PHILADELPHIA—Results of preclinical research suggest the BCL-2 inhibitor ABT-199 (venetoclax) may be effective in certain pediatric patients with acute lymphoblastic leukemia (ALL).

In xenograft models of various ALL subtypes, ABT-199 produced an objective response rate below 30%.

However, additional analyses unearthed information that could potentially help us identify which ALL patients might respond to the drug.

Santi Suryani, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues presented this research at the AACR Annual Meeting 2015 (abstract 3276*). The work was supported by AbbVie, one of the companies developing ABT-199.

Dr Suryani and her colleagues decided to investigate ABT-199 in pediatric ALL after observing mixed results with the BCL-2/BCL-W/BCL-XL inhibitor ABT-263 (navitoclax).

ABT-263 delayed ALL progression in nearly all of the xenograft models the team tested and produced a 61% response rate. However, the drug also induced BCL-XL-mediated thrombocytopenia.

As ABT-199 doesn’t target BCL-XL, the researchers thought the drug might produce similar responses as ABT-263 without inducing thrombocytopenia.

“When ABT-199 came into the picture, we were very excited,” Dr Suryani said. “We thought, ‘This is a wonder drug. This will cure pediatric ALL.’”

To test this hypothesis, the team compared ABT-199 (100 mg/kg x 21 days) and vehicle control in 19 pediatric ALL patient-derived xenografts, including infant mixed-lineage leukemia (MLL) ALL (n=4), B-cell precursor (BCP) ALL (n=5), BCP-ALL categorized as Ph-like (n=4), T-cell ALL (n=4), and early T-cell precursor (ETP) ALL (n=2).

ABT-199 significantly delayed progression in 12 xenografts (63%) for periods ranging from 0.4 days to 28 days. And the drug produced objective responses in 5 xenografts (26%).

Responses occurred in MLL-ALL, BCP-ALL, and Ph-like BCP ALL, but not T-cell ALL or ETP-ALL. Complete responses were seen in MLL-ALL (n=1) and BCP-ALL (n=2), and partial responses occurred in MLL-ALL (n=1) and Ph-like BCP-ALL (n=1).

As the response rate with ABT-263 was more than double that of ABT-199 (61% vs 26%), the researchers found the results with ABT-199 “a little bit disappointing,” according to Dr Suryani.

“But we thought, ‘That’s okay. That already tells us the science behind it—that pediatric ALL is probably more BCL-XL-dependent, rather than BCL-2-dependent,’” she said. “We wondered if there was any way we could come up with a predictive biomarker so we could select patients who will benefit from this treatment.”

With that in mind, the researchers evaluated the link between protein expression and response. They looked at BCL-2 and BCL-XL, as well as a range of other proteins, including BCL-W, MCL1, BAK1, and BAX, among others.

And they found that high BCL-XL and low BCL-2 expression were significantly associated with ABT-199 resistance.

The researchers are still investigating ways to guide treatment with ABT-199 in ALL. They are also hoping to improve responses by administering the drug in combination with other agents.

*Information in the abstract differs from that presented at the meeting.

PHILADELPHIA—Results of preclinical research suggest the BCL-2 inhibitor ABT-199 (venetoclax) may be effective in certain pediatric patients with acute lymphoblastic leukemia (ALL).

In xenograft models of various ALL subtypes, ABT-199 produced an objective response rate below 30%.

However, additional analyses unearthed information that could potentially help us identify which ALL patients might respond to the drug.

Santi Suryani, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues presented this research at the AACR Annual Meeting 2015 (abstract 3276*). The work was supported by AbbVie, one of the companies developing ABT-199.

Dr Suryani and her colleagues decided to investigate ABT-199 in pediatric ALL after observing mixed results with the BCL-2/BCL-W/BCL-XL inhibitor ABT-263 (navitoclax).

ABT-263 delayed ALL progression in nearly all of the xenograft models the team tested and produced a 61% response rate. However, the drug also induced BCL-XL-mediated thrombocytopenia.

As ABT-199 doesn’t target BCL-XL, the researchers thought the drug might produce similar responses as ABT-263 without inducing thrombocytopenia.

“When ABT-199 came into the picture, we were very excited,” Dr Suryani said. “We thought, ‘This is a wonder drug. This will cure pediatric ALL.’”

To test this hypothesis, the team compared ABT-199 (100 mg/kg x 21 days) and vehicle control in 19 pediatric ALL patient-derived xenografts, including infant mixed-lineage leukemia (MLL) ALL (n=4), B-cell precursor (BCP) ALL (n=5), BCP-ALL categorized as Ph-like (n=4), T-cell ALL (n=4), and early T-cell precursor (ETP) ALL (n=2).

ABT-199 significantly delayed progression in 12 xenografts (63%) for periods ranging from 0.4 days to 28 days. And the drug produced objective responses in 5 xenografts (26%).

Responses occurred in MLL-ALL, BCP-ALL, and Ph-like BCP ALL, but not T-cell ALL or ETP-ALL. Complete responses were seen in MLL-ALL (n=1) and BCP-ALL (n=2), and partial responses occurred in MLL-ALL (n=1) and Ph-like BCP-ALL (n=1).

As the response rate with ABT-263 was more than double that of ABT-199 (61% vs 26%), the researchers found the results with ABT-199 “a little bit disappointing,” according to Dr Suryani.

“But we thought, ‘That’s okay. That already tells us the science behind it—that pediatric ALL is probably more BCL-XL-dependent, rather than BCL-2-dependent,’” she said. “We wondered if there was any way we could come up with a predictive biomarker so we could select patients who will benefit from this treatment.”

With that in mind, the researchers evaluated the link between protein expression and response. They looked at BCL-2 and BCL-XL, as well as a range of other proteins, including BCL-W, MCL1, BAK1, and BAX, among others.

And they found that high BCL-XL and low BCL-2 expression were significantly associated with ABT-199 resistance.

The researchers are still investigating ways to guide treatment with ABT-199 in ALL. They are also hoping to improve responses by administering the drug in combination with other agents.

*Information in the abstract differs from that presented at the meeting.

PHILADELPHIA—Results of preclinical research suggest the BCL-2 inhibitor ABT-199 (venetoclax) may be effective in certain pediatric patients with acute lymphoblastic leukemia (ALL).

In xenograft models of various ALL subtypes, ABT-199 produced an objective response rate below 30%.

However, additional analyses unearthed information that could potentially help us identify which ALL patients might respond to the drug.

Santi Suryani, PhD, of the Children’s Cancer Institute in Sydney, New South Wales, Australia, and her colleagues presented this research at the AACR Annual Meeting 2015 (abstract 3276*). The work was supported by AbbVie, one of the companies developing ABT-199.

Dr Suryani and her colleagues decided to investigate ABT-199 in pediatric ALL after observing mixed results with the BCL-2/BCL-W/BCL-XL inhibitor ABT-263 (navitoclax).

ABT-263 delayed ALL progression in nearly all of the xenograft models the team tested and produced a 61% response rate. However, the drug also induced BCL-XL-mediated thrombocytopenia.

As ABT-199 doesn’t target BCL-XL, the researchers thought the drug might produce similar responses as ABT-263 without inducing thrombocytopenia.

“When ABT-199 came into the picture, we were very excited,” Dr Suryani said. “We thought, ‘This is a wonder drug. This will cure pediatric ALL.’”

To test this hypothesis, the team compared ABT-199 (100 mg/kg x 21 days) and vehicle control in 19 pediatric ALL patient-derived xenografts, including infant mixed-lineage leukemia (MLL) ALL (n=4), B-cell precursor (BCP) ALL (n=5), BCP-ALL categorized as Ph-like (n=4), T-cell ALL (n=4), and early T-cell precursor (ETP) ALL (n=2).

ABT-199 significantly delayed progression in 12 xenografts (63%) for periods ranging from 0.4 days to 28 days. And the drug produced objective responses in 5 xenografts (26%).

Responses occurred in MLL-ALL, BCP-ALL, and Ph-like BCP ALL, but not T-cell ALL or ETP-ALL. Complete responses were seen in MLL-ALL (n=1) and BCP-ALL (n=2), and partial responses occurred in MLL-ALL (n=1) and Ph-like BCP-ALL (n=1).

As the response rate with ABT-263 was more than double that of ABT-199 (61% vs 26%), the researchers found the results with ABT-199 “a little bit disappointing,” according to Dr Suryani.

“But we thought, ‘That’s okay. That already tells us the science behind it—that pediatric ALL is probably more BCL-XL-dependent, rather than BCL-2-dependent,’” she said. “We wondered if there was any way we could come up with a predictive biomarker so we could select patients who will benefit from this treatment.”

With that in mind, the researchers evaluated the link between protein expression and response. They looked at BCL-2 and BCL-XL, as well as a range of other proteins, including BCL-W, MCL1, BAK1, and BAX, among others.

And they found that high BCL-XL and low BCL-2 expression were significantly associated with ABT-199 resistance.

The researchers are still investigating ways to guide treatment with ABT-199 in ALL. They are also hoping to improve responses by administering the drug in combination with other agents.

*Information in the abstract differs from that presented at the meeting.

WASHINGTON – Scheduled administration of bilateral deep brain stimulation of the centromedian thalamus for less than 2 hours a day resulted in a significant reduction in tics in several patients with Tourette syndrome over 2 years in a proof-of-concept study presented at the annual meeting of the American Academy of Neurology.

Of the four patients who completed the 24-month study, three experienced significant improvements, said Justin Rossi, an MD-PhD candidate at the University of Florida in Gainesville.

Instead of using the standard continuous deep brain stimulation (DBS), Mr. Rossi and colleagues at the university's Center for Movement Disorders and Neurorestoration evaluated a scheduled, personalized stimulation approach, with stimulation of the centromedian thalamus (bilaterally) tailored to the times of the day when patients experienced the most sequelae from the tics, such as when they were driving, exercising, or working, and when the intensity of the tics was the greatest.

The rationale for investigating this approach is that instead of using the “classical continuous approach” to DBS, a tailored approach might be effective in these patients, with the potential benefits of increasing battery life (and delaying another surgical procedure to replace the battery) and reducing side effects associated with stimulation, Mr. Rossi said.

Many studies have found that DBS is effective in “select medication-refractory cases of Tourette syndrome,” he noted. “However, in contrast to Parkinson’s disease, essential tremor, and other movement disorders for which DBS has been commonly used as a therapy, Tourette syndrome is a paroxysmal disorder,” and the frequency of tics can vary from patient to patient, with individual patients reporting that the intensity of tics “waxes and wanes throughout the day, often predictably.”

