Minimally invasive cardiac surgery has experienced a meteoric rise since its development in the 1990s. The first thoracic aortic stent graft was placed in July 1992, at Stanford (Calif.) University. Five years later, the Stanford group published their approach to mitral valve surgery through a right anterior thoracotomy. Just a year later, Dr. Alain Carpentier performed the first robotic-assisted mitral valve operation.1 There has been an explosion of new techniques, broadening the cardiac surgeon’s armamentarium far beyond the typical median sternotomy and occasional left thoracotomy.

While many of these techniques will undoubtedly become historical footnotes, it is clear that minimally invasive cardiac surgery is here to stay, as 20% of mitral repairs are performed with some element of minimally invasive technique. Similarly, thoracic endovascular aortic repair has become a well-established treatment for aneurysmal disease and dissection of the thoracic aorta, and is rapidly catching up with open repair as the treatment of choice.²

Training has also changed. The last decade brought a surge of applications to traditional fellowship programs, and the integrated thoracic surgery programs graduated their first trainees last year. With the variety of new operations and techniques, novel training formats, and professional goals for cardiothoracic surgery trainees, how can we be sure that young cardiac surgeons are learning the skills they need to succeed in the coming decades?

To ask how new surgeons should learn, you must start by asking what needs to be learned. After I asked a number of different surgeons in a variety of practice set-ups, the answer became obvious, and it is deceptively basic. The purpose of training is simply to ensure that each trainee can do all of the commonly performed operations of their specialty. This includes open valve and coronary surgery on the cardiac side, while for thoracic surgery, this includes all of the traditional lung and esophageal resections, chest wall and pleural operations, and importantly, the widely practiced VATS lobectomy. When I asked about more advanced VATS skills and minimally invasive cardiac skills, I was always told that those would be icing on the cake, as it were, to make a graduate more valuable to a potential employer. The first step in learning a minimally invasive operation is to understand the traditional, open approach, and VATS lung surgery is no different.

The VATS lobectomy has been a recent but well-received addition to the expected repertoire of graduates, and Dr. Chadrick Denlinger, associate professor of surgery at the Medical University of South Carolina, Charleston, allows his chief residents to take other trainees through the case, and expects that all new graduates can do one. Across the coast, Dr. Joseph Woo, newly appointed chair of cardiovascular surgery at Stanford, agrees. This expectation alone informs us that our specialty is dynamic and that the definition of an essential skill is in constant flux. On the other hand, cardiac surgery has no touchstone or standard minimally invasive procedure. However, Dr. Woo explains, the ABTS has set its recommendations in anticipation of the continued success of minimally invasive approaches to cardiovascular problems. The board doesn’t require mastery of any specific minimally invasive cardiac operation by the end of a training program, but it does require that we are exposed to a number of different endovascular and nontraditional approaches to coronary, valve, and aortic surgery. Coupled with our presumed mastery of the standard, open operations, we should then have the basic skills necessary to learn whatever minimally invasive operations we like, depending on our interests and our post-training mentorship.

Of course, the safety and efficacy of thoracic aortic stent grafting and minimally invasive mitral surgery have already been proven to some degree, and the operations aren’t going away anytime soon.^3,4 So what is stopping us from learning this stuff during our training? The answer is complicated. Dr. Woo cites the lack of visualization for two surgeons, the difficulty in preventing and controlling technical complications in a limited field, and the very nature the operations themselves.

Take, for example, the minimally invasive mitral valve repair. Its open counterpart requires a skill set that few trainees, if any, can claim mastery of until the very end of their training. The skill required, patient selection, and pathology treated make the operation sort of a "boutique" treatment. The patients that are offered right thoracotomy approach tend to be younger, less symptomatic, and with less complex disease. They have higher expectations. As Dr. Woo put it, "if you perform an absolutely perfect repair, then you’ve only done your job. But there is no way to do any better." With that sort of standard, many attending surgeons are hesitant to hand over the instruments to a trainee. Furthermore, not every resident’s technical ability lines up with what is required of that interest, and more importantly, not every resident is interested. Because of the highly specialized nature of the operation, the relatively smaller patient base, and the technical difficulty involved, it is often up to the highly motivated fellow or resident to gravitate to these repairs and seek out the training on their own.

Dr. James Fann, cofounder of the annual TSDA boot camp and a national surgical education leader, has some perspective on the matter. If residents are interested in gaining added endovascular or minimally invasive skills, he suggests, they first have to prove themselves in the operating room. When they’ve mastered the skills for an open technique and have proven they can get out of trouble, then an attending might feel comfortable letting them take on these more complex cases. It takes a combination of skill and interest – and as only a minority of trainees will have both, most training programs do not require that every TEVAR or mini-mitral be staffed with a resident.

It seems that simulation does not provide an easy shortcut beyond this approach, though it does have a role. To be honest, I expected Dr. Fann to preach the simulation gospel, and tell me about some incredible TEVAR or TAVR simulator he was getting ready to unveil, but his response was far more measured. "The role of simulation," he said, "is not to teach a resident how to operate. It is an adjunct – a tool that can be used to identify and address specific technical issues outside of the operating room." He reinforced the importance of mastering traditional surgical techniques before embarking on miniaturization. Simulation can help trainees operate more efficiently and effectively, but it cannot and should not replace mentored operative experience.

MICS simulation does exist, as anyone who has worked with Dr. L. Wiley Nifong and Dr. Randolph Chitwood’s high-fidelity tissue simulators for minimally invasive mitral valve repair knows. Simbionix USA (Cleveland) has just obtained FDA clearance for its TEVAR simulator that can be tailored to rehearse an upcoming case using a patient’s CT scan. On the lower end of the cost spectrum, a Dutch group and a separate Hannover group have developed low-cost, reproducible models of mini-mitral surgery that can be built from materials from a hardware store.⁵ Again, all of these tools are designed to be adjuncts to experiential training and mentorship, not mentors in and of themselves.

