed faster rates of aggregation in response to 5HT.

“Since platelets in the blood stick together more if you are short of iron, we think this may explain why being short of iron can lead to strokes, though much more research will be needed to prove this link,” Dr Shovlin said.

“The next step is to test whether we can reduce high-risk patients’ chances of having a stroke by treating their iron deficiency. We will be able to look at whether their platelets become less sticky.”

“There are many additional steps from a clot blocking a blood vessel to the final stroke developing, so it is still unclear just how important sticky platelets are to the overall process. We would certainly encourage more studies to investigate this link.”

Platelets (blue) in a thrombus

Credit: Andre E.X. Brown

New research suggests patients with hereditary hemorrhagic telangiectasia (HHT) have an increased risk of ischemic stroke if they are iron deficient, and this may be due to enhanced platelet aggregation.

In the last few years, several studies have shown that iron deficiency may be a risk factor for ischemic stroke, but exactly how this occurs has been unclear.

Previous research also revealed a possible link between iron deficiency and platelet aggregation, but it has been largely overlooked, until now.

Claire Shovlin, PhD, of Imperial College London in the UK, and her colleagues found that HHT patients who are iron deficient have both an increased risk of stroke and enhanced aggregation of circulating platelets.

The researchers reported these findings in PLOS ONE.

The team had studied 497 HHT patients who had enlarged blood vessels in the lungs known as pulmonary arteriovenous malformations.

Normally, the lungs’ blood vessels act as a filter to remove small clots before blood enters arteries. In patients with pulmonary arteriovenous malformations, blood is able to bypass the filter, so small blood clots can travel to the brain.

Dr Shovlin and her colleagues found that patients with iron deficiency had a greater risk of stroke than patients with normal iron levels. Even moderately low iron levels, around 6 μmol/L, approximately doubled the risk of stroke when compared with levels in the middle of the normal range (7 to 27 μmol/L).

The researchers evaluated platelet activity in 15 patients, dividing them into 2 groups according to serum ferritin. Iron-deficient patients (n=7) had ferritin levels ranging from 2 μg/L to 17 μg/L. Control subjects (n=8) had ferritin levels of 24 μg/L to 98 μg/L. (None of the patients had levels between 17μg/L and 24 μg/L.)

The team found that ADP induced similar, dose-dependent platelet aggregation in iron-deficient patients and control subjects. But iron-deficient patients exhibited enhanced total aggregation to 5HT over a 5-minute period. And the iron-deficient group displayed faster rates of aggregation in response to 5HT.

“Since platelets in the blood stick together more if you are short of iron, we think this may explain why being short of iron can lead to strokes, though much more research will be needed to prove this link,” Dr Shovlin said.

“The next step is to test whether we can reduce high-risk patients’ chances of having a stroke by treating their iron deficiency. We will be able to look at whether their platelets become less sticky.”

“There are many additional steps from a clot blocking a blood vessel to the final stroke developing, so it is still unclear just how important sticky platelets are to the overall process. We would certainly encourage more studies to investigate this link.”

Steven Grant, MD

Credit: VCU

The experimental drug dinaciclib could potentially improve the treatment of multiple myeloma (MM) and myeloid leukemias, according to preclinical research published in Molecular Cancer Therapeutics.

The study showed that dinaciclib disrupts a cell survival mechanism known as the unfolded protein response (UPR).

And without the UPR, MM and myeloid leukemia cells were unable to combat damage caused by anticancer agents that induce stress in the endoplasmic reticulum (ER).

“Although dinaciclib has shown promising preclinical activity against a variety of tumor cells and is currently undergoing phase 1/2 clinical trials in several malignancies, the mechanisms responsible for its antitumor activity are not fully understood,” said study author Steven Grant, MD, of the Virginia Commonwealth University Massey Cancer Center.

“Our research highlights a potentially new mechanism of dinaciclib action and raises the possibility that this agent could be a useful addition to current multiple myeloma and myeloid leukemia therapies.”

Dinaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDKs are overactive in many cancers, which results in unregulated proliferation of cancer cells.