The study enrolled five patients; responses were evaluated with two rating scales, the Yale Global Tic Severity Scale (YGTSS) and the Modified Rush Video-Based Tic Rating Scale (MRTRS). A patient was considered a responder if there was more than a 40% improvement in the YGTSS or MRTRS from the preoperative baseline level, at 24 months, the primary outcome. (One patient was lost to follow-up after 18 months because the center was too far away.) Patients had the opportunity to modify the schedule at each 6-month visit.

At 24 months, the YGTSS total scores improved by 46%, 58%, and 17% and the MRTRS total scores improved by 79%, 81%, and 44% in the three responders. These patients had a mean stimulation time of 1.85 hours a day, ranging from 47 to 186 minutes per day. The one patient who did not meet the primary endpoint – with a 10% response on the YGTSS and a 21% response in the MRTRS – had the greatest amount of stimulation per day (4 hours a day). At 24 months, the responders had statistically significant improvements from baseline in components of the two scales, including the number of phonic tics per minute, motor tic severity, and phonic tic severity, Mr. Rossi said.

This is a proof-of-concept study and the results and conclusions are preliminary, but the results “warrant larger studies,” he concluded.

More research is needed to understand this mechanism on a more physiological level, which is being pursued at his center, he added. The results shed some light on whether the mechanism of DBS in Tourette syndrome is a cumulative effect of stimulation over time or whether DBS has an effect around the time the tics occur, and these results support the latter explanation, Mr. Rossi speculated.

He had no disclosures. The study was sponsored by the National Institutes of Health.

[email protected]

WASHINGTON – Scheduled administration of bilateral deep brain stimulation of the centromedian thalamus for less than 2 hours a day resulted in a significant reduction in tics in several patients with Tourette syndrome over 2 years in a proof-of-concept study presented at the annual meeting of the American Academy of Neurology.

Of the four patients who completed the 24-month study, three experienced significant improvements, said Justin Rossi, an MD-PhD candidate at the University of Florida in Gainesville.

Instead of using the standard continuous deep brain stimulation (DBS), Mr. Rossi and colleagues at the university's Center for Movement Disorders and Neurorestoration evaluated a scheduled, personalized stimulation approach, with stimulation of the centromedian thalamus (bilaterally) tailored to the times of the day when patients experienced the most sequelae from the tics, such as when they were driving, exercising, or working, and when the intensity of the tics was the greatest.

The rationale for investigating this approach is that instead of using the “classical continuous approach” to DBS, a tailored approach might be effective in these patients, with the potential benefits of increasing battery life (and delaying another surgical procedure to replace the battery) and reducing side effects associated with stimulation, Mr. Rossi said.

Many studies have found that DBS is effective in “select medication-refractory cases of Tourette syndrome,” he noted. “However, in contrast to Parkinson’s disease, essential tremor, and other movement disorders for which DBS has been commonly used as a therapy, Tourette syndrome is a paroxysmal disorder,” and the frequency of tics can vary from patient to patient, with individual patients reporting that the intensity of tics “waxes and wanes throughout the day, often predictably.”

The study enrolled five patients; responses were evaluated with two rating scales, the Yale Global Tic Severity Scale (YGTSS) and the Modified Rush Video-Based Tic Rating Scale (MRTRS). A patient was considered a responder if there was more than a 40% improvement in the YGTSS or MRTRS from the preoperative baseline level, at 24 months, the primary outcome. (One patient was lost to follow-up after 18 months because the center was too far away.) Patients had the opportunity to modify the schedule at each 6-month visit.

At 24 months, the YGTSS total scores improved by 46%, 58%, and 17% and the MRTRS total scores improved by 79%, 81%, and 44% in the three responders. These patients had a mean stimulation time of 1.85 hours a day, ranging from 47 to 186 minutes per day. The one patient who did not meet the primary endpoint – with a 10% response on the YGTSS and a 21% response in the MRTRS – had the greatest amount of stimulation per day (4 hours a day). At 24 months, the responders had statistically significant improvements from baseline in components of the two scales, including the number of phonic tics per minute, motor tic severity, and phonic tic severity, Mr. Rossi said.

This is a proof-of-concept study and the results and conclusions are preliminary, but the results “warrant larger studies,” he concluded.

More research is needed to understand this mechanism on a more physiological level, which is being pursued at his center, he added. The results shed some light on whether the mechanism of DBS in Tourette syndrome is a cumulative effect of stimulation over time or whether DBS has an effect around the time the tics occur, and these results support the latter explanation, Mr. Rossi speculated.

He had no disclosures. The study was sponsored by the National Institutes of Health.

[email protected]

WASHINGTON – Scheduled administration of bilateral deep brain stimulation of the centromedian thalamus for less than 2 hours a day resulted in a significant reduction in tics in several patients with Tourette syndrome over 2 years in a proof-of-concept study presented at the annual meeting of the American Academy of Neurology.

Of the four patients who completed the 24-month study, three experienced significant improvements, said Justin Rossi, an MD-PhD candidate at the University of Florida in Gainesville.

Instead of using the standard continuous deep brain stimulation (DBS), Mr. Rossi and colleagues at the university's Center for Movement Disorders and Neurorestoration evaluated a scheduled, personalized stimulation approach, with stimulation of the centromedian thalamus (bilaterally) tailored to the times of the day when patients experienced the most sequelae from the tics, such as when they were driving, exercising, or working, and when the intensity of the tics was the greatest.

The rationale for investigating this approach is that instead of using the “classical continuous approach” to DBS, a tailored approach might be effective in these patients, with the potential benefits of increasing battery life (and delaying another surgical procedure to replace the battery) and reducing side effects associated with stimulation, Mr. Rossi said.

Many studies have found that DBS is effective in “select medication-refractory cases of Tourette syndrome,” he noted. “However, in contrast to Parkinson’s disease, essential tremor, and other movement disorders for which DBS has been commonly used as a therapy, Tourette syndrome is a paroxysmal disorder,” and the frequency of tics can vary from patient to patient, with individual patients reporting that the intensity of tics “waxes and wanes throughout the day, often predictably.”

The study enrolled five patients; responses were evaluated with two rating scales, the Yale Global Tic Severity Scale (YGTSS) and the Modified Rush Video-Based Tic Rating Scale (MRTRS). A patient was considered a responder if there was more than a 40% improvement in the YGTSS or MRTRS from the preoperative baseline level, at 24 months, the primary outcome. (One patient was lost to follow-up after 18 months because the center was too far away.) Patients had the opportunity to modify the schedule at each 6-month visit.

At 24 months, the YGTSS total scores improved by 46%, 58%, and 17% and the MRTRS total scores improved by 79%, 81%, and 44% in the three responders. These patients had a mean stimulation time of 1.85 hours a day, ranging from 47 to 186 minutes per day. The one patient who did not meet the primary endpoint – with a 10% response on the YGTSS and a 21% response in the MRTRS – had the greatest amount of stimulation per day (4 hours a day). At 24 months, the responders had statistically significant improvements from baseline in components of the two scales, including the number of phonic tics per minute, motor tic severity, and phonic tic severity, Mr. Rossi said.

This is a proof-of-concept study and the results and conclusions are preliminary, but the results “warrant larger studies,” he concluded.

More research is needed to understand this mechanism on a more physiological level, which is being pursued at his center, he added. The results shed some light on whether the mechanism of DBS in Tourette syndrome is a cumulative effect of stimulation over time or whether DBS has an effect around the time the tics occur, and these results support the latter explanation, Mr. Rossi speculated.

He had no disclosures. The study was sponsored by the National Institutes of Health.

[email protected]

Obese patients on warfarin may be at greater risk of bleeding than those of normal weight, according to a study presented at the American Heart Association’s Arteriosclerosis, Thrombosis, and Vascular Biology/Peripheral Vascular Disease Scientific Sessions 2015.

Researchers followed 863 patients attending an anticoagulation clinic for 1 year and found that obesity (body mass index greater than 30 kg/m²) was associated with a statistically significant 84% increase in the risk of major bleeds, such as gastrointestinal, intracerebral, and retroperitoneal hemorrhage.

The study also showed that increasing obesity increased bleeding risk; there was a 30% increase in bleeding risk for patients with class I obesity but a 93% increase in patients with class III obesity.

“This result suggests that BMI plays a role in bleeding events in patients on warfarin [and] future studies are needed to understand the mechanism by which obesity increases bleeding risk for patients on warfarin, and whether similar risk exists for the novel oral anticoagulants,” said Dr. Adedotun A. Ogunsua of the University of Massachusetts, Worcester, and coauthors.

There were no conflicts of interest disclosed.

Obese patients on warfarin may be at greater risk of bleeding than those of normal weight, according to a study presented at the American Heart Association’s Arteriosclerosis, Thrombosis, and Vascular Biology/Peripheral Vascular Disease Scientific Sessions 2015.

Researchers followed 863 patients attending an anticoagulation clinic for 1 year and found that obesity (body mass index greater than 30 kg/m²) was associated with a statistically significant 84% increase in the risk of major bleeds, such as gastrointestinal, intracerebral, and retroperitoneal hemorrhage.

The study also showed that increasing obesity increased bleeding risk; there was a 30% increase in bleeding risk for patients with class I obesity but a 93% increase in patients with class III obesity.

“This result suggests that BMI plays a role in bleeding events in patients on warfarin [and] future studies are needed to understand the mechanism by which obesity increases bleeding risk for patients on warfarin, and whether similar risk exists for the novel oral anticoagulants,” said Dr. Adedotun A. Ogunsua of the University of Massachusetts, Worcester, and coauthors.

There were no conflicts of interest disclosed.

Obese patients on warfarin may be at greater risk of bleeding than those of normal weight, according to a study presented at the American Heart Association’s Arteriosclerosis, Thrombosis, and Vascular Biology/Peripheral Vascular Disease Scientific Sessions 2015.

Researchers followed 863 patients attending an anticoagulation clinic for 1 year and found that obesity (body mass index greater than 30 kg/m²) was associated with a statistically significant 84% increase in the risk of major bleeds, such as gastrointestinal, intracerebral, and retroperitoneal hemorrhage.

The study also showed that increasing obesity increased bleeding risk; there was a 30% increase in bleeding risk for patients with class I obesity but a 93% increase in patients with class III obesity.

“This result suggests that BMI plays a role in bleeding events in patients on warfarin [and] future studies are needed to understand the mechanism by which obesity increases bleeding risk for patients on warfarin, and whether similar risk exists for the novel oral anticoagulants,” said Dr. Adedotun A. Ogunsua of the University of Massachusetts, Worcester, and coauthors.

There were no conflicts of interest disclosed.

Despite the many changes in medicine over the past century, traumatic injury remains a surgical disease.