Residents can and should be exposed to TEVAR, TAVR, mini-mitral repair, and other less invasive approaches that are offered at their institution if they are interested. These, along with any other skills beyond traditional open techniques, make the surgeon better. More importantly, they help the trainee gain the basic wire and small incision skills they will need to learn quickly any newly developed operations that the changing specialty requires. They may not master the skills as a resident, but they are that much more prepared to hone those skills with their mentors when that time comes. In fact, the faculty I spoke with placed far more emphasis on mentorship after residency than aggressive residency training, simulation, and superfellowship as the key to gaining these advanced skills. Trainees should be soaking up all of the skills that they possibly can while they can, and if one is smart, ambitious, and skilled enough to become technically proficient at a more technically advanced skill, it certainly makes them a more desirable surgeon. For most of us, however, it is more important to realize that the training never truly ends, to take advantage of the opportunities afforded by residency, and to continue getting those reps in the OR.

References

1. Cardiac Surgery in the Adult, 4e. New York, N.Y.: McGraw-Hill; 2012.

2. J. Thorac. Cardiovasc. Surg. 2012; 144:612-16.

3. Circulation 2013;6:407-16.

4. Ann. Cardiothorac. Surg. 2013;2:744-50.

5. Interact. Cardiovasc. Thorac. Surg. 2013;16:97-101.

Minimally invasive cardiac surgery has experienced a meteoric rise since its development in the 1990s. The first thoracic aortic stent graft was placed in July 1992, at Stanford (Calif.) University. Five years later, the Stanford group published their approach to mitral valve surgery through a right anterior thoracotomy. Just a year later, Dr. Alain Carpentier performed the first robotic-assisted mitral valve operation.1 There has been an explosion of new techniques, broadening the cardiac surgeon’s armamentarium far beyond the typical median sternotomy and occasional left thoracotomy.

While many of these techniques will undoubtedly become historical footnotes, it is clear that minimally invasive cardiac surgery is here to stay, as 20% of mitral repairs are performed with some element of minimally invasive technique. Similarly, thoracic endovascular aortic repair has become a well-established treatment for aneurysmal disease and dissection of the thoracic aorta, and is rapidly catching up with open repair as the treatment of choice.²

Training has also changed. The last decade brought a surge of applications to traditional fellowship programs, and the integrated thoracic surgery programs graduated their first trainees last year. With the variety of new operations and techniques, novel training formats, and professional goals for cardiothoracic surgery trainees, how can we be sure that young cardiac surgeons are learning the skills they need to succeed in the coming decades?

To ask how new surgeons should learn, you must start by asking what needs to be learned. After I asked a number of different surgeons in a variety of practice set-ups, the answer became obvious, and it is deceptively basic. The purpose of training is simply to ensure that each trainee can do all of the commonly performed operations of their specialty. This includes open valve and coronary surgery on the cardiac side, while for thoracic surgery, this includes all of the traditional lung and esophageal resections, chest wall and pleural operations, and importantly, the widely practiced VATS lobectomy. When I asked about more advanced VATS skills and minimally invasive cardiac skills, I was always told that those would be icing on the cake, as it were, to make a graduate more valuable to a potential employer. The first step in learning a minimally invasive operation is to understand the traditional, open approach, and VATS lung surgery is no different.

The VATS lobectomy has been a recent but well-received addition to the expected repertoire of graduates, and Dr. Chadrick Denlinger, associate professor of surgery at the Medical University of South Carolina, Charleston, allows his chief residents to take other trainees through the case, and expects that all new graduates can do one. Across the coast, Dr. Joseph Woo, newly appointed chair of cardiovascular surgery at Stanford, agrees. This expectation alone informs us that our specialty is dynamic and that the definition of an essential skill is in constant flux. On the other hand, cardiac surgery has no touchstone or standard minimally invasive procedure. However, Dr. Woo explains, the ABTS has set its recommendations in anticipation of the continued success of minimally invasive approaches to cardiovascular problems. The board doesn’t require mastery of any specific minimally invasive cardiac operation by the end of a training program, but it does require that we are exposed to a number of different endovascular and nontraditional approaches to coronary, valve, and aortic surgery. Coupled with our presumed mastery of the standard, open operations, we should then have the basic skills necessary to learn whatever minimally invasive operations we like, depending on our interests and our post-training mentorship.

Of course, the safety and efficacy of thoracic aortic stent grafting and minimally invasive mitral surgery have already been proven to some degree, and the operations aren’t going away anytime soon.^3,4 So what is stopping us from learning this stuff during our training? The answer is complicated. Dr. Woo cites the lack of visualization for two surgeons, the difficulty in preventing and controlling technical complications in a limited field, and the very nature the operations themselves.

Take, for example, the minimally invasive mitral valve repair. Its open counterpart requires a skill set that few trainees, if any, can claim mastery of until the very end of their training. The skill required, patient selection, and pathology treated make the operation sort of a "boutique" treatment. The patients that are offered right thoracotomy approach tend to be younger, less symptomatic, and with less complex disease. They have higher expectations. As Dr. Woo put it, "if you perform an absolutely perfect repair, then you’ve only done your job. But there is no way to do any better." With that sort of standard, many attending surgeons are hesitant to hand over the instruments to a trainee. Furthermore, not every resident’s technical ability lines up with what is required of that interest, and more importantly, not every resident is interested. Because of the highly specialized nature of the operation, the relatively smaller patient base, and the technical difficulty involved, it is often up to the highly motivated fellow or resident to gravitate to these repairs and seek out the training on their own.

Dr. James Fann, cofounder of the annual TSDA boot camp and a national surgical education leader, has some perspective on the matter. If residents are interested in gaining added endovascular or minimally invasive skills, he suggests, they first have to prove themselves in the operating room. When they’ve mastered the skills for an open technique and have proven they can get out of trouble, then an attending might feel comfortable letting them take on these more complex cases. It takes a combination of skill and interest – and as only a minority of trainees will have both, most training programs do not require that every TEVAR or mini-mitral be staffed with a resident.