Observations from this study suggest that 2 specific CDKs, CDK1 and CDK5, play key roles in regulating the UPR by helping to control the production and accumulation of X-box binding pretein-1 (XBP-1). The spliced form of XBP-1 (XBP-1s) helps regulate the expression of genes critical to cellular stress responses.

External stressors, including certain anticancer agents, can cause misfolded proteins to accumulate in the ER. These stressors can also cause XBP-1s to accumulate in the cell’s nucleus, which promotes the UPR and helps cells withstand the damaging effects of misfolded proteins.

This research showed that dinaciclib, by interfering with UPR activation, caused MM and myeloid leukemia cells to initiate apoptosis when exposed to thapsigargin and tunicamycin—2 agents that induce ER stress.

And single-agent dinaciclib treatment significantly decreased tumor growth in mouse models of MM, when compared to vehicle control.

“These findings build on a long history of work in our laboratory investigating mechanisms by which cancer cells respond to environmental stresses,” Dr Grant said.

“We intend to continue investigating ways in which dinaciclib and other CDK inhibitors might be used to disrupt the UPR and potentially improve the effectiveness of certain agents for the treatment of multiple myeloma or myeloid leukemia.”

Steven Grant, MD

Credit: VCU

The experimental drug dinaciclib could potentially improve the treatment of multiple myeloma (MM) and myeloid leukemias, according to preclinical research published in Molecular Cancer Therapeutics.

The study showed that dinaciclib disrupts a cell survival mechanism known as the unfolded protein response (UPR).

And without the UPR, MM and myeloid leukemia cells were unable to combat damage caused by anticancer agents that induce stress in the endoplasmic reticulum (ER).

“Although dinaciclib has shown promising preclinical activity against a variety of tumor cells and is currently undergoing phase 1/2 clinical trials in several malignancies, the mechanisms responsible for its antitumor activity are not fully understood,” said study author Steven Grant, MD, of the Virginia Commonwealth University Massey Cancer Center.

“Our research highlights a potentially new mechanism of dinaciclib action and raises the possibility that this agent could be a useful addition to current multiple myeloma and myeloid leukemia therapies.”

Dinaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDKs are overactive in many cancers, which results in unregulated proliferation of cancer cells.

Observations from this study suggest that 2 specific CDKs, CDK1 and CDK5, play key roles in regulating the UPR by helping to control the production and accumulation of X-box binding pretein-1 (XBP-1). The spliced form of XBP-1 (XBP-1s) helps regulate the expression of genes critical to cellular stress responses.

External stressors, including certain anticancer agents, can cause misfolded proteins to accumulate in the ER. These stressors can also cause XBP-1s to accumulate in the cell’s nucleus, which promotes the UPR and helps cells withstand the damaging effects of misfolded proteins.

This research showed that dinaciclib, by interfering with UPR activation, caused MM and myeloid leukemia cells to initiate apoptosis when exposed to thapsigargin and tunicamycin—2 agents that induce ER stress.

And single-agent dinaciclib treatment significantly decreased tumor growth in mouse models of MM, when compared to vehicle control.

“These findings build on a long history of work in our laboratory investigating mechanisms by which cancer cells respond to environmental stresses,” Dr Grant said.

“We intend to continue investigating ways in which dinaciclib and other CDK inhibitors might be used to disrupt the UPR and potentially improve the effectiveness of certain agents for the treatment of multiple myeloma or myeloid leukemia.”

Steven Grant, MD

Credit: VCU

The experimental drug dinaciclib could potentially improve the treatment of multiple myeloma (MM) and myeloid leukemias, according to preclinical research published in Molecular Cancer Therapeutics.

The study showed that dinaciclib disrupts a cell survival mechanism known as the unfolded protein response (UPR).

And without the UPR, MM and myeloid leukemia cells were unable to combat damage caused by anticancer agents that induce stress in the endoplasmic reticulum (ER).

“Although dinaciclib has shown promising preclinical activity against a variety of tumor cells and is currently undergoing phase 1/2 clinical trials in several malignancies, the mechanisms responsible for its antitumor activity are not fully understood,” said study author Steven Grant, MD, of the Virginia Commonwealth University Massey Cancer Center.