Trauma injury is a major public health concern in rural areas, where death rates from unintentional injuries are higher than in metropolitan areas (Am. J. Public Health 2004;10:1689-93). The rural surgeon sees more than his or her fair share of victims of automobile accidents, falls, unintentional firearms injuries, and occupational accidents (think tractor accidents and injuries involving machinery and animals).

Another reality of the rural areas of the United States is that the number of broadly trained general surgeons who can treat a wide variety of trauma injuries is shrinking. Aging and retirements of the “old school rural surgeons” are accelerating and precipitating a lack of surgical coverage crisis, including trauma, in rural areas (Arch. Surg. 2005;140:74-9).

These well-documented developments have combined to reduce the availability of rural surgeons to manage injured patients in planned and consistent ways. Because of the current training paradigm of increasing subspecialization, injured rural patients may be cared for at rural hospitals with reduced capabilities and by rural surgeons with limited trauma training and experience.

What is the action plan to help counteract these developments and to provide the highest-quality patient care at facilities staffed by surgeons who have sworn to “serve all with skill and fidelity”?

The most straightforward and well-established action plan to achieve those goals is the verification process developed by the ACS Verification, Review, and Consultation Program (VRC) in 1987 to help hospitals improve trauma care. The process involves a pre-review questionnaire, a site visit, and report of findings. Verification as a trauma center guarantees that the facility has the required resources listed in the current, evidence-based guide, Resources for Optimal Care of the Injured Patient (2014). If successful, the trauma center receives a certificate of verification that is valid for 3 years.

Most rural hospitals are designated as Level III and IV verified trauma centers on the basis of their available resources. ACS verification confirms that these centers have the commitments and capabilities to manage the initial care of injured patients by providing stabilization and instituting life-saving maneuvers. In addition, verification confirms that protocols and agreements with higher-level trauma centers within a system enable the safe and efficient transfer of injured patients.

During many years of practice in the rural hospitals verified as trauma centers, including being the medical director of a Level II and Level III facility, I provided care to injured patients who presented to the emergency departments (EDs). My experiences confirmed the unequivocal value of practicing in those facilities, and I can attest to the benefits of verification within a system, like Iowa’s state program.

The following case report validates such assertions. A helicopter, unable to complete the transfer to a Level I center for a deteriorating patient with a left chest gunshot wound, landed at my Level III hospital. There was a “Hot Off Load,” which was followed by a full trauma alert for the patient in profound shock. After placing a chest tube during a 20-minute ED stay, the patient transferred to the OR for further resuscitation, and stabilization with required operative treatment. With the patient stabilized and fully resuscitated, according to established agreements, I contacted the Level I center from the OR. After 3 hours, the patient returned to the helicopter and completed the transfer to the Level I trauma center. The patient survived because of the local trauma team’s commitment, organization, and skill brought about by the trauma center verification.

Most research to date has focused on higher-level trauma centers, but recent studies have shown that ACS verification was an independent predictor of survival of trauma patients at Level II centers (J. Trauma Acute Care Surg. 2013;75:44-9; J. Trauma Acute Care Surg. 2010;69:1362-6).

I have firsthand experience with the verification process. Following my involvement with the ACS Committee on Trauma, I became a national site surveyor for the ACSVRC. I became an Advanced Trauma Life Support (ATLS) instructor and then worked as a course director. ATLS is an essential component for trauma center verification. It supports the rural surgeon by giving the local trauma team a format for consistent, life-saving care for the most severely injured patients. I subsequently completed the ACS Advanced Trauma Operative Management course and elected to become an instructor.

I have made site visits to many rural hospitals as a part of the ACSVRC process and have met with a wide range of reactions from “Let’s show off how good we are” to “We really don’t know why we’re doing this” to “Just give us the merit badge and then get out of our hair.” I am gratified to note that ACS Fellows are uniformly supportive. They understand the need for organization, standards, and performance improvement.

Opposition to the ACSVRC process by hospitals and staff is no doubt rooted in cost concerns and general resistance to change. But, as most of us know, demonstrated benefits for patient care can be highly persuasive to most medical professionals.

It is also worth noting that in an effort to decrease stress, the ACSVRC takes significant steps to support facilities that seek verification by eliminating ambiguity from application to on-site visit, by defining criteria deficiencies, and by providing evidence for the entire verification process. The complete VRC program along with an FAQ is available on the ACS website (facs.org/quality-programs/trauma/vrc).

For me, trauma care has always been about what is best for the injured patient. I often ask colleagues this question: “What care do you want for an injured member of your family?” I then answer my own question: “I want the best care possible. That means organized, efficient, and life-saving [care] if needed.” Fortunately, I experienced these benefits at my verified trauma center hospital when my second son was in a rollover motor vehicle crash. He survived.

Verified rural trauma centers do indeed offer the best opportunities for high-quality patient care and for support of the rural surgeons who render that care to “serve all with skill and fidelity.” I know. I have been there.

Dr. Caropreso is a general surgeon at Keokuk (Iowa) Area Hospital and clinical professor of surgery at the University of Iowa Carver College of Medicine, Iowa City. He has practiced surgery in the rural communities of Mason City, Iowa; Keokuk, Iowa; and Carthage, Ill., for 37 years.

Despite the many changes in medicine over the past century, traumatic injury remains a surgical disease.

Trauma injury is a major public health concern in rural areas, where death rates from unintentional injuries are higher than in metropolitan areas (Am. J. Public Health 2004;10:1689-93). The rural surgeon sees more than his or her fair share of victims of automobile accidents, falls, unintentional firearms injuries, and occupational accidents (think tractor accidents and injuries involving machinery and animals).

Another reality of the rural areas of the United States is that the number of broadly trained general surgeons who can treat a wide variety of trauma injuries is shrinking. Aging and retirements of the “old school rural surgeons” are accelerating and precipitating a lack of surgical coverage crisis, including trauma, in rural areas (Arch. Surg. 2005;140:74-9).

These well-documented developments have combined to reduce the availability of rural surgeons to manage injured patients in planned and consistent ways. Because of the current training paradigm of increasing subspecialization, injured rural patients may be cared for at rural hospitals with reduced capabilities and by rural surgeons with limited trauma training and experience.

What is the action plan to help counteract these developments and to provide the highest-quality patient care at facilities staffed by surgeons who have sworn to “serve all with skill and fidelity”?

The most straightforward and well-established action plan to achieve those goals is the verification process developed by the ACS Verification, Review, and Consultation Program (VRC) in 1987 to help hospitals improve trauma care. The process involves a pre-review questionnaire, a site visit, and report of findings. Verification as a trauma center guarantees that the facility has the required resources listed in the current, evidence-based guide, Resources for Optimal Care of the Injured Patient (2014). If successful, the trauma center receives a certificate of verification that is valid for 3 years.

Most rural hospitals are designated as Level III and IV verified trauma centers on the basis of their available resources. ACS verification confirms that these centers have the commitments and capabilities to manage the initial care of injured patients by providing stabilization and instituting life-saving maneuvers. In addition, verification confirms that protocols and agreements with higher-level trauma centers within a system enable the safe and efficient transfer of injured patients.

During many years of practice in the rural hospitals verified as trauma centers, including being the medical director of a Level II and Level III facility, I provided care to injured patients who presented to the emergency departments (EDs). My experiences confirmed the unequivocal value of practicing in those facilities, and I can attest to the benefits of verification within a system, like Iowa’s state program.

The following case report validates such assertions. A helicopter, unable to complete the transfer to a Level I center for a deteriorating patient with a left chest gunshot wound, landed at my Level III hospital. There was a “Hot Off Load,” which was followed by a full trauma alert for the patient in profound shock. After placing a chest tube during a 20-minute ED stay, the patient transferred to the OR for further resuscitation, and stabilization with required operative treatment. With the patient stabilized and fully resuscitated, according to established agreements, I contacted the Level I center from the OR. After 3 hours, the patient returned to the helicopter and completed the transfer to the Level I trauma center. The patient survived because of the local trauma team’s commitment, organization, and skill brought about by the trauma center verification.

Most research to date has focused on higher-level trauma centers, but recent studies have shown that ACS verification was an independent predictor of survival of trauma patients at Level II centers (J. Trauma Acute Care Surg. 2013;75:44-9; J. Trauma Acute Care Surg. 2010;69:1362-6).

I have firsthand experience with the verification process. Following my involvement with the ACS Committee on Trauma, I became a national site surveyor for the ACSVRC. I became an Advanced Trauma Life Support (ATLS) instructor and then worked as a course director. ATLS is an essential component for trauma center verification. It supports the rural surgeon by giving the local trauma team a format for consistent, life-saving care for the most severely injured patients. I subsequently completed the ACS Advanced Trauma Operative Management course and elected to become an instructor.

I have made site visits to many rural hospitals as a part of the ACSVRC process and have met with a wide range of reactions from “Let’s show off how good we are” to “We really don’t know why we’re doing this” to “Just give us the merit badge and then get out of our hair.” I am gratified to note that ACS Fellows are uniformly supportive. They understand the need for organization, standards, and performance improvement.

Opposition to the ACSVRC process by hospitals and staff is no doubt rooted in cost concerns and general resistance to change. But, as most of us know, demonstrated benefits for patient care can be highly persuasive to most medical professionals.

It is also worth noting that in an effort to decrease stress, the ACSVRC takes significant steps to support facilities that seek verification by eliminating ambiguity from application to on-site visit, by defining criteria deficiencies, and by providing evidence for the entire verification process. The complete VRC program along with an FAQ is available on the ACS website (facs.org/quality-programs/trauma/vrc).

For me, trauma care has always been about what is best for the injured patient. I often ask colleagues this question: “What care do you want for an injured member of your family?” I then answer my own question: “I want the best care possible. That means organized, efficient, and life-saving [care] if needed.” Fortunately, I experienced these benefits at my verified trauma center hospital when my second son was in a rollover motor vehicle crash. He survived.

Verified rural trauma centers do indeed offer the best opportunities for high-quality patient care and for support of the rural surgeons who render that care to “serve all with skill and fidelity.” I know. I have been there.

Dr. Caropreso is a general surgeon at Keokuk (Iowa) Area Hospital and clinical professor of surgery at the University of Iowa Carver College of Medicine, Iowa City. He has practiced surgery in the rural communities of Mason City, Iowa; Keokuk, Iowa; and Carthage, Ill., for 37 years.

Despite the many changes in medicine over the past century, traumatic injury remains a surgical disease.

Trauma injury is a major public health concern in rural areas, where death rates from unintentional injuries are higher than in metropolitan areas (Am. J. Public Health 2004;10:1689-93). The rural surgeon sees more than his or her fair share of victims of automobile accidents, falls, unintentional firearms injuries, and occupational accidents (think tractor accidents and injuries involving machinery and animals).