It seems that simulation does not provide an easy shortcut beyond this approach, though it does have a role. To be honest, I expected Dr. Fann to preach the simulation gospel, and tell me about some incredible TEVAR or TAVR simulator he was getting ready to unveil, but his response was far more measured. "The role of simulation," he said, "is not to teach a resident how to operate. It is an adjunct – a tool that can be used to identify and address specific technical issues outside of the operating room." He reinforced the importance of mastering traditional surgical techniques before embarking on miniaturization. Simulation can help trainees operate more efficiently and effectively, but it cannot and should not replace mentored operative experience.

MICS simulation does exist, as anyone who has worked with Dr. L. Wiley Nifong and Dr. Randolph Chitwood’s high-fidelity tissue simulators for minimally invasive mitral valve repair knows. Simbionix USA (Cleveland) has just obtained FDA clearance for its TEVAR simulator that can be tailored to rehearse an upcoming case using a patient’s CT scan. On the lower end of the cost spectrum, a Dutch group and a separate Hannover group have developed low-cost, reproducible models of mini-mitral surgery that can be built from materials from a hardware store.⁵ Again, all of these tools are designed to be adjuncts to experiential training and mentorship, not mentors in and of themselves.

Residents can and should be exposed to TEVAR, TAVR, mini-mitral repair, and other less invasive approaches that are offered at their institution if they are interested. These, along with any other skills beyond traditional open techniques, make the surgeon better. More importantly, they help the trainee gain the basic wire and small incision skills they will need to learn quickly any newly developed operations that the changing specialty requires. They may not master the skills as a resident, but they are that much more prepared to hone those skills with their mentors when that time comes. In fact, the faculty I spoke with placed far more emphasis on mentorship after residency than aggressive residency training, simulation, and superfellowship as the key to gaining these advanced skills. Trainees should be soaking up all of the skills that they possibly can while they can, and if one is smart, ambitious, and skilled enough to become technically proficient at a more technically advanced skill, it certainly makes them a more desirable surgeon. For most of us, however, it is more important to realize that the training never truly ends, to take advantage of the opportunities afforded by residency, and to continue getting those reps in the OR.

References

1. Cardiac Surgery in the Adult, 4e. New York, N.Y.: McGraw-Hill; 2012.

2. J. Thorac. Cardiovasc. Surg. 2012; 144:612-16.

3. Circulation 2013;6:407-16.

4. Ann. Cardiothorac. Surg. 2013;2:744-50.

5. Interact. Cardiovasc. Thorac. Surg. 2013;16:97-101.

Minimally invasive cardiac surgery has experienced a meteoric rise since its development in the 1990s. The first thoracic aortic stent graft was placed in July 1992, at Stanford (Calif.) University. Five years later, the Stanford group published their approach to mitral valve surgery through a right anterior thoracotomy. Just a year later, Dr. Alain Carpentier performed the first robotic-assisted mitral valve operation.1 There has been an explosion of new techniques, broadening the cardiac surgeon’s armamentarium far beyond the typical median sternotomy and occasional left thoracotomy.

While many of these techniques will undoubtedly become historical footnotes, it is clear that minimally invasive cardiac surgery is here to stay, as 20% of mitral repairs are performed with some element of minimally invasive technique. Similarly, thoracic endovascular aortic repair has become a well-established treatment for aneurysmal disease and dissection of the thoracic aorta, and is rapidly catching up with open repair as the treatment of choice.²

Training has also changed. The last decade brought a surge of applications to traditional fellowship programs, and the integrated thoracic surgery programs graduated their first trainees last year. With the variety of new operations and techniques, novel training formats, and professional goals for cardiothoracic surgery trainees, how can we be sure that young cardiac surgeons are learning the skills they need to succeed in the coming decades?

To ask how new surgeons should learn, you must start by asking what needs to be learned. After I asked a number of different surgeons in a variety of practice set-ups, the answer became obvious, and it is deceptively basic. The purpose of training is simply to ensure that each trainee can do all of the commonly performed operations of their specialty. This includes open valve and coronary surgery on the cardiac side, while for thoracic surgery, this includes all of the traditional lung and esophageal resections, chest wall and pleural operations, and importantly, the widely practiced VATS lobectomy. When I asked about more advanced VATS skills and minimally invasive cardiac skills, I was always told that those would be icing on the cake, as it were, to make a graduate more valuable to a potential employer. The first step in learning a minimally invasive operation is to understand the traditional, open approach, and VATS lung surgery is no different.

The VATS lobectomy has been a recent but well-received addition to the expected repertoire of graduates, and Dr. Chadrick Denlinger, associate professor of surgery at the Medical University of South Carolina, Charleston, allows his chief residents to take other trainees through the case, and expects that all new graduates can do one. Across the coast, Dr. Joseph Woo, newly appointed chair of cardiovascular surgery at Stanford, agrees. This expectation alone informs us that our specialty is dynamic and that the definition of an essential skill is in constant flux. On the other hand, cardiac surgery has no touchstone or standard minimally invasive procedure. However, Dr. Woo explains, the ABTS has set its recommendations in anticipation of the continued success of minimally invasive approaches to cardiovascular problems. The board doesn’t require mastery of any specific minimally invasive cardiac operation by the end of a training program, but it does require that we are exposed to a number of different endovascular and nontraditional approaches to coronary, valve, and aortic surgery. Coupled with our presumed mastery of the standard, open operations, we should then have the basic skills necessary to learn whatever minimally invasive operations we like, depending on our interests and our post-training mentorship.

Of course, the safety and efficacy of thoracic aortic stent grafting and minimally invasive mitral surgery have already been proven to some degree, and the operations aren’t going away anytime soon.^3,4 So what is stopping us from learning this stuff during our training? The answer is complicated. Dr. Woo cites the lack of visualization for two surgeons, the difficulty in preventing and controlling technical complications in a limited field, and the very nature the operations themselves.

Take, for example, the minimally invasive mitral valve repair. Its open counterpart requires a skill set that few trainees, if any, can claim mastery of until the very end of their training. The skill required, patient selection, and pathology treated make the operation sort of a "boutique" treatment. The patients that are offered right thoracotomy approach tend to be younger, less symptomatic, and with less complex disease. They have higher expectations. As Dr. Woo put it, "if you perform an absolutely perfect repair, then you’ve only done your job. But there is no way to do any better." With that sort of standard, many attending surgeons are hesitant to hand over the instruments to a trainee. Furthermore, not every resident’s technical ability lines up with what is required of that interest, and more importantly, not every resident is interested. Because of the highly specialized nature of the operation, the relatively smaller patient base, and the technical difficulty involved, it is often up to the highly motivated fellow or resident to gravitate to these repairs and seek out the training on their own.