“Our research highlights a potentially new mechanism of dinaciclib action and raises the possibility that this agent could be a useful addition to current multiple myeloma and myeloid leukemia therapies.”

Dinaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDKs are overactive in many cancers, which results in unregulated proliferation of cancer cells.

Observations from this study suggest that 2 specific CDKs, CDK1 and CDK5, play key roles in regulating the UPR by helping to control the production and accumulation of X-box binding pretein-1 (XBP-1). The spliced form of XBP-1 (XBP-1s) helps regulate the expression of genes critical to cellular stress responses.

External stressors, including certain anticancer agents, can cause misfolded proteins to accumulate in the ER. These stressors can also cause XBP-1s to accumulate in the cell’s nucleus, which promotes the UPR and helps cells withstand the damaging effects of misfolded proteins.

This research showed that dinaciclib, by interfering with UPR activation, caused MM and myeloid leukemia cells to initiate apoptosis when exposed to thapsigargin and tunicamycin—2 agents that induce ER stress.

And single-agent dinaciclib treatment significantly decreased tumor growth in mouse models of MM, when compared to vehicle control.

“These findings build on a long history of work in our laboratory investigating mechanisms by which cancer cells respond to environmental stresses,” Dr Grant said.

“We intend to continue investigating ways in which dinaciclib and other CDK inhibitors might be used to disrupt the UPR and potentially improve the effectiveness of certain agents for the treatment of multiple myeloma or myeloid leukemia.”

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has launched a program that allows certain companies to expedite the importation of drugs and drug ingredients.

Thirteen companies have been selected to take part in this 2-year program, called the Secure Supply Chain Pilot Program.

As the companies meet certain criteria, they are eligible to receive expedited entry for up to 5 drug products. These products can enter the US after electronic screening without undergoing human examination.

The FDA said its goal with this program is to allow the agency to focus its imports surveillance resources on preventing the entry of drugs that are most likely to compromise the quality and safety of the US drug supply.

The companies that have been accepted into the program are:

• AbbVie Inc.
• Allergan, Inc.
• Astellas U.S. Technologies, Inc.
• Bristol-Myers Squibb Company
• Celgene Corporation
• GE Healthcare Inc.
• GlaxoSmithKline LLC
• Merck Sharp & Dohme Corporation
• Mylan Pharmaceuticals Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer, Inc.
• Teva Pharmaceutcials USA, Inc.
• Watson Laboratories, Inc.

Each of these companies met the participation conditions, including:

• Committing to comply with requirements of the Food, Drug, and Cosmetics Act (FDCA)
• Having a validated, secure supply chain protocol per the US Customs and Border Protection’s Customs-Trade Partnership Against Terrorism (C-TPAT) program
• Having a plan in place to quickly correct potential problems the FDA identifies regarding importation of specific products
• Having effective recall and corrective action plans in place
• Maintaining control over their drugs from the time of manufacture abroad through entry into the US.

Over the next 2 years, the FDA will evaluate whether this program enhances imported drug compliance with FDA regulations and the security of the drug supply chain. If the FDA deems the program effective, a more permanent program may be established and possibly extended to additional companies.

For more information, see the FDA’s notice about the program, published in the Federal Register last August.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has launched a program that allows certain companies to expedite the importation of drugs and drug ingredients.

Thirteen companies have been selected to take part in this 2-year program, called the Secure Supply Chain Pilot Program.

As the companies meet certain criteria, they are eligible to receive expedited entry for up to 5 drug products. These products can enter the US after electronic screening without undergoing human examination.

The FDA said its goal with this program is to allow the agency to focus its imports surveillance resources on preventing the entry of drugs that are most likely to compromise the quality and safety of the US drug supply.

The companies that have been accepted into the program are:

• AbbVie Inc.
• Allergan, Inc.
• Astellas U.S. Technologies, Inc.
• Bristol-Myers Squibb Company
• Celgene Corporation
• GE Healthcare Inc.
• GlaxoSmithKline LLC
• Merck Sharp & Dohme Corporation
• Mylan Pharmaceuticals Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer, Inc.
• Teva Pharmaceutcials USA, Inc.
• Watson Laboratories, Inc.