Another reality of the rural areas of the United States is that the number of broadly trained general surgeons who can treat a wide variety of trauma injuries is shrinking. Aging and retirements of the “old school rural surgeons” are accelerating and precipitating a lack of surgical coverage crisis, including trauma, in rural areas (Arch. Surg. 2005;140:74-9).

These well-documented developments have combined to reduce the availability of rural surgeons to manage injured patients in planned and consistent ways. Because of the current training paradigm of increasing subspecialization, injured rural patients may be cared for at rural hospitals with reduced capabilities and by rural surgeons with limited trauma training and experience.

What is the action plan to help counteract these developments and to provide the highest-quality patient care at facilities staffed by surgeons who have sworn to “serve all with skill and fidelity”?

The most straightforward and well-established action plan to achieve those goals is the verification process developed by the ACS Verification, Review, and Consultation Program (VRC) in 1987 to help hospitals improve trauma care. The process involves a pre-review questionnaire, a site visit, and report of findings. Verification as a trauma center guarantees that the facility has the required resources listed in the current, evidence-based guide, Resources for Optimal Care of the Injured Patient (2014). If successful, the trauma center receives a certificate of verification that is valid for 3 years.

Most rural hospitals are designated as Level III and IV verified trauma centers on the basis of their available resources. ACS verification confirms that these centers have the commitments and capabilities to manage the initial care of injured patients by providing stabilization and instituting life-saving maneuvers. In addition, verification confirms that protocols and agreements with higher-level trauma centers within a system enable the safe and efficient transfer of injured patients.

During many years of practice in the rural hospitals verified as trauma centers, including being the medical director of a Level II and Level III facility, I provided care to injured patients who presented to the emergency departments (EDs). My experiences confirmed the unequivocal value of practicing in those facilities, and I can attest to the benefits of verification within a system, like Iowa’s state program.

The following case report validates such assertions. A helicopter, unable to complete the transfer to a Level I center for a deteriorating patient with a left chest gunshot wound, landed at my Level III hospital. There was a “Hot Off Load,” which was followed by a full trauma alert for the patient in profound shock. After placing a chest tube during a 20-minute ED stay, the patient transferred to the OR for further resuscitation, and stabilization with required operative treatment. With the patient stabilized and fully resuscitated, according to established agreements, I contacted the Level I center from the OR. After 3 hours, the patient returned to the helicopter and completed the transfer to the Level I trauma center. The patient survived because of the local trauma team’s commitment, organization, and skill brought about by the trauma center verification.

Most research to date has focused on higher-level trauma centers, but recent studies have shown that ACS verification was an independent predictor of survival of trauma patients at Level II centers (J. Trauma Acute Care Surg. 2013;75:44-9; J. Trauma Acute Care Surg. 2010;69:1362-6).

I have firsthand experience with the verification process. Following my involvement with the ACS Committee on Trauma, I became a national site surveyor for the ACSVRC. I became an Advanced Trauma Life Support (ATLS) instructor and then worked as a course director. ATLS is an essential component for trauma center verification. It supports the rural surgeon by giving the local trauma team a format for consistent, life-saving care for the most severely injured patients. I subsequently completed the ACS Advanced Trauma Operative Management course and elected to become an instructor.

I have made site visits to many rural hospitals as a part of the ACSVRC process and have met with a wide range of reactions from “Let’s show off how good we are” to “We really don’t know why we’re doing this” to “Just give us the merit badge and then get out of our hair.” I am gratified to note that ACS Fellows are uniformly supportive. They understand the need for organization, standards, and performance improvement.

Opposition to the ACSVRC process by hospitals and staff is no doubt rooted in cost concerns and general resistance to change. But, as most of us know, demonstrated benefits for patient care can be highly persuasive to most medical professionals.

It is also worth noting that in an effort to decrease stress, the ACSVRC takes significant steps to support facilities that seek verification by eliminating ambiguity from application to on-site visit, by defining criteria deficiencies, and by providing evidence for the entire verification process. The complete VRC program along with an FAQ is available on the ACS website (facs.org/quality-programs/trauma/vrc).

For me, trauma care has always been about what is best for the injured patient. I often ask colleagues this question: “What care do you want for an injured member of your family?” I then answer my own question: “I want the best care possible. That means organized, efficient, and life-saving [care] if needed.” Fortunately, I experienced these benefits at my verified trauma center hospital when my second son was in a rollover motor vehicle crash. He survived.

Verified rural trauma centers do indeed offer the best opportunities for high-quality patient care and for support of the rural surgeons who render that care to “serve all with skill and fidelity.” I know. I have been there.

Dr. Caropreso is a general surgeon at Keokuk (Iowa) Area Hospital and clinical professor of surgery at the University of Iowa Carver College of Medicine, Iowa City. He has practiced surgery in the rural communities of Mason City, Iowa; Keokuk, Iowa; and Carthage, Ill., for 37 years.

S…G…R (continued) – It is much to all of our collective delight and relief that the SGR has finally been relegated to the ash heap of history.

In the late evening of April 14, in an act of historic bipartisanship, the Senate voted 92-8 in favor of H.R. 2 thus completing legislative action about which I wrote last month. President Obama signed the bill into law on April 16. As I write, Dave Hoyt, ACS Executive Director, is attending an event at the White House, along with other leaders of the physician community, to celebrate the full and permanent repeal of the SGR.

In the coming months, I will use this column to inform surgeons about various components of the legislation and its attendant policy. To start this process, I would first like to cover the key provisions of what is now known as MACRA – the Medicare Access and CHIP Reauthorization Act.

For starters, MACRA fully and permanently repeals the sustainable growth rate (SGR), thus providing stability to the Medicare physician fee schedule. Such repeal averts a 21% SGR-induced cut scheduled for April 1, 2015. MACRA also provides modest but stable positive updates of 0.5%/year for 5 years. When the legislative template that ultimately became MACRA was negotiated in late 2013 and early 2014, no provision was initially made for a positive update to physician payment. However, as a direct result of objections made by the leadership of the ACS, the legislation was subsequently revised to include the 0.5%/year update.

In addition, MACRA provides for the elimination, in 2018, of the current-law penalties associated with the existing quality programs, namely the Physician Quality Reporting System (PQRS), the Value-Based Modifier (VBM) program, and the Electronic Health Record-Meaningful Use (EHR-MU) program. The monies expected from those penalties will be returned to the pool, thus increasing the amount of funds available for incentive updates.

Beginning in 2019, these three programs will be combined into a single program known as the Merit-Based Incentive Payment System (MIPS). The MIPS makes it possible for all surgeons to receive an annual positive update based on their individual performance in four categories of Quality, Resource Use, Meaningful use of the electronic health record, and Clinical practice improvement activities. Surgeons will receive an annual, individual, single composite score based on their performance in these four categories. This score will be compared to a threshold score, defined as either the mean or median of composite scores from a prior performance period. Those with a score above the threshold will receive a positive adjustment and those with a score below the threshold will receive a negative adjustment.The legislation also provides the opportunity to receive a 5% bonus beginning in 2019 for participation in an Alternative Payment Model (APM). Surgeons who meet the full APM criteria will also be excluded from the MIPS assessment and most EHR-MU requirements. Those who participate in an APM at lower levels will receive credit toward their MIPS score. The bonus payment encourages the development of, testing of, and participation in an alternative payment model.

The passage of MACRA also represents a major victory relative to the College’s efforts to rescind the CMS policy transitioning 10- and 90-day global codes to zero-day global codes. ACS leadership and staff of the D.C. office had direct input into the specific language included in the legislation through multiple exchanges with congressional committee staff. In short, MACRA prohibits CMS from implementing its flawed plan relative to the transitioning of the global codes. Instead, beginning no later than 2017, CMS will collect samples of data on the number and level of postoperative visits furnished during the global period. Beginning in 2019, CMS will use this data to improve the accuracy of the valuation of surgical services. CMS is allowed to withhold 5% of the surgical payment until the sample information is reported at the end of the global period.

While MACRA does not implement broad medical liability reforms, it does include a provision which assures that MIPS participation cannot be used in a medical liability action. Specifically, the legislation specifies that the development, recognition or implementation of any guideline or other standard under any federal health care provision, including Medicare, cannot be construed as to establish the standard of care or duty of care owed by a surgeon to a patient in any medical malpractice claim.

Finally, and of particular interest to pediatric surgeons and other surgeons who care for children, MACRA includes two years of additional funding for the Children’s Health Insurance Program (CHIP) at the level provided under the Affordable Care Act.

Unfortunately, surgeons will need to become familiar with an entire new lexicon of acronyms associated with this new law and its policy. While this may initially seem daunting and confusing, it can be mastered with relative ease. It is my hope to continue to facilitate such with the content provided herein with the June edition of this column.

Until next month …

Dr. Bailey is a pediatric surgeon and Medical Director, Advocacy for the Division of Advocacy and Health Policy in the ACS offices in Washington, DC.

S…G…R (continued) – It is much to all of our collective delight and relief that the SGR has finally been relegated to the ash heap of history.

In the late evening of April 14, in an act of historic bipartisanship, the Senate voted 92-8 in favor of H.R. 2 thus completing legislative action about which I wrote last month. President Obama signed the bill into law on April 16. As I write, Dave Hoyt, ACS Executive Director, is attending an event at the White House, along with other leaders of the physician community, to celebrate the full and permanent repeal of the SGR.

In the coming months, I will use this column to inform surgeons about various components of the legislation and its attendant policy. To start this process, I would first like to cover the key provisions of what is now known as MACRA – the Medicare Access and CHIP Reauthorization Act.

For starters, MACRA fully and permanently repeals the sustainable growth rate (SGR), thus providing stability to the Medicare physician fee schedule. Such repeal averts a 21% SGR-induced cut scheduled for April 1, 2015. MACRA also provides modest but stable positive updates of 0.5%/year for 5 years. When the legislative template that ultimately became MACRA was negotiated in late 2013 and early 2014, no provision was initially made for a positive update to physician payment. However, as a direct result of objections made by the leadership of the ACS, the legislation was subsequently revised to include the 0.5%/year update.

In addition, MACRA provides for the elimination, in 2018, of the current-law penalties associated with the existing quality programs, namely the Physician Quality Reporting System (PQRS), the Value-Based Modifier (VBM) program, and the Electronic Health Record-Meaningful Use (EHR-MU) program. The monies expected from those penalties will be returned to the pool, thus increasing the amount of funds available for incentive updates.