Dr. James Fann, cofounder of the annual TSDA boot camp and a national surgical education leader, has some perspective on the matter. If residents are interested in gaining added endovascular or minimally invasive skills, he suggests, they first have to prove themselves in the operating room. When they’ve mastered the skills for an open technique and have proven they can get out of trouble, then an attending might feel comfortable letting them take on these more complex cases. It takes a combination of skill and interest – and as only a minority of trainees will have both, most training programs do not require that every TEVAR or mini-mitral be staffed with a resident.

It seems that simulation does not provide an easy shortcut beyond this approach, though it does have a role. To be honest, I expected Dr. Fann to preach the simulation gospel, and tell me about some incredible TEVAR or TAVR simulator he was getting ready to unveil, but his response was far more measured. "The role of simulation," he said, "is not to teach a resident how to operate. It is an adjunct – a tool that can be used to identify and address specific technical issues outside of the operating room." He reinforced the importance of mastering traditional surgical techniques before embarking on miniaturization. Simulation can help trainees operate more efficiently and effectively, but it cannot and should not replace mentored operative experience.

MICS simulation does exist, as anyone who has worked with Dr. L. Wiley Nifong and Dr. Randolph Chitwood’s high-fidelity tissue simulators for minimally invasive mitral valve repair knows. Simbionix USA (Cleveland) has just obtained FDA clearance for its TEVAR simulator that can be tailored to rehearse an upcoming case using a patient’s CT scan. On the lower end of the cost spectrum, a Dutch group and a separate Hannover group have developed low-cost, reproducible models of mini-mitral surgery that can be built from materials from a hardware store.⁵ Again, all of these tools are designed to be adjuncts to experiential training and mentorship, not mentors in and of themselves.

Residents can and should be exposed to TEVAR, TAVR, mini-mitral repair, and other less invasive approaches that are offered at their institution if they are interested. These, along with any other skills beyond traditional open techniques, make the surgeon better. More importantly, they help the trainee gain the basic wire and small incision skills they will need to learn quickly any newly developed operations that the changing specialty requires. They may not master the skills as a resident, but they are that much more prepared to hone those skills with their mentors when that time comes. In fact, the faculty I spoke with placed far more emphasis on mentorship after residency than aggressive residency training, simulation, and superfellowship as the key to gaining these advanced skills. Trainees should be soaking up all of the skills that they possibly can while they can, and if one is smart, ambitious, and skilled enough to become technically proficient at a more technically advanced skill, it certainly makes them a more desirable surgeon. For most of us, however, it is more important to realize that the training never truly ends, to take advantage of the opportunities afforded by residency, and to continue getting those reps in the OR.

References

1. Cardiac Surgery in the Adult, 4e. New York, N.Y.: McGraw-Hill; 2012.

2. J. Thorac. Cardiovasc. Surg. 2012; 144:612-16.

3. Circulation 2013;6:407-16.

4. Ann. Cardiothorac. Surg. 2013;2:744-50.

5. Interact. Cardiovasc. Thorac. Surg. 2013;16:97-101.

Elevated growth hormone levels had a negative impact on remission in acromegaly patients undergoing transsphenoidal adenomectomies, researchers from Emory University in Atlanta concluded after a retrospective, multivariate analysis of case studies.

To determine the impact of preoperative growth hormone (GH), Dr. Jeremy Anthony and his associates examined the case files of 79 acromegaly patients who underwent transsphenoidal adenomectomy between 1994 and 2013 at Emory and assigned them to two groups on the basis of their preoperative GH levels, using 40 ng/mL as the cutoff.

Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) during follow-up of more than 3 months in the absence of adjuvant therapy. The results were released at the annual meeting of the American Association of Clinical Endocrinologists on May 15 in Las Vegas.

Group A, with preoperative GH levels greater than 40 ng/mL, comprised 19 patients with a mean age of 43 years and an average follow-up of 38 months. They had larger, more invasive tumors, higher preoperative IGF-1 levels, higher immediate postoperative GH, and more residual tumors at 3 months, compared with the 60 patients in group B, who had preop GH levels of 40 ng/mL or less, a mean age of 47 years, and 43 months of follow-up.

In group A, three patients (15%) had remission at 3 months, but two patients had recurrence within 2 years. In group B, 35 patients (58%) had remission at 3 months with no recurrence during follow-up.

On univariate analysis, lower preoperative GH was a predictor of remission. In a multivariate analysis, however, lack of cavernous sinus invasion was the only predictor of remission.

"The relationship of GH elevation and cavernous sinus invasion should be further defined, as should the molecular fingerprint and the potential role of preoperative medical treatment in this group of patients," Dr. Anthony and his associates wrote.

No disclosures were reported.

[email protected]

Elevated growth hormone levels had a negative impact on remission in acromegaly patients undergoing transsphenoidal adenomectomies, researchers from Emory University in Atlanta concluded after a retrospective, multivariate analysis of case studies.

To determine the impact of preoperative growth hormone (GH), Dr. Jeremy Anthony and his associates examined the case files of 79 acromegaly patients who underwent transsphenoidal adenomectomy between 1994 and 2013 at Emory and assigned them to two groups on the basis of their preoperative GH levels, using 40 ng/mL as the cutoff.

Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) during follow-up of more than 3 months in the absence of adjuvant therapy. The results were released at the annual meeting of the American Association of Clinical Endocrinologists on May 15 in Las Vegas.

Group A, with preoperative GH levels greater than 40 ng/mL, comprised 19 patients with a mean age of 43 years and an average follow-up of 38 months. They had larger, more invasive tumors, higher preoperative IGF-1 levels, higher immediate postoperative GH, and more residual tumors at 3 months, compared with the 60 patients in group B, who had preop GH levels of 40 ng/mL or less, a mean age of 47 years, and 43 months of follow-up.