Each of these companies met the participation conditions, including:

• Committing to comply with requirements of the Food, Drug, and Cosmetics Act (FDCA)
• Having a validated, secure supply chain protocol per the US Customs and Border Protection’s Customs-Trade Partnership Against Terrorism (C-TPAT) program
• Having a plan in place to quickly correct potential problems the FDA identifies regarding importation of specific products
• Having effective recall and corrective action plans in place
• Maintaining control over their drugs from the time of manufacture abroad through entry into the US.

Over the next 2 years, the FDA will evaluate whether this program enhances imported drug compliance with FDA regulations and the security of the drug supply chain. If the FDA deems the program effective, a more permanent program may be established and possibly extended to additional companies.

For more information, see the FDA’s notice about the program, published in the Federal Register last August.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has launched a program that allows certain companies to expedite the importation of drugs and drug ingredients.

Thirteen companies have been selected to take part in this 2-year program, called the Secure Supply Chain Pilot Program.

As the companies meet certain criteria, they are eligible to receive expedited entry for up to 5 drug products. These products can enter the US after electronic screening without undergoing human examination.

The FDA said its goal with this program is to allow the agency to focus its imports surveillance resources on preventing the entry of drugs that are most likely to compromise the quality and safety of the US drug supply.

The companies that have been accepted into the program are:

• AbbVie Inc.
• Allergan, Inc.
• Astellas U.S. Technologies, Inc.
• Bristol-Myers Squibb Company
• Celgene Corporation
• GE Healthcare Inc.
• GlaxoSmithKline LLC
• Merck Sharp & Dohme Corporation
• Mylan Pharmaceuticals Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer, Inc.
• Teva Pharmaceutcials USA, Inc.
• Watson Laboratories, Inc.

Each of these companies met the participation conditions, including:

• Committing to comply with requirements of the Food, Drug, and Cosmetics Act (FDCA)
• Having a validated, secure supply chain protocol per the US Customs and Border Protection’s Customs-Trade Partnership Against Terrorism (C-TPAT) program
• Having a plan in place to quickly correct potential problems the FDA identifies regarding importation of specific products
• Having effective recall and corrective action plans in place
• Maintaining control over their drugs from the time of manufacture abroad through entry into the US.

Over the next 2 years, the FDA will evaluate whether this program enhances imported drug compliance with FDA regulations and the security of the drug supply chain. If the FDA deems the program effective, a more permanent program may be established and possibly extended to additional companies.

For more information, see the FDA’s notice about the program, published in the Federal Register last August.

Michel Sadelain, MD, PhD

Credit: MSKCC

Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.

However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).

With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).

But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.

Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.

Response, bridge to allo-SCT

Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.

After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.

Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.

Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.

Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.

“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”

CRS diagnosis, stratification

In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.

Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).

Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.

The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.

Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.

Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.

Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.

Michel Sadelain, MD, PhD

Credit: MSKCC

Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.

However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).

With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).

But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.

Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.

Response, bridge to allo-SCT

Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.

After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.

Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.

Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.

Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.

“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”

CRS diagnosis, stratification

In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.

Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).

Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.

The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.

Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.

Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.

Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.

Michel Sadelain, MD, PhD

Credit: MSKCC

Several studies have shown that infusions of T cells modified with chimeric antigen receptors (CARs) can elicit complete responses in leukemia patients who have run out of treatment options.

However, the therapy also puts patients at risk of developing cytokine release syndrome (CRS).

With updated research, investigators have again shown that CAR T cells can produce complete responses in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), thereby allowing them to receive allogeneic stem cell transplant (allo-SCT).

But the researchers have also used this group of patients to define diagnostic criteria for severe CRS. And the team has discovered that measuring C-reactive protein levels can help predict the severity of CRS.

Michel Sadelain, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York, and his colleagues described these findings in Science Translational Medicine.

Response, bridge to allo-SCT

Dr Sadelain and his colleagues previously reported results in 5 patients with relapsed/refractory B-ALL who received autologous T cells expressing a CD19-specific, CD28/CD3z CAR called 19-28z.