Beginning in 2019, these three programs will be combined into a single program known as the Merit-Based Incentive Payment System (MIPS). The MIPS makes it possible for all surgeons to receive an annual positive update based on their individual performance in four categories of Quality, Resource Use, Meaningful use of the electronic health record, and Clinical practice improvement activities. Surgeons will receive an annual, individual, single composite score based on their performance in these four categories. This score will be compared to a threshold score, defined as either the mean or median of composite scores from a prior performance period. Those with a score above the threshold will receive a positive adjustment and those with a score below the threshold will receive a negative adjustment.The legislation also provides the opportunity to receive a 5% bonus beginning in 2019 for participation in an Alternative Payment Model (APM). Surgeons who meet the full APM criteria will also be excluded from the MIPS assessment and most EHR-MU requirements. Those who participate in an APM at lower levels will receive credit toward their MIPS score. The bonus payment encourages the development of, testing of, and participation in an alternative payment model.

The passage of MACRA also represents a major victory relative to the College’s efforts to rescind the CMS policy transitioning 10- and 90-day global codes to zero-day global codes. ACS leadership and staff of the D.C. office had direct input into the specific language included in the legislation through multiple exchanges with congressional committee staff. In short, MACRA prohibits CMS from implementing its flawed plan relative to the transitioning of the global codes. Instead, beginning no later than 2017, CMS will collect samples of data on the number and level of postoperative visits furnished during the global period. Beginning in 2019, CMS will use this data to improve the accuracy of the valuation of surgical services. CMS is allowed to withhold 5% of the surgical payment until the sample information is reported at the end of the global period.

While MACRA does not implement broad medical liability reforms, it does include a provision which assures that MIPS participation cannot be used in a medical liability action. Specifically, the legislation specifies that the development, recognition or implementation of any guideline or other standard under any federal health care provision, including Medicare, cannot be construed as to establish the standard of care or duty of care owed by a surgeon to a patient in any medical malpractice claim.

Finally, and of particular interest to pediatric surgeons and other surgeons who care for children, MACRA includes two years of additional funding for the Children’s Health Insurance Program (CHIP) at the level provided under the Affordable Care Act.

Unfortunately, surgeons will need to become familiar with an entire new lexicon of acronyms associated with this new law and its policy. While this may initially seem daunting and confusing, it can be mastered with relative ease. It is my hope to continue to facilitate such with the content provided herein with the June edition of this column.

Until next month …

Dr. Bailey is a pediatric surgeon and Medical Director, Advocacy for the Division of Advocacy and Health Policy in the ACS offices in Washington, DC.

S…G…R (continued) – It is much to all of our collective delight and relief that the SGR has finally been relegated to the ash heap of history.

In the late evening of April 14, in an act of historic bipartisanship, the Senate voted 92-8 in favor of H.R. 2 thus completing legislative action about which I wrote last month. President Obama signed the bill into law on April 16. As I write, Dave Hoyt, ACS Executive Director, is attending an event at the White House, along with other leaders of the physician community, to celebrate the full and permanent repeal of the SGR.

In the coming months, I will use this column to inform surgeons about various components of the legislation and its attendant policy. To start this process, I would first like to cover the key provisions of what is now known as MACRA – the Medicare Access and CHIP Reauthorization Act.

For starters, MACRA fully and permanently repeals the sustainable growth rate (SGR), thus providing stability to the Medicare physician fee schedule. Such repeal averts a 21% SGR-induced cut scheduled for April 1, 2015. MACRA also provides modest but stable positive updates of 0.5%/year for 5 years. When the legislative template that ultimately became MACRA was negotiated in late 2013 and early 2014, no provision was initially made for a positive update to physician payment. However, as a direct result of objections made by the leadership of the ACS, the legislation was subsequently revised to include the 0.5%/year update.

In addition, MACRA provides for the elimination, in 2018, of the current-law penalties associated with the existing quality programs, namely the Physician Quality Reporting System (PQRS), the Value-Based Modifier (VBM) program, and the Electronic Health Record-Meaningful Use (EHR-MU) program. The monies expected from those penalties will be returned to the pool, thus increasing the amount of funds available for incentive updates.

Beginning in 2019, these three programs will be combined into a single program known as the Merit-Based Incentive Payment System (MIPS). The MIPS makes it possible for all surgeons to receive an annual positive update based on their individual performance in four categories of Quality, Resource Use, Meaningful use of the electronic health record, and Clinical practice improvement activities. Surgeons will receive an annual, individual, single composite score based on their performance in these four categories. This score will be compared to a threshold score, defined as either the mean or median of composite scores from a prior performance period. Those with a score above the threshold will receive a positive adjustment and those with a score below the threshold will receive a negative adjustment.The legislation also provides the opportunity to receive a 5% bonus beginning in 2019 for participation in an Alternative Payment Model (APM). Surgeons who meet the full APM criteria will also be excluded from the MIPS assessment and most EHR-MU requirements. Those who participate in an APM at lower levels will receive credit toward their MIPS score. The bonus payment encourages the development of, testing of, and participation in an alternative payment model.

The passage of MACRA also represents a major victory relative to the College’s efforts to rescind the CMS policy transitioning 10- and 90-day global codes to zero-day global codes. ACS leadership and staff of the D.C. office had direct input into the specific language included in the legislation through multiple exchanges with congressional committee staff. In short, MACRA prohibits CMS from implementing its flawed plan relative to the transitioning of the global codes. Instead, beginning no later than 2017, CMS will collect samples of data on the number and level of postoperative visits furnished during the global period. Beginning in 2019, CMS will use this data to improve the accuracy of the valuation of surgical services. CMS is allowed to withhold 5% of the surgical payment until the sample information is reported at the end of the global period.

While MACRA does not implement broad medical liability reforms, it does include a provision which assures that MIPS participation cannot be used in a medical liability action. Specifically, the legislation specifies that the development, recognition or implementation of any guideline or other standard under any federal health care provision, including Medicare, cannot be construed as to establish the standard of care or duty of care owed by a surgeon to a patient in any medical malpractice claim.

Finally, and of particular interest to pediatric surgeons and other surgeons who care for children, MACRA includes two years of additional funding for the Children’s Health Insurance Program (CHIP) at the level provided under the Affordable Care Act.

Unfortunately, surgeons will need to become familiar with an entire new lexicon of acronyms associated with this new law and its policy. While this may initially seem daunting and confusing, it can be mastered with relative ease. It is my hope to continue to facilitate such with the content provided herein with the June edition of this column.

Until next month …

Dr. Bailey is a pediatric surgeon and Medical Director, Advocacy for the Division of Advocacy and Health Policy in the ACS offices in Washington, DC.

Dying patients teach us to think more carefully about whether or not our surgical interventions will be beneficial.

I work in palliative care, and my surgical colleagues, especially the residents, are often surprised when I call them and ask them to consult on my patients who are very ill and have a “Do Not Resuscitate” order in their charts. I’m also an anesthesiologist working in interventional pain management, and I regularly do procedures on patients who have prognoses that are extremely limited. For other patients, I recommend against any interventions at all.

How do we know when to intervene on patients who are dying? Perhaps more importantly, how do we know when NOT to intervene? Two recent
cases of almost identical fractures illustrated for me the need to think beyond the anatomic problem when evaluating options for care.

Last year, I admitted a woman, “Donna,” with widely metastatic breast cancer to our inpatient palliative care service. She had fallen at home and hurt her arm about 2 months prior to admission. She had been confined to her bed for about 6 weeks. She was brought to the hospital because she was becoming delirious. She had many sources of pain that were relatively well controlled when she was lying down, but her worst pain was in her left arm. We found a fracture of her humerus. When her family learned that the fracture would not heal on its own because of the large metastasis there, they demanded surgery to fix it. Shortly thereafter, I re-admitted a patient, “Cindy,” with a very similar story. She also had widely metastatic breast cancer, and her pain had been very difficult to control. We had found a pain regimen that worked well for her on her previous admission, but she had fallen over her walker and broke her humerus after we had discharged her to a rehab facility. When I saw her back in the hospital, I told her that I thought she would need surgery to fix her arm. She was depressed by this setback, she was in pain again, and she told me that she would prefer not to have any intervention because she feared the additional pain that it would cause.

With Donna, we sat down with her and her family to hear what their hopes were for her care. They understood that she did not have further chemotherapy or radiation options for her cancer, but they thought if she got the surgery that at least she would be able to get out of bed and walk again. My colleague carefully explained that yes, he could fix the fracture and that this could mean that the pain in her left arm would improve. He went on to say, however, that he did not think that the surgery would allow her to walk again as she had not been able to walk for a few weeks after the injury. When the family heard that the surgery probably wouldn’t restore her mobility, they decided against the procedure. With Cindy, we had a very different conversation. She was not inclined to have the procedure, but I expressed my concern that she wouldn’t be able to walk again unless she had the procedure because she needed her arms to use her walker. Although she did not have any further chemotherapy or radiation options, her oncologist had told us that her prognosis could be several months. In this case, my surgical colleague explained that he could perform surgery for the fracture and that he thought that it would both help her pain and allow her to use her walker again. We recommended that she have the surgery given her hope to continue to live independently, as she had been, for as long as possible. She ultimately agreed to do so and was able to return home.

These two patients reminded me again of how important it is for us to understand what our patients’ hopes and expectations are for a procedure. It is very distressing for clinicians when desperate families want treatments that likely have little benefit. When patients have limited prognoses, aligning patient goals and procedure goals is especially important as the outcome of the procedure can define the patient’s remaining days.

Donna’s family demanded a surgery expecting a result that was very unlikely, and Cindy initially declined the same surgery that ultimately benefitted her greatly. Our job is to make and execute the medical recommendations that best fit with our patients’ goals and understanding. Sometimes this will mean performing procedures on patients who are extremely ill and have “Do Not Resuscitate” orders, and at other times, it will mean not doing procedures, even if a patient and family want them to be done.

Dr. Rickerson is an anesthesiologist at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.


Dying patients teach us to think more carefully about whether or not our surgical interventions will be beneficial.

I work in palliative care, and my surgical colleagues, especially the residents, are often surprised when I call them and ask them to consult on my patients who are very ill and have a “Do Not Resuscitate” order in their charts. I’m also an anesthesiologist working in interventional pain management, and I regularly do procedures on patients who have prognoses that are extremely limited. For other patients, I recommend against any interventions at all.

How do we know when to intervene on patients who are dying? Perhaps more importantly, how do we know when NOT to intervene? Two recent
cases of almost identical fractures illustrated for me the need to think beyond the anatomic problem when evaluating options for care.