In group A, three patients (15%) had remission at 3 months, but two patients had recurrence within 2 years. In group B, 35 patients (58%) had remission at 3 months with no recurrence during follow-up.

On univariate analysis, lower preoperative GH was a predictor of remission. In a multivariate analysis, however, lack of cavernous sinus invasion was the only predictor of remission.

"The relationship of GH elevation and cavernous sinus invasion should be further defined, as should the molecular fingerprint and the potential role of preoperative medical treatment in this group of patients," Dr. Anthony and his associates wrote.

No disclosures were reported.

[email protected]

Elevated growth hormone levels had a negative impact on remission in acromegaly patients undergoing transsphenoidal adenomectomies, researchers from Emory University in Atlanta concluded after a retrospective, multivariate analysis of case studies.

To determine the impact of preoperative growth hormone (GH), Dr. Jeremy Anthony and his associates examined the case files of 79 acromegaly patients who underwent transsphenoidal adenomectomy between 1994 and 2013 at Emory and assigned them to two groups on the basis of their preoperative GH levels, using 40 ng/mL as the cutoff.

Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) during follow-up of more than 3 months in the absence of adjuvant therapy. The results were released at the annual meeting of the American Association of Clinical Endocrinologists on May 15 in Las Vegas.

Group A, with preoperative GH levels greater than 40 ng/mL, comprised 19 patients with a mean age of 43 years and an average follow-up of 38 months. They had larger, more invasive tumors, higher preoperative IGF-1 levels, higher immediate postoperative GH, and more residual tumors at 3 months, compared with the 60 patients in group B, who had preop GH levels of 40 ng/mL or less, a mean age of 47 years, and 43 months of follow-up.

In group A, three patients (15%) had remission at 3 months, but two patients had recurrence within 2 years. In group B, 35 patients (58%) had remission at 3 months with no recurrence during follow-up.

On univariate analysis, lower preoperative GH was a predictor of remission. In a multivariate analysis, however, lack of cavernous sinus invasion was the only predictor of remission.

"The relationship of GH elevation and cavernous sinus invasion should be further defined, as should the molecular fingerprint and the potential role of preoperative medical treatment in this group of patients," Dr. Anthony and his associates wrote.

No disclosures were reported.

[email protected]

Researchers in the lab

Credit: NIH

A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.

The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.

Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.

The researchers reported these discoveries in Cancer Cell.

Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.

The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin^-CD34⁺CD38^-CD90⁺CD45RA^- cells—that appeared to have all the properties of cancer stem cells.

These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.

“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”

Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.

But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.

“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.

Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.

“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”

Researchers in the lab

Credit: NIH

A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.

The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.

Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.

The researchers reported these discoveries in Cancer Cell.

Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.

The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin^-CD34⁺CD38^-CD90⁺CD45RA^- cells—that appeared to have all the properties of cancer stem cells.

These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.

“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”

Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.

But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.

“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.

Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.

“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”

Researchers in the lab

Credit: NIH

A new study provides “conclusive evidence” to support the existence of cancer stem cells in patients with myelodysplastic syndromes (MDS), according to researchers.

The group analyzed malignant cells in the bone marrow of MDS patients and identified a distinct subset of cells that showed all the hallmarks of cancer stem cells.

Only these MDS stem cells—none of the other malignant cells—were able to propagate the disease.

The researchers reported these discoveries in Cancer Cell.

Petter Woll, PhD, of the University of Oxford in the UK, and his colleagues conducted this research, analyzing bone marrow cells from 15 patients with low- or intermediate-risk MDS.

The team set out to establish in which cells cancer-driving mutations originated. This led them to a rare subset of MDS cells—Lin^-CD34⁺CD38^-CD90⁺CD45RA^- cells—that appeared to have all the properties of cancer stem cells.

These cells sat at the top of a hierarchy of MDS cells, could sustain themselves and replenish the other MDS cells, and were the origin of all stable DNA changes and mutations that drove the progression of MDS.

“This is conclusive evidence for the existence of cancer stem cells in myelodysplastic syndromes,” Dr Woll said. “We have identified a subset of cancer cells [and] shown that these rare cells are invariably the cells in which the cancer originates and also are the only cancer-propagating cells in the patients.”

Study author Sten Eirik W. Jacobsen, MD, PhD, also of the University of Oxford, noted that cancer stem cells have already been reported in a number of malignancies.

But previous findings have remained controversial, since the lab tests used to establish the identity of cancer stem cells have been shown to be unreliable.

“In our studies, we avoided the problem of unreliable lab tests by tracking the origin and development of cancer-driving mutations in MDS patients,” Dr Jacobsen said.

Dr Woll added that this research provides a target for the development of more efficient therapies for MDS.

“We need to understand more about what makes these cancer stem cells unique, what makes them different to all the other cancer cells,” he said. “If we can find biological pathways that are specifically dysregulated in cancer stem cells, we might be able to target them with new drugs.”

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Lab mouse

Researchers believe they may have discovered a method for treating and preventing radiation-induced gastrointestinal toxicity.

The investigators found that inhibiting prolyl hydroxylase domain (PHD) proteins in mice could help protect them from radiation-induced toxicity and prolong their life spans.

“We were very surprised by the amount of protection the animals received,” said Amato Giaccia, PhD, of the Stanford University School of Medicine in California.

“The important thing to note is that we didn’t change the amount of damage the intestinal cells sustained as a result of the radiation. We simply changed the physiology of that tissue and how it responded to that damage.”

Dr Giaccia and his colleagues described this research in Science Translational Medicine.

The study began with an interest in hypoxia-inducible factor (HIF) proteins, which are known to help cells survive stressful conditions.

“Previous studies from our group and others have suggested that the HIF proteins are important in protecting cells from many types of stress,” Dr Giaccia said. “So we wondered whether stabilizing HIF proteins, and therefore increasing their levels within the cells, could also protect the intestine from the effects of radiation.”

The researchers inhibited the degradation of HIF proteins in 2 ways. In the first experiment, they engineered mice that were unable to express PHD isoforms, a group of 3 proteins that tag HIF proteins for destruction.