After receiving salvage chemotherapy and CAR T cells, all 5 patients were negative for minimal residual disease. And 4 of the patients went on to receive allo-SCT.

Now, the investigators have expanded upon these findings, reporting results in a total of 16 patients with relapsed/refractory B-ALL who received the 19-28z CAR T cells.

Forty-four percent of patients (n=7) had a complete response to the salvage chemotherapy, and 88% (n=14) had a complete response after CAR T-cell therapy (alghough some had incomplete count recovery). Sixty-three percent of patients (n=10) achieved a complete remission.

Of the 10 patients who were eligible for allo-SCT, 7 underwent the procedure, and all 7 remain free of relapse.

“These extraordinary results demonstrate that cell therapy is a powerful treatment for patients who have exhausted all conventional therapies,” Dr Sadelain said. “Our initial findings have held up in a larger cohort of patients, and we are already looking at new clinical studies to advance this novel therapeutic approach in fighting cancer.”

CRS diagnosis, stratification

In their analysis of 5 B-ALL patients, Dr Sadelain and his colleagues observed a correlation between cytokine elevation and tumor burden at the time of CAR T-cell administration. The team confirmed this correlation in the larger cohort of 16 patients and identified 7 cytokines whose elevation was correlated with pretreatment tumor burden and severe CRS.

Patients with CRS that required intensive medical intervention had a 75-fold increase over baseline levels in 2 of the 7 cytokines, which included IFN-γ, IL-5, IL-6, IL-10, Flt-3L, Fracktalkine, and GM-CSF. These patients also had at least 1 of the following: hypoxia, hypotension, and neurologic changes (such as delirium and seizure-like activity).

Taking these findings together, the researchers concluded that patients had severe CRS if they had persistent fevers (38°C) for more than 3 days, selected cytokine elevations, and additional clinical evidence of toxicity.

The investigators stressed that these patients should be closely monitored. Patients with severe CRS are more likely to need medical intervention than patients with mild CRS, which is characterized by low-grade fever and mild cytokine increases, or absent CRS, which is defined as no fevers and/or no significant cytokine elevations.

Finally, the researchers found that measuring C-reactive protein in serum samples could predict the severity of CRS. Only those patients who met the criteria for severe CRS had a C-reactive protein level of 20 mg/dL or higher.

Patients who had received high-dose steroids were excluded from this analysis, due to the inverse correlation between high-dose steroid treatment and serum C-reactive protein.

Incidentally, the investigators confirmed prior findings that the monoclonal antibody tocilizumab can ameliorate severe CRS as effectively as steroid treatment, without inhibiting the expansion of CAR T cells.

Clinical question: What antibiotic-resistant bacteria are the greatest threats for the next 10 years?

Background: Two million people suffer antibiotic-resistant infections yearly, and 23,000 die each year as a result. Most of these infections occur in the community, but deaths usually occur in healthcare settings. Cost estimates vary but may be as high as $20 billion in excess direct healthcare costs.

Study design: The CDC used several different surveys and databanks, including the National Antimicrobial Resistance Monitoring System, to collect data. The threat level for antibiotic-resistant bacteria was determined using several factors: clinical impact, economic impact, incidence, 10-year projection of incidence, transmissibility, availability of effective antibiotics, and barriers to prevention.

Setting: United States.

Synopsis: The CDC has three classifications of antibiotic-resistant bacteria: urgent, serious, and concerning. Urgent threats are high-consequence, antibiotic-resistant threats because of significant risks identified across several criteria. These threats might not currently be widespread but have the potential to become so and require urgent public health attention to identify infections and to limit transmission. They include carbapenem-resistant Enterobacteriaceae, drug-resistant Neisseria gonorrhoeae, and Clostridium difficile (does not have true resistance, but is a consequence of antibiotic overuse).

Serious threats are significant antibiotic-resistant threats. These threats will worsen, and might become urgent without ongoing public health monitoring and prevention activities. They include multidrug-resistant Acinetobacter, drug-resistant Campylobacter, fluconazole-resistant Candida (a fungus), extended-spectrum ß-lactamase-producing Enterobacteriaceae, vancomycin-resistant Enterococcus, multidrug-resistant Pseudomonas aeruginosa, drug-resistant non-typhoidal Salmonella, drug-resistant Salmonella Typhimurium, drug-resistant Shigella, methicillin-resistant Staphylococcus aureus, drug-resistant Streptococcus pneumonia, and drug-resistant tuberculosis.