Last year, I admitted a woman, “Donna,” with widely metastatic breast cancer to our inpatient palliative care service. She had fallen at home and hurt her arm about 2 months prior to admission. She had been confined to her bed for about 6 weeks. She was brought to the hospital because she was becoming delirious. She had many sources of pain that were relatively well controlled when she was lying down, but her worst pain was in her left arm. We found a fracture of her humerus. When her family learned that the fracture would not heal on its own because of the large metastasis there, they demanded surgery to fix it. Shortly thereafter, I re-admitted a patient, “Cindy,” with a very similar story. She also had widely metastatic breast cancer, and her pain had been very difficult to control. We had found a pain regimen that worked well for her on her previous admission, but she had fallen over her walker and broke her humerus after we had discharged her to a rehab facility. When I saw her back in the hospital, I told her that I thought she would need surgery to fix her arm. She was depressed by this setback, she was in pain again, and she told me that she would prefer not to have any intervention because she feared the additional pain that it would cause.

With Donna, we sat down with her and her family to hear what their hopes were for her care. They understood that she did not have further chemotherapy or radiation options for her cancer, but they thought if she got the surgery that at least she would be able to get out of bed and walk again. My colleague carefully explained that yes, he could fix the fracture and that this could mean that the pain in her left arm would improve. He went on to say, however, that he did not think that the surgery would allow her to walk again as she had not been able to walk for a few weeks after the injury. When the family heard that the surgery probably wouldn’t restore her mobility, they decided against the procedure. With Cindy, we had a very different conversation. She was not inclined to have the procedure, but I expressed my concern that she wouldn’t be able to walk again unless she had the procedure because she needed her arms to use her walker. Although she did not have any further chemotherapy or radiation options, her oncologist had told us that her prognosis could be several months. In this case, my surgical colleague explained that he could perform surgery for the fracture and that he thought that it would both help her pain and allow her to use her walker again. We recommended that she have the surgery given her hope to continue to live independently, as she had been, for as long as possible. She ultimately agreed to do so and was able to return home.

These two patients reminded me again of how important it is for us to understand what our patients’ hopes and expectations are for a procedure. It is very distressing for clinicians when desperate families want treatments that likely have little benefit. When patients have limited prognoses, aligning patient goals and procedure goals is especially important as the outcome of the procedure can define the patient’s remaining days.

Donna’s family demanded a surgery expecting a result that was very unlikely, and Cindy initially declined the same surgery that ultimately benefitted her greatly. Our job is to make and execute the medical recommendations that best fit with our patients’ goals and understanding. Sometimes this will mean performing procedures on patients who are extremely ill and have “Do Not Resuscitate” orders, and at other times, it will mean not doing procedures, even if a patient and family want them to be done.

Dr. Rickerson is an anesthesiologist at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.


Dying patients teach us to think more carefully about whether or not our surgical interventions will be beneficial.

I work in palliative care, and my surgical colleagues, especially the residents, are often surprised when I call them and ask them to consult on my patients who are very ill and have a “Do Not Resuscitate” order in their charts. I’m also an anesthesiologist working in interventional pain management, and I regularly do procedures on patients who have prognoses that are extremely limited. For other patients, I recommend against any interventions at all.

How do we know when to intervene on patients who are dying? Perhaps more importantly, how do we know when NOT to intervene? Two recent
cases of almost identical fractures illustrated for me the need to think beyond the anatomic problem when evaluating options for care.

Last year, I admitted a woman, “Donna,” with widely metastatic breast cancer to our inpatient palliative care service. She had fallen at home and hurt her arm about 2 months prior to admission. She had been confined to her bed for about 6 weeks. She was brought to the hospital because she was becoming delirious. She had many sources of pain that were relatively well controlled when she was lying down, but her worst pain was in her left arm. We found a fracture of her humerus. When her family learned that the fracture would not heal on its own because of the large metastasis there, they demanded surgery to fix it. Shortly thereafter, I re-admitted a patient, “Cindy,” with a very similar story. She also had widely metastatic breast cancer, and her pain had been very difficult to control. We had found a pain regimen that worked well for her on her previous admission, but she had fallen over her walker and broke her humerus after we had discharged her to a rehab facility. When I saw her back in the hospital, I told her that I thought she would need surgery to fix her arm. She was depressed by this setback, she was in pain again, and she told me that she would prefer not to have any intervention because she feared the additional pain that it would cause.

With Donna, we sat down with her and her family to hear what their hopes were for her care. They understood that she did not have further chemotherapy or radiation options for her cancer, but they thought if she got the surgery that at least she would be able to get out of bed and walk again. My colleague carefully explained that yes, he could fix the fracture and that this could mean that the pain in her left arm would improve. He went on to say, however, that he did not think that the surgery would allow her to walk again as she had not been able to walk for a few weeks after the injury. When the family heard that the surgery probably wouldn’t restore her mobility, they decided against the procedure. With Cindy, we had a very different conversation. She was not inclined to have the procedure, but I expressed my concern that she wouldn’t be able to walk again unless she had the procedure because she needed her arms to use her walker. Although she did not have any further chemotherapy or radiation options, her oncologist had told us that her prognosis could be several months. In this case, my surgical colleague explained that he could perform surgery for the fracture and that he thought that it would both help her pain and allow her to use her walker again. We recommended that she have the surgery given her hope to continue to live independently, as she had been, for as long as possible. She ultimately agreed to do so and was able to return home.

These two patients reminded me again of how important it is for us to understand what our patients’ hopes and expectations are for a procedure. It is very distressing for clinicians when desperate families want treatments that likely have little benefit. When patients have limited prognoses, aligning patient goals and procedure goals is especially important as the outcome of the procedure can define the patient’s remaining days.

Donna’s family demanded a surgery expecting a result that was very unlikely, and Cindy initially declined the same surgery that ultimately benefitted her greatly. Our job is to make and execute the medical recommendations that best fit with our patients’ goals and understanding. Sometimes this will mean performing procedures on patients who are extremely ill and have “Do Not Resuscitate” orders, and at other times, it will mean not doing procedures, even if a patient and family want them to be done.

Dr. Rickerson is an anesthesiologist at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.


Malaria-carrying mosquito

Photo by James Gathany

A new malaria vaccine candidate proved partially effective in adult males living in an area of low malaria transmission.

The T-cell vaccine consists of the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the multiple epitope string and thrombospondin-related adhesion protein (ME-TRAP), a fusion of protein fragments found on the surface of the malaria parasite Plasmodium falciparum.

In what’s known as a prime-boost strategy, an initial dose of the vaccine “primes” the immune system by exposing it to the malaria antigen and is followed by a vaccine booster, which re-stimulates the immune system to further solidify immunity.

Caroline Ogwang, of the Kenya Medical Research Institute–Wellcome Trust Research Programme in Kilifi, Kenya, and her colleagues described their trial of the vaccine in Science Translational Medicine.

The researchers tested the vaccine in an area of low malaria transmission in Kenya. They enrolled 121 healthy adult men and randomized them to receive the malaria vaccine or a control rabies vaccine.

The subjects were also treated with antimalarial drugs to clear any previous infection and were closely monitored for 8 weeks for P falciparum infection.

The malaria vaccine appeared to be safe, prompting no serious adverse events. The most common local adverse event associated with both ChAd63 ME-TRAP and MVA ME-TRAP was mild to moderate pain that lasted from a few hours to 3 days.

Subjects also experienced various systemic adverse events of mild to moderate intensity that lasted from a few hours to 5 days. Other events were reported within 30 days of vaccination as well, but these were not considered vaccine-related.

As for efficacy, blood tests revealed that the vaccine activated a strong immune response from T cells. For at least 2 weeks after vaccination, the vaccine showed partial efficacy in protecting against malaria infection.

The vaccine reduced subjects’ risk of infection by 67% (P=0.002) during the 8-week monitoring period. And the researchers said T-cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio=0.24, P=0.016).

The team is continuing clinical testing of the vaccine, including possible combinations with other vaccination strategies to increase efficacy.

Malaria-carrying mosquito

Photo by James Gathany

A new malaria vaccine candidate proved partially effective in adult males living in an area of low malaria transmission.

The T-cell vaccine consists of the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the multiple epitope string and thrombospondin-related adhesion protein (ME-TRAP), a fusion of protein fragments found on the surface of the malaria parasite Plasmodium falciparum.

In what’s known as a prime-boost strategy, an initial dose of the vaccine “primes” the immune system by exposing it to the malaria antigen and is followed by a vaccine booster, which re-stimulates the immune system to further solidify immunity.

Caroline Ogwang, of the Kenya Medical Research Institute–Wellcome Trust Research Programme in Kilifi, Kenya, and her colleagues described their trial of the vaccine in Science Translational Medicine.

The researchers tested the vaccine in an area of low malaria transmission in Kenya. They enrolled 121 healthy adult men and randomized them to receive the malaria vaccine or a control rabies vaccine.

The subjects were also treated with antimalarial drugs to clear any previous infection and were closely monitored for 8 weeks for P falciparum infection.

The malaria vaccine appeared to be safe, prompting no serious adverse events. The most common local adverse event associated with both ChAd63 ME-TRAP and MVA ME-TRAP was mild to moderate pain that lasted from a few hours to 3 days.

Subjects also experienced various systemic adverse events of mild to moderate intensity that lasted from a few hours to 5 days. Other events were reported within 30 days of vaccination as well, but these were not considered vaccine-related.

As for efficacy, blood tests revealed that the vaccine activated a strong immune response from T cells. For at least 2 weeks after vaccination, the vaccine showed partial efficacy in protecting against malaria infection.

The vaccine reduced subjects’ risk of infection by 67% (P=0.002) during the 8-week monitoring period. And the researchers said T-cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio=0.24, P=0.016).

The team is continuing clinical testing of the vaccine, including possible combinations with other vaccination strategies to increase efficacy.

Malaria-carrying mosquito

Photo by James Gathany

A new malaria vaccine candidate proved partially effective in adult males living in an area of low malaria transmission.

The T-cell vaccine consists of the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the multiple epitope string and thrombospondin-related adhesion protein (ME-TRAP), a fusion of protein fragments found on the surface of the malaria parasite Plasmodium falciparum.

In what’s known as a prime-boost strategy, an initial dose of the vaccine “primes” the immune system by exposing it to the malaria antigen and is followed by a vaccine booster, which re-stimulates the immune system to further solidify immunity.

Caroline Ogwang, of the Kenya Medical Research Institute–Wellcome Trust Research Programme in Kilifi, Kenya, and her colleagues described their trial of the vaccine in Science Translational Medicine.

The researchers tested the vaccine in an area of low malaria transmission in Kenya. They enrolled 121 healthy adult men and randomized them to receive the malaria vaccine or a control rabies vaccine.

The subjects were also treated with antimalarial drugs to clear any previous infection and were closely monitored for 8 weeks for P falciparum infection.