In another experiment, the investigators treated unmodified mice with a small molecule called dimethyloxyallyl glycine (DMOG), which also inhibits the activity of PHD proteins.

In both cases, the levels of HIF1 and HIF2 proteins increased significantly in the manipulated mice, as compared to controls.

In addition, 70% of the genetically modified mice lived for at least 30 days after receiving a normally lethal dose of abdominal radiation, and 27% survived at least 30 days after a normally lethal dose of whole-body radiation.

Sixty-seven percent of DMOG-treated mice survived for at least 60 days after receiving a normally lethal dose of abdominal radiation, and 40% lived for at least 30 days after a normally lethal dose of whole-body radiation.

The control mice in both experiments did not survive longer than 10 days after either type of radiation exposure.

Elucidating the mechanism

Further experiments showed that HIF2, rather than HIF1, is responsible for the radioprotection the researchers observed.

To determine the cause of the treated animals’ prolonged survival, the investigators looked directly at the epithelial cells lining the intestines.

Treated mice exhibited lower levels of cell death in response to abdominal radiation exposure and improved survival of crypts, which host the rapidly dividing stem cells necessary to accommodate the intestines’ need for repeated cell turnover.

The treated animals also experienced less diarrhea and fewer imbalances in fluid and electrolyte levels than untreated animals exposed to the same dose of radiation. And they quickly gained back the weight they had lost as a result of the exposure.

Treatment after radiation exposure

“The animals that survived the abdominal radiation have a life span that is similar to unexposed animals, which was very exciting to us,” Dr Giaccia said. “However, we realized it would be impossible to pretreat humans unexpectedly exposed to large amounts of radiation like at Chernobyl or Fukushima because those exposures are, by nature, unpredictable.”

So Dr Giaccia and his colleagues experimented with treating the mice with DMOG after abdominal radiation exposure. They found that, although the protective qualities of the molecule were diminished, it did help.

When DMOG was given 4 hours after radiation exposure, 45% of the treated mice, but no untreated mice, survived at least 10 days.

After 24 hours, the effect was more subtle. DMOG treatment showed little benefit at higher doses of radiation. But at a lower dose, 75% of the treated animals lived for at least 30 days, compared to 18.2% of the untreated animals.

“We found we were still able to rescue a significant proportion of the animals,” Dr Giaccia said.

Finally, the researchers tested the effect of DMOG treatment 24 hours after total-body irradiation.

They found that 37.5% of the treated mice survived for at least 30 days, but only if the mice were also given a bone marrow transplant to restore blood and immune stem cells killed by the radiation. None of the untreated mice lived beyond 10 days.

The investigators pointed out that, although this study suggests a possible way to mitigate the effects of therapeutic radiation exposure, more work remains. But the next steps are clear.

“There are a number of drug molecules that act in a manner similar to DMOG that are already in clinical trials for unrelated conditions,” Dr Giaccia said. “Our next step will be to test some of these molecules to see if they also offer radioprotection.”

Stanford University has filed a patent application, “Use of Prolyl Hydroxylase Inhibitors as a Radioprotective Drug for the Lower Gastrointestinal Tract” (international application No. PCT/US2012/052232), based on the results of this study.

Doctor and patient

Credit: CDC

Results of a proof-of-principle study suggest virotherapy can be effective against multiple myeloma (MM).

The study included 2 MM patients who each received a single dose of a measles virus engineered to target myeloma plasma cells (MV-NIS).

Both patients responded to the treatment, with initial reductions in M protein and complete resolution of bone marrow plasmacytosis. One of the patients achieved a complete remission that lasted 9 months.

The patients did experience adverse effects associated with MV-NIS, but all were resolved with appropriate treatment.

“This is the first study to establish the feasibility of systemic oncolytic virotherapy for disseminated cancer,” said Stephen Russell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.

“These patients were not responsive to other therapies and had experienced several recurrences of their disease.”

Dr Russell and his colleagues described this research in Mayo Clinic Proceedings.

Patient characteristics, treatment

The researchers explained that the 2 patients described in this report were the first to receive MV-NIS at the highest possible dose. They both received the virus at a dose of 10¹¹ TCID₅₀, infused into a superficial arm vein in 100 mL of normal saline over 60 minutes.

Both patients had limited previous exposure to measles (and therefore fewer antibodies to the virus) and essentially no remaining treatment options.

The first patient was a 49-year-old woman with heavily pretreated, light chain MM. Her last relapse was 9 months after her second autologous stem cell transplant, while she was not receiving therapy.

The second patient was a 65-year-old woman with relapsing IgA k MM that was refractory to all approved antimyeloma drugs. Her disease had progressed while she was receiving carfilzomib, pomalidomide, and dexamethasone therapy.

Adverse events

Patient 1 experienced a number of adverse effects related to MV-NIS, including a severe headache during treatment that required clinicians to temporarily stop her infusion.

This was followed by fever, tachycardia, hypotension, severe nausea and vomiting, and a superficial venous thrombosis extending from the wrist to the upper humerus. But all of these events responded to treatment.

Patient 2 also experienced adverse effects related to MV-NIS, including fever, tachycardia, hypotension, and headache. She responded to treatment for these events, and her recurring fever resolved spontaneously after a few hours.

Treatment response

Both patients’ disease responded to MV-NIS. They experienced initial reductions in M protein and complete resolution of bone marrow plasmacytosis at 6 weeks after treatment.

Patient 1 achieved a complete remission that lasted 9 months. A scan at 6 weeks showed the patient had experienced substantial improvement in all 5 of her previously identified lesions.

Although patient 2 initially responded to treatment, her plasmacytomas were progressing at the 6-week mark, and her free light chain level was increasing. Her 6-week scan revealed increased size and FDG uptake in most soft tissue lesions, although a few lesions did show varying degrees of improvement.

Doctor and patient

Credit: CDC

Results of a proof-of-principle study suggest virotherapy can be effective against multiple myeloma (MM).

The study included 2 MM patients who each received a single dose of a measles virus engineered to target myeloma plasma cells (MV-NIS).

Both patients responded to the treatment, with initial reductions in M protein and complete resolution of bone marrow plasmacytosis. One of the patients achieved a complete remission that lasted 9 months.