Concerning threats are bacteria for which the threat of antibiotic resistance is low, and/or there are multiple therapeutic options for resistant infections. These bacterial pathogens cause severe illness.

Threats in this category require monitoring and, in some cases, rapid incident or outbreak response. These include vancomycin-resistant Staphylococcus aureus, erythromycin-resistant Group A Streptococcus, and clindamycin-resistant Group B Streptococcus.

Research has shown patients with resistant infections have significantly longer hospital stays, delayed recuperation, long-term disability, and higher mortality. As resistance to current antibiotics occurs, providers are forced to use antibiotics that are more toxic, more expensive, and less effective.

The CDC recommends four core actions to fight antibiotic resistance:

• Preventing infections from occurring and preventing resistant bacteria from spreading (immunization, infection control, screening, treatment, and education);
• Tracking resistant bacteria;
• Improving the use of antibiotics (antibiotic stewardship); and
• Promoting the development of new antibiotics and new diagnostic tests for resistant bacteria.

Bottom line: Antibiotics are a limited resource. The more antibiotics are used today, the less likely they will continue to be effective in the future. The CDC lists 18 antibiotic-resistant organisms as urgent, serious, or concerning and recommends actions to combat the spread of current organisms and emergence of new antibiotic organisms.

Citation: Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. CDC website. September 16, 2013. Available at: www.cdc.gov/drugresistance/threat-report-2013. Accessed Nov. 30, 2013.

Clinical question: What antibiotic-resistant bacteria are the greatest threats for the next 10 years?

Background: Two million people suffer antibiotic-resistant infections yearly, and 23,000 die each year as a result. Most of these infections occur in the community, but deaths usually occur in healthcare settings. Cost estimates vary but may be as high as $20 billion in excess direct healthcare costs.

Study design: The CDC used several different surveys and databanks, including the National Antimicrobial Resistance Monitoring System, to collect data. The threat level for antibiotic-resistant bacteria was determined using several factors: clinical impact, economic impact, incidence, 10-year projection of incidence, transmissibility, availability of effective antibiotics, and barriers to prevention.

Setting: United States.

Synopsis: The CDC has three classifications of antibiotic-resistant bacteria: urgent, serious, and concerning. Urgent threats are high-consequence, antibiotic-resistant threats because of significant risks identified across several criteria. These threats might not currently be widespread but have the potential to become so and require urgent public health attention to identify infections and to limit transmission. They include carbapenem-resistant Enterobacteriaceae, drug-resistant Neisseria gonorrhoeae, and Clostridium difficile (does not have true resistance, but is a consequence of antibiotic overuse).

Serious threats are significant antibiotic-resistant threats. These threats will worsen, and might become urgent without ongoing public health monitoring and prevention activities. They include multidrug-resistant Acinetobacter, drug-resistant Campylobacter, fluconazole-resistant Candida (a fungus), extended-spectrum ß-lactamase-producing Enterobacteriaceae, vancomycin-resistant Enterococcus, multidrug-resistant Pseudomonas aeruginosa, drug-resistant non-typhoidal Salmonella, drug-resistant Salmonella Typhimurium, drug-resistant Shigella, methicillin-resistant Staphylococcus aureus, drug-resistant Streptococcus pneumonia, and drug-resistant tuberculosis.

Concerning threats are bacteria for which the threat of antibiotic resistance is low, and/or there are multiple therapeutic options for resistant infections. These bacterial pathogens cause severe illness.

Threats in this category require monitoring and, in some cases, rapid incident or outbreak response. These include vancomycin-resistant Staphylococcus aureus, erythromycin-resistant Group A Streptococcus, and clindamycin-resistant Group B Streptococcus.

Research has shown patients with resistant infections have significantly longer hospital stays, delayed recuperation, long-term disability, and higher mortality. As resistance to current antibiotics occurs, providers are forced to use antibiotics that are more toxic, more expensive, and less effective.