The malaria vaccine appeared to be safe, prompting no serious adverse events. The most common local adverse event associated with both ChAd63 ME-TRAP and MVA ME-TRAP was mild to moderate pain that lasted from a few hours to 3 days.

Subjects also experienced various systemic adverse events of mild to moderate intensity that lasted from a few hours to 5 days. Other events were reported within 30 days of vaccination as well, but these were not considered vaccine-related.

As for efficacy, blood tests revealed that the vaccine activated a strong immune response from T cells. For at least 2 weeks after vaccination, the vaccine showed partial efficacy in protecting against malaria infection.

The vaccine reduced subjects’ risk of infection by 67% (P=0.002) during the 8-week monitoring period. And the researchers said T-cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio=0.24, P=0.016).

The team is continuing clinical testing of the vaccine, including possible combinations with other vaccination strategies to increase efficacy.

Steven Reed, PhD

Photo courtesy of

The Scripps Research Institute

Overexpression of the cyclin E protein may cause leukemia and breast cancer, according to research published in Current Biology.

The study suggested that overexpression of cyclin E slows down DNA replication and introduces potentially harmful oncogenic mutations when cells divide.

“Overexpression of cyclin E is one route to cancer,” said study author Steven Reed, PhD, of The Scripps Research Institute in La Jolla, California.

Dr Reed and his colleagues originally discovered cyclin E, and their previous studies showed that abnormally high levels of cyclin E are associated with chromosome instability, increasing the chances that a chromosome will acquire more mutations as it divides.

The researchers found that cyclin E is frequently overexpressed in cancer cells, and that overexpression is linked to a decreased survival rate for breast cancer patients.

However, until they conducted the current study, the team didn’t know exactly how cyclin E introduces chromosome instability and errors into DNA.

DNA ‘tug-of-war’

The researchers investigated the role of cyclin E by comparing normal human mammary cells with mammary cells forced to overexpress cyclin E at the same levels seen in some breast cancer cells.

They found that DNA replication took significantly longer in the cyclin E-deregulated cells. In fact, the cells seemed to enter the next stage of cell division before the DNA was even done replicating. A small number (n=16) of very specific regions on the chromosomes frequently failed to complete replication.

The researchers then screened the cyclin E-deregulated cells for errors later in the cell division process. And they found that chromosomes of the deregulated cells’ daughter cells stuck together in the spots where replication had not finished.

“You could see a tug-of-war going on,” Dr Reed said. “That would cause either the chromosome to tear or both chromosomes to go to one side.”

The researchers spotted abnormal DNA “bridges” tying daughter cells together, as well as cells in which chunks of chromosomes ripped away and floated nearby. After these abnormal divisions took place, a third of the cyclin E-deregulated cells showed DNA deletions at the previously identified regions where replication failed.

The link to cancers

Next, the researchers investigated how the genetic instability from DNA deletions in cyclin E-deregulated cells could contribute to cancer. Many of the sites with DNA deletions were areas in which DNA was already known to be fragile or difficult to replicate.

Using a database of tumor DNA sequences, the team found that 6 of the 16 DNA regions they had identified in their cell-based studies showed damage in breast tumors that could be directly linked to cyclin E overexpression.

In addition, an area commonly damaged in cyclin E-deregulated cells matched up with an area commonly rearranged in mixed-lineage leukemia, where cyclin E had already been shown to be a contributing factor.

One of the unanswered questions posed by this work is how cells are allowed to divide before all the chromosomes are completely replicated. It was believed that “checkpoints” exist to prevent this from happening.

Dr Reed thinks these unreplicated regions are small enough to bypass the cellular checkpoints and keep cells dividing and accumulating potentially harmful mutations.

His team’s next step is to sequence the entire genomes of cells that undergo damage from cyclin E overexpression to understand exactly how the deletions contribute to cancer.

Steven Reed, PhD

Photo courtesy of

The Scripps Research Institute

Overexpression of the cyclin E protein may cause leukemia and breast cancer, according to research published in Current Biology.

The study suggested that overexpression of cyclin E slows down DNA replication and introduces potentially harmful oncogenic mutations when cells divide.

“Overexpression of cyclin E is one route to cancer,” said study author Steven Reed, PhD, of The Scripps Research Institute in La Jolla, California.

Dr Reed and his colleagues originally discovered cyclin E, and their previous studies showed that abnormally high levels of cyclin E are associated with chromosome instability, increasing the chances that a chromosome will acquire more mutations as it divides.

The researchers found that cyclin E is frequently overexpressed in cancer cells, and that overexpression is linked to a decreased survival rate for breast cancer patients.

However, until they conducted the current study, the team didn’t know exactly how cyclin E introduces chromosome instability and errors into DNA.

DNA ‘tug-of-war’

The researchers investigated the role of cyclin E by comparing normal human mammary cells with mammary cells forced to overexpress cyclin E at the same levels seen in some breast cancer cells.

They found that DNA replication took significantly longer in the cyclin E-deregulated cells. In fact, the cells seemed to enter the next stage of cell division before the DNA was even done replicating. A small number (n=16) of very specific regions on the chromosomes frequently failed to complete replication.

The researchers then screened the cyclin E-deregulated cells for errors later in the cell division process. And they found that chromosomes of the deregulated cells’ daughter cells stuck together in the spots where replication had not finished.

“You could see a tug-of-war going on,” Dr Reed said. “That would cause either the chromosome to tear or both chromosomes to go to one side.”

The researchers spotted abnormal DNA “bridges” tying daughter cells together, as well as cells in which chunks of chromosomes ripped away and floated nearby. After these abnormal divisions took place, a third of the cyclin E-deregulated cells showed DNA deletions at the previously identified regions where replication failed.

The link to cancers

Next, the researchers investigated how the genetic instability from DNA deletions in cyclin E-deregulated cells could contribute to cancer. Many of the sites with DNA deletions were areas in which DNA was already known to be fragile or difficult to replicate.

Using a database of tumor DNA sequences, the team found that 6 of the 16 DNA regions they had identified in their cell-based studies showed damage in breast tumors that could be directly linked to cyclin E overexpression.

In addition, an area commonly damaged in cyclin E-deregulated cells matched up with an area commonly rearranged in mixed-lineage leukemia, where cyclin E had already been shown to be a contributing factor.

One of the unanswered questions posed by this work is how cells are allowed to divide before all the chromosomes are completely replicated. It was believed that “checkpoints” exist to prevent this from happening.

Dr Reed thinks these unreplicated regions are small enough to bypass the cellular checkpoints and keep cells dividing and accumulating potentially harmful mutations.

His team’s next step is to sequence the entire genomes of cells that undergo damage from cyclin E overexpression to understand exactly how the deletions contribute to cancer.

Steven Reed, PhD

Photo courtesy of

The Scripps Research Institute

Overexpression of the cyclin E protein may cause leukemia and breast cancer, according to research published in Current Biology.

The study suggested that overexpression of cyclin E slows down DNA replication and introduces potentially harmful oncogenic mutations when cells divide.

“Overexpression of cyclin E is one route to cancer,” said study author Steven Reed, PhD, of The Scripps Research Institute in La Jolla, California.

Dr Reed and his colleagues originally discovered cyclin E, and their previous studies showed that abnormally high levels of cyclin E are associated with chromosome instability, increasing the chances that a chromosome will acquire more mutations as it divides.

The researchers found that cyclin E is frequently overexpressed in cancer cells, and that overexpression is linked to a decreased survival rate for breast cancer patients.

However, until they conducted the current study, the team didn’t know exactly how cyclin E introduces chromosome instability and errors into DNA.

DNA ‘tug-of-war’

The researchers investigated the role of cyclin E by comparing normal human mammary cells with mammary cells forced to overexpress cyclin E at the same levels seen in some breast cancer cells.

They found that DNA replication took significantly longer in the cyclin E-deregulated cells. In fact, the cells seemed to enter the next stage of cell division before the DNA was even done replicating. A small number (n=16) of very specific regions on the chromosomes frequently failed to complete replication.

The researchers then screened the cyclin E-deregulated cells for errors later in the cell division process. And they found that chromosomes of the deregulated cells’ daughter cells stuck together in the spots where replication had not finished.

“You could see a tug-of-war going on,” Dr Reed said. “That would cause either the chromosome to tear or both chromosomes to go to one side.”

The researchers spotted abnormal DNA “bridges” tying daughter cells together, as well as cells in which chunks of chromosomes ripped away and floated nearby. After these abnormal divisions took place, a third of the cyclin E-deregulated cells showed DNA deletions at the previously identified regions where replication failed.

The link to cancers

Next, the researchers investigated how the genetic instability from DNA deletions in cyclin E-deregulated cells could contribute to cancer. Many of the sites with DNA deletions were areas in which DNA was already known to be fragile or difficult to replicate.

Using a database of tumor DNA sequences, the team found that 6 of the 16 DNA regions they had identified in their cell-based studies showed damage in breast tumors that could be directly linked to cyclin E overexpression.

In addition, an area commonly damaged in cyclin E-deregulated cells matched up with an area commonly rearranged in mixed-lineage leukemia, where cyclin E had already been shown to be a contributing factor.

One of the unanswered questions posed by this work is how cells are allowed to divide before all the chromosomes are completely replicated. It was believed that “checkpoints” exist to prevent this from happening.

Dr Reed thinks these unreplicated regions are small enough to bypass the cellular checkpoints and keep cells dividing and accumulating potentially harmful mutations.

His team’s next step is to sequence the entire genomes of cells that undergo damage from cyclin E overexpression to understand exactly how the deletions contribute to cancer.

Doctor evaluating patient

Photo courtesy of CDC

Patients with gastrointestinal stromal tumors (GIST) have an increased risk of developing non-Hodgkin lymphoma (NHL) and other cancers, a new study suggests.

About 1 in 6 of the patients studied were diagnosed with an additional malignancy.

The patients had an increased risk of other sarcomas, NHL, carcinoid tumors, melanoma, and colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate, and renal cell cancers.

“Only 5% of patients with gastrointestinal stromal tumors have a hereditary disorder that predisposes them to develop multiple benign and malignant tumors,” said study author Jason K. Sicklick, MD, of the University of California San Diego Moores Cancer Center.

“The research indicates that these patients may develop cancers outside of these syndromes, but the exact mechanisms are not yet known.”

Dr Sicklick and his colleagues described their research in Cancer.

The team analyzed 6112 GIST patients and found that 1047 of them (17.1%) had additional cancers.

When compared to the general US population, patients had a 44% increased prevalence of cancers occurring before a GIST diagnosis and a 66% higher risk of developing cancers after GIST diagnosis.

That corresponds to a standardized prevalence ratio (SPR) of 1.44 (risk before GIST diagnosis) and a standardized incidence ratio (SIR) of 1.66 (risk after GIST diagnosis).