The patients did experience adverse effects associated with MV-NIS, but all were resolved with appropriate treatment.

“This is the first study to establish the feasibility of systemic oncolytic virotherapy for disseminated cancer,” said Stephen Russell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.

“These patients were not responsive to other therapies and had experienced several recurrences of their disease.”

Dr Russell and his colleagues described this research in Mayo Clinic Proceedings.

Patient characteristics, treatment

The researchers explained that the 2 patients described in this report were the first to receive MV-NIS at the highest possible dose. They both received the virus at a dose of 10¹¹ TCID₅₀, infused into a superficial arm vein in 100 mL of normal saline over 60 minutes.

Both patients had limited previous exposure to measles (and therefore fewer antibodies to the virus) and essentially no remaining treatment options.

The first patient was a 49-year-old woman with heavily pretreated, light chain MM. Her last relapse was 9 months after her second autologous stem cell transplant, while she was not receiving therapy.

The second patient was a 65-year-old woman with relapsing IgA k MM that was refractory to all approved antimyeloma drugs. Her disease had progressed while she was receiving carfilzomib, pomalidomide, and dexamethasone therapy.

Adverse events

Patient 1 experienced a number of adverse effects related to MV-NIS, including a severe headache during treatment that required clinicians to temporarily stop her infusion.

This was followed by fever, tachycardia, hypotension, severe nausea and vomiting, and a superficial venous thrombosis extending from the wrist to the upper humerus. But all of these events responded to treatment.

Patient 2 also experienced adverse effects related to MV-NIS, including fever, tachycardia, hypotension, and headache. She responded to treatment for these events, and her recurring fever resolved spontaneously after a few hours.

Treatment response

Both patients’ disease responded to MV-NIS. They experienced initial reductions in M protein and complete resolution of bone marrow plasmacytosis at 6 weeks after treatment.

Patient 1 achieved a complete remission that lasted 9 months. A scan at 6 weeks showed the patient had experienced substantial improvement in all 5 of her previously identified lesions.

Although patient 2 initially responded to treatment, her plasmacytomas were progressing at the 6-week mark, and her free light chain level was increasing. Her 6-week scan revealed increased size and FDG uptake in most soft tissue lesions, although a few lesions did show varying degrees of improvement.

Doctor and patient

Credit: CDC

Results of a proof-of-principle study suggest virotherapy can be effective against multiple myeloma (MM).

The study included 2 MM patients who each received a single dose of a measles virus engineered to target myeloma plasma cells (MV-NIS).

Both patients responded to the treatment, with initial reductions in M protein and complete resolution of bone marrow plasmacytosis. One of the patients achieved a complete remission that lasted 9 months.

The patients did experience adverse effects associated with MV-NIS, but all were resolved with appropriate treatment.

“This is the first study to establish the feasibility of systemic oncolytic virotherapy for disseminated cancer,” said Stephen Russell, MD, PhD, of the Mayo Clinic in Rochester, Minnesota.

“These patients were not responsive to other therapies and had experienced several recurrences of their disease.”

Dr Russell and his colleagues described this research in Mayo Clinic Proceedings.

Patient characteristics, treatment

The researchers explained that the 2 patients described in this report were the first to receive MV-NIS at the highest possible dose. They both received the virus at a dose of 10¹¹ TCID₅₀, infused into a superficial arm vein in 100 mL of normal saline over 60 minutes.

Both patients had limited previous exposure to measles (and therefore fewer antibodies to the virus) and essentially no remaining treatment options.

The first patient was a 49-year-old woman with heavily pretreated, light chain MM. Her last relapse was 9 months after her second autologous stem cell transplant, while she was not receiving therapy.

The second patient was a 65-year-old woman with relapsing IgA k MM that was refractory to all approved antimyeloma drugs. Her disease had progressed while she was receiving carfilzomib, pomalidomide, and dexamethasone therapy.

Adverse events

Patient 1 experienced a number of adverse effects related to MV-NIS, including a severe headache during treatment that required clinicians to temporarily stop her infusion.

This was followed by fever, tachycardia, hypotension, severe nausea and vomiting, and a superficial venous thrombosis extending from the wrist to the upper humerus. But all of these events responded to treatment.

Patient 2 also experienced adverse effects related to MV-NIS, including fever, tachycardia, hypotension, and headache. She responded to treatment for these events, and her recurring fever resolved spontaneously after a few hours.

Treatment response

Both patients’ disease responded to MV-NIS. They experienced initial reductions in M protein and complete resolution of bone marrow plasmacytosis at 6 weeks after treatment.

Patient 1 achieved a complete remission that lasted 9 months. A scan at 6 weeks showed the patient had experienced substantial improvement in all 5 of her previously identified lesions.

Although patient 2 initially responded to treatment, her plasmacytomas were progressing at the 6-week mark, and her free light chain level was increasing. Her 6-week scan revealed increased size and FDG uptake in most soft tissue lesions, although a few lesions did show varying degrees of improvement.

Benjamin Yellen, PhD

Credit: Duke University

Using components similar to those that control electrons in microchips, engineers have designed a device that can sort, store, and retrieve individual cells for study.

The team hopes this chip-like device could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes.

Benjamin Yellen, PhD, of Duke University in Durham, North Carolina, and his colleagues described the device in Nature Communications.

The team created the device by printing thin electromagnetic components, like those found on microchips, onto a slide. These patterns create magnetic tracks and elements like switches, transistors, and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin, liquid film.

Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much the way electrons are controlled on computer chips.

The engineers showed that a grid of 9 compartments—3 across by 3 down—allows the magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied, and retrieved.

“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” Dr Yellen said. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

As an example, Dr Yellen pointed to cells affected by cancers. Most afflicted cells are active and can be targeted by therapeutics. But a few rare cells remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission.

With the new technology, Dr Yellen and his colleagues hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them, and analyze their genetic activity.

“Our technology can offer new tools to improve our basic understanding of cancer metastasis at the single-cell level, how cancer cells respond to chemical and physical stimuli, and to test new concepts for gene delivery and metabolite transfer during cell division and growth,” said study author CheolGi Kim, PhD, of the Daegu Gyeongbuk Institute of Science and Technology in the Republic of Korea.