The CDC recommends four core actions to fight antibiotic resistance:

• Preventing infections from occurring and preventing resistant bacteria from spreading (immunization, infection control, screening, treatment, and education);
• Tracking resistant bacteria;
• Improving the use of antibiotics (antibiotic stewardship); and
• Promoting the development of new antibiotics and new diagnostic tests for resistant bacteria.

Bottom line: Antibiotics are a limited resource. The more antibiotics are used today, the less likely they will continue to be effective in the future. The CDC lists 18 antibiotic-resistant organisms as urgent, serious, or concerning and recommends actions to combat the spread of current organisms and emergence of new antibiotic organisms.

Citation: Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. CDC website. September 16, 2013. Available at: www.cdc.gov/drugresistance/threat-report-2013. Accessed Nov. 30, 2013.

Clinical question: What antibiotic-resistant bacteria are the greatest threats for the next 10 years?

Background: Two million people suffer antibiotic-resistant infections yearly, and 23,000 die each year as a result. Most of these infections occur in the community, but deaths usually occur in healthcare settings. Cost estimates vary but may be as high as $20 billion in excess direct healthcare costs.

Study design: The CDC used several different surveys and databanks, including the National Antimicrobial Resistance Monitoring System, to collect data. The threat level for antibiotic-resistant bacteria was determined using several factors: clinical impact, economic impact, incidence, 10-year projection of incidence, transmissibility, availability of effective antibiotics, and barriers to prevention.

Setting: United States.

Synopsis: The CDC has three classifications of antibiotic-resistant bacteria: urgent, serious, and concerning. Urgent threats are high-consequence, antibiotic-resistant threats because of significant risks identified across several criteria. These threats might not currently be widespread but have the potential to become so and require urgent public health attention to identify infections and to limit transmission. They include carbapenem-resistant Enterobacteriaceae, drug-resistant Neisseria gonorrhoeae, and Clostridium difficile (does not have true resistance, but is a consequence of antibiotic overuse).

Serious threats are significant antibiotic-resistant threats. These threats will worsen, and might become urgent without ongoing public health monitoring and prevention activities. They include multidrug-resistant Acinetobacter, drug-resistant Campylobacter, fluconazole-resistant Candida (a fungus), extended-spectrum ß-lactamase-producing Enterobacteriaceae, vancomycin-resistant Enterococcus, multidrug-resistant Pseudomonas aeruginosa, drug-resistant non-typhoidal Salmonella, drug-resistant Salmonella Typhimurium, drug-resistant Shigella, methicillin-resistant Staphylococcus aureus, drug-resistant Streptococcus pneumonia, and drug-resistant tuberculosis.

Concerning threats are bacteria for which the threat of antibiotic resistance is low, and/or there are multiple therapeutic options for resistant infections. These bacterial pathogens cause severe illness.

Threats in this category require monitoring and, in some cases, rapid incident or outbreak response. These include vancomycin-resistant Staphylococcus aureus, erythromycin-resistant Group A Streptococcus, and clindamycin-resistant Group B Streptococcus.

Research has shown patients with resistant infections have significantly longer hospital stays, delayed recuperation, long-term disability, and higher mortality. As resistance to current antibiotics occurs, providers are forced to use antibiotics that are more toxic, more expensive, and less effective.

The CDC recommends four core actions to fight antibiotic resistance:

• Preventing infections from occurring and preventing resistant bacteria from spreading (immunization, infection control, screening, treatment, and education);
• Tracking resistant bacteria;
• Improving the use of antibiotics (antibiotic stewardship); and
• Promoting the development of new antibiotics and new diagnostic tests for resistant bacteria.

Bottom line: Antibiotics are a limited resource. The more antibiotics are used today, the less likely they will continue to be effective in the future. The CDC lists 18 antibiotic-resistant organisms as urgent, serious, or concerning and recommends actions to combat the spread of current organisms and emergence of new antibiotic organisms.

Citation: Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. CDC website. September 16, 2013. Available at: www.cdc.gov/drugresistance/threat-report-2013. Accessed Nov. 30, 2013.