Both before and after GIST diagnosis, patients had a significantly increased risk of NHL (SPR=1.69, SIR=1.76), other sarcomas (SPR=5.24, SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56, SIR=4.79), and colorectal adenocarcinoma (SPR=1.51, SIR=2.16).

Before GIST diagnosis, patients had an increased risk of esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20).

And after GIST diagnosis, they had an increased risk of ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinoma (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65).

The researchers said further studies are needed to understand the connection between GIST and other cancers, but these findings may have clinical implications.

“Patients diagnosed with gastrointestinal stromal tumors may warrant consideration for additional screenings based on the other cancers that they are most susceptible to contract,” said James D. Murphy, MD, also of the University of California San Diego Moores Cancer Center.

Doctor evaluating patient

Photo courtesy of CDC

Patients with gastrointestinal stromal tumors (GIST) have an increased risk of developing non-Hodgkin lymphoma (NHL) and other cancers, a new study suggests.

About 1 in 6 of the patients studied were diagnosed with an additional malignancy.

The patients had an increased risk of other sarcomas, NHL, carcinoid tumors, melanoma, and colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate, and renal cell cancers.

“Only 5% of patients with gastrointestinal stromal tumors have a hereditary disorder that predisposes them to develop multiple benign and malignant tumors,” said study author Jason K. Sicklick, MD, of the University of California San Diego Moores Cancer Center.

“The research indicates that these patients may develop cancers outside of these syndromes, but the exact mechanisms are not yet known.”

Dr Sicklick and his colleagues described their research in Cancer.

The team analyzed 6112 GIST patients and found that 1047 of them (17.1%) had additional cancers.

When compared to the general US population, patients had a 44% increased prevalence of cancers occurring before a GIST diagnosis and a 66% higher risk of developing cancers after GIST diagnosis.

That corresponds to a standardized prevalence ratio (SPR) of 1.44 (risk before GIST diagnosis) and a standardized incidence ratio (SIR) of 1.66 (risk after GIST diagnosis).

Both before and after GIST diagnosis, patients had a significantly increased risk of NHL (SPR=1.69, SIR=1.76), other sarcomas (SPR=5.24, SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56, SIR=4.79), and colorectal adenocarcinoma (SPR=1.51, SIR=2.16).

Before GIST diagnosis, patients had an increased risk of esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20).

And after GIST diagnosis, they had an increased risk of ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinoma (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65).

The researchers said further studies are needed to understand the connection between GIST and other cancers, but these findings may have clinical implications.

“Patients diagnosed with gastrointestinal stromal tumors may warrant consideration for additional screenings based on the other cancers that they are most susceptible to contract,” said James D. Murphy, MD, also of the University of California San Diego Moores Cancer Center.

Doctor evaluating patient

Photo courtesy of CDC

Patients with gastrointestinal stromal tumors (GIST) have an increased risk of developing non-Hodgkin lymphoma (NHL) and other cancers, a new study suggests.

About 1 in 6 of the patients studied were diagnosed with an additional malignancy.

The patients had an increased risk of other sarcomas, NHL, carcinoid tumors, melanoma, and colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate, and renal cell cancers.

“Only 5% of patients with gastrointestinal stromal tumors have a hereditary disorder that predisposes them to develop multiple benign and malignant tumors,” said study author Jason K. Sicklick, MD, of the University of California San Diego Moores Cancer Center.

“The research indicates that these patients may develop cancers outside of these syndromes, but the exact mechanisms are not yet known.”

Dr Sicklick and his colleagues described their research in Cancer.

The team analyzed 6112 GIST patients and found that 1047 of them (17.1%) had additional cancers.

When compared to the general US population, patients had a 44% increased prevalence of cancers occurring before a GIST diagnosis and a 66% higher risk of developing cancers after GIST diagnosis.

That corresponds to a standardized prevalence ratio (SPR) of 1.44 (risk before GIST diagnosis) and a standardized incidence ratio (SIR) of 1.66 (risk after GIST diagnosis).

Both before and after GIST diagnosis, patients had a significantly increased risk of NHL (SPR=1.69, SIR=1.76), other sarcomas (SPR=5.24, SIR=4.02), neuroendocrine-carcinoid tumors (SPR=3.56, SIR=4.79), and colorectal adenocarcinoma (SPR=1.51, SIR=2.16).

Before GIST diagnosis, patients had an increased risk of esophageal adenocarcinoma (SPR=12.0), bladder adenocarcinoma (SPR=7.51), melanoma (SPR=1.46), and prostate adenocarcinoma (SPR=1.20).

And after GIST diagnosis, they had an increased risk of ovarian carcinoma (SIR=8.72), small intestine adenocarcinoma (SIR=5.89), papillary thyroid cancer (SIR=5.16), renal cell carcinoma (SIR=4.46), hepatobiliary adenocarcinoma (SIR=3.10), gastric adenocarcinoma (SIR=2.70), pancreatic adenocarcinoma (SIR=2.03), uterine adenocarcinoma (SIR=1.96), non-small cell lung cancer (SIR=1.74), and transitional cell carcinoma of the bladder (SIR=1.65).

The researchers said further studies are needed to understand the connection between GIST and other cancers, but these findings may have clinical implications.

“Patients diagnosed with gastrointestinal stromal tumors may warrant consideration for additional screenings based on the other cancers that they are most susceptible to contract,” said James D. Murphy, MD, also of the University of California San Diego Moores Cancer Center.

Plasmodium parasite

infecting an RBC

Photo courtesy of St. Jude

Children’s Research Hospital

A protein on the surface of red blood cells (RBCs) serves as an essential entry point for malaria parasite invasion, according to researchers.

They found the presence of this protein, CD55, was critical to the Plasmodium falciparum parasite’s ability to attach itself to the RBC surface.

The team believes this discovery, published in Science, opens up a promising new avenue for developing therapies to treat and prevent malaria.

“Plasmodium falciparum malaria parasites have evolved several key-like molecules to enter into human red blood cells through different door-like host receptors,” said study author Manoj Duraisingh, PhD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.

“Hence, if one red blood cell door is blocked, the parasite finds another way to enter. We have now identified an essential host factor which, when removed, prevents all parasite strains from entering red blood cells.”

The researchers accomplished this by developing a new technique to tap into a relatively unexplored area: identifying characteristics of a host RBC that make it susceptible to parasites. RBCs are difficult targets for such efforts as they lack a nucleus, which makes genetic manipulation impossible.

So the team transformed stem cells into RBCs, which allowed them to conduct a genetic screen for host determinants of P falciparum infection. They found that malaria parasites failed to attach properly to the surface of RBCs that lacked CD55.

The protein was required for invasion in all tested strains of the parasite, including those developed in a lab and those isolated from patients. This makes CD55 a primary candidate for intervention, the researchers said.

“The discovery of CD55 as an essential host factor for P falciparum raises the intriguing possibility of host-directed therapeutics for malaria, as is used in HIV,” said study author Elizabeth Egan, MD, PhD, also of the Harvard T. H. Chan School of Public Health.

“CD55 also gives us a hook with which to search for new parasite proteins important for invasion, which could serve as vaccine targets.”

Plasmodium parasite

infecting an RBC

Photo courtesy of St. Jude

Children’s Research Hospital

A protein on the surface of red blood cells (RBCs) serves as an essential entry point for malaria parasite invasion, according to researchers.

They found the presence of this protein, CD55, was critical to the Plasmodium falciparum parasite’s ability to attach itself to the RBC surface.

The team believes this discovery, published in Science, opens up a promising new avenue for developing therapies to treat and prevent malaria.

“Plasmodium falciparum malaria parasites have evolved several key-like molecules to enter into human red blood cells through different door-like host receptors,” said study author Manoj Duraisingh, PhD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.

“Hence, if one red blood cell door is blocked, the parasite finds another way to enter. We have now identified an essential host factor which, when removed, prevents all parasite strains from entering red blood cells.”

The researchers accomplished this by developing a new technique to tap into a relatively unexplored area: identifying characteristics of a host RBC that make it susceptible to parasites. RBCs are difficult targets for such efforts as they lack a nucleus, which makes genetic manipulation impossible.

So the team transformed stem cells into RBCs, which allowed them to conduct a genetic screen for host determinants of P falciparum infection. They found that malaria parasites failed to attach properly to the surface of RBCs that lacked CD55.

The protein was required for invasion in all tested strains of the parasite, including those developed in a lab and those isolated from patients. This makes CD55 a primary candidate for intervention, the researchers said.

“The discovery of CD55 as an essential host factor for P falciparum raises the intriguing possibility of host-directed therapeutics for malaria, as is used in HIV,” said study author Elizabeth Egan, MD, PhD, also of the Harvard T. H. Chan School of Public Health.

“CD55 also gives us a hook with which to search for new parasite proteins important for invasion, which could serve as vaccine targets.”

Plasmodium parasite

infecting an RBC

Photo courtesy of St. Jude

Children’s Research Hospital

A protein on the surface of red blood cells (RBCs) serves as an essential entry point for malaria parasite invasion, according to researchers.

They found the presence of this protein, CD55, was critical to the Plasmodium falciparum parasite’s ability to attach itself to the RBC surface.

The team believes this discovery, published in Science, opens up a promising new avenue for developing therapies to treat and prevent malaria.

“Plasmodium falciparum malaria parasites have evolved several key-like molecules to enter into human red blood cells through different door-like host receptors,” said study author Manoj Duraisingh, PhD, of the Harvard T. H. Chan School of Public Health in Boston, Massachusetts.

“Hence, if one red blood cell door is blocked, the parasite finds another way to enter. We have now identified an essential host factor which, when removed, prevents all parasite strains from entering red blood cells.”

The researchers accomplished this by developing a new technique to tap into a relatively unexplored area: identifying characteristics of a host RBC that make it susceptible to parasites. RBCs are difficult targets for such efforts as they lack a nucleus, which makes genetic manipulation impossible.

So the team transformed stem cells into RBCs, which allowed them to conduct a genetic screen for host determinants of P falciparum infection. They found that malaria parasites failed to attach properly to the surface of RBCs that lacked CD55.

The protein was required for invasion in all tested strains of the parasite, including those developed in a lab and those isolated from patients. This makes CD55 a primary candidate for intervention, the researchers said.

“The discovery of CD55 as an essential host factor for P falciparum raises the intriguing possibility of host-directed therapeutics for malaria, as is used in HIV,” said study author Elizabeth Egan, MD, PhD, also of the Harvard T. H. Chan School of Public Health.

“CD55 also gives us a hook with which to search for new parasite proteins important for invasion, which could serve as vaccine targets.”