The researchers now plan to demonstrate a larger grid of 8-by-8 or 16-by-16 compartments with cells, and then to scale it up to hundreds of thousands of compartments.

“Our idea is a simple one,” Dr Kim said. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialization.”

“There’s another technique paper we need to do as a follow-up before we get to actual biological applications,” Dr Yellen added. “But they’re on their way.”

Benjamin Yellen, PhD

Credit: Duke University

Using components similar to those that control electrons in microchips, engineers have designed a device that can sort, store, and retrieve individual cells for study.

The team hopes this chip-like device could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes.

Benjamin Yellen, PhD, of Duke University in Durham, North Carolina, and his colleagues described the device in Nature Communications.

The team created the device by printing thin electromagnetic components, like those found on microchips, onto a slide. These patterns create magnetic tracks and elements like switches, transistors, and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin, liquid film.

Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much the way electrons are controlled on computer chips.

The engineers showed that a grid of 9 compartments—3 across by 3 down—allows the magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied, and retrieved.

“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” Dr Yellen said. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

As an example, Dr Yellen pointed to cells affected by cancers. Most afflicted cells are active and can be targeted by therapeutics. But a few rare cells remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission.

With the new technology, Dr Yellen and his colleagues hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them, and analyze their genetic activity.

“Our technology can offer new tools to improve our basic understanding of cancer metastasis at the single-cell level, how cancer cells respond to chemical and physical stimuli, and to test new concepts for gene delivery and metabolite transfer during cell division and growth,” said study author CheolGi Kim, PhD, of the Daegu Gyeongbuk Institute of Science and Technology in the Republic of Korea.

The researchers now plan to demonstrate a larger grid of 8-by-8 or 16-by-16 compartments with cells, and then to scale it up to hundreds of thousands of compartments.

“Our idea is a simple one,” Dr Kim said. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialization.”

“There’s another technique paper we need to do as a follow-up before we get to actual biological applications,” Dr Yellen added. “But they’re on their way.”

Benjamin Yellen, PhD

Credit: Duke University

Using components similar to those that control electrons in microchips, engineers have designed a device that can sort, store, and retrieve individual cells for study.

The team hopes this chip-like device could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes.

Benjamin Yellen, PhD, of Duke University in Durham, North Carolina, and his colleagues described the device in Nature Communications.

The team created the device by printing thin electromagnetic components, like those found on microchips, onto a slide. These patterns create magnetic tracks and elements like switches, transistors, and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin, liquid film.

Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much the way electrons are controlled on computer chips.

The engineers showed that a grid of 9 compartments—3 across by 3 down—allows the magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied, and retrieved.

“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” Dr Yellen said. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

As an example, Dr Yellen pointed to cells affected by cancers. Most afflicted cells are active and can be targeted by therapeutics. But a few rare cells remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission.

With the new technology, Dr Yellen and his colleagues hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them, and analyze their genetic activity.

“Our technology can offer new tools to improve our basic understanding of cancer metastasis at the single-cell level, how cancer cells respond to chemical and physical stimuli, and to test new concepts for gene delivery and metabolite transfer during cell division and growth,” said study author CheolGi Kim, PhD, of the Daegu Gyeongbuk Institute of Science and Technology in the Republic of Korea.

The researchers now plan to demonstrate a larger grid of 8-by-8 or 16-by-16 compartments with cells, and then to scale it up to hundreds of thousands of compartments.

“Our idea is a simple one,” Dr Kim said. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialization.”

“There’s another technique paper we need to do as a follow-up before we get to actual biological applications,” Dr Yellen added. “But they’re on their way.”

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

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

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

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

Clinical question

Does use of protocol-based early goal-directed therapy with central venous monitoring decrease mortality in patients presenting with septic shock?

Bottom line

Protocol-based care for resuscitation in septic shock, with or without the use of central venous monitoring, does not confer a mortality advantage over care provided according to a physician’s bedside judgment. (LOE = 1b)

Reference

The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014 Mar 18. [Epub ahead of print]

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (any location)

Synopsis

Previous research suggested that a 6-hour protocol of early goal-directed therapy (EGDT) using central hemodynamic monitoring to guide the use of intravenous fluids, vasopressors, inotropes, and transfusions reduces mortality in patients who present with septic shock. In the current study, investigators randomized 1341 patients, using concealed allocation, to 1 of 3 groups: (1) protocol-based EGDT, (2) protocol-based standard therapy, or (3) usual care. Protocol-based standard therapy required peripheral venous access only with the administration of fluids and vasopressors to maintain blood pressure, optimize fluid status, and address hypoperfusion. In the usual care group, care was at the discretion of the bedside physicians. Both protocol-based groups had approximately 90% or greater adherence to the protocols. Notably, although central venous catheter placement was not required in the protocol-based standard therapy or usual care groups, the majority of patients in each had such catheters placed, though only 4% were used for actual central venous monitoring. Analysis was by intention to treat. During the first 6 hours of resuscitation, more patients in the 2 protocol-based groups received vasopressors than patients in the usual care group. Patients in the EGDT group were also more likely to receive dobutamine and red-cell transfusions. Between 6 hours and 72 hours, however, the 3 groups had similar use of intravenous fluids, vasopressors, and transfusions. For the primary outcome of 60-day in-hospital mortality, there were no significant differences among the 3 groups. Patients in the protocol-based standard therapy group were slightly more likely to require renal replacement therapy (6% vs 3% in the other 2 groups; P = .04), whereas patients in the EGDT group were more likely to require intensive care unit admission (90% vs 85% in the other 2 groups; P = .01). Serious adverse events were rare and did not differ among the groups.

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

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

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

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

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

Clinical question

Does albumin administration reduce mortality in critically ill patients with sepsis?

Bottom line

The use of albumin along with crystalloid solutions in patients with severe sepsis does not affect mortality. (LOE = 1b-)

Reference

Caironi P, Tognoni G, Masson S, et al, for the ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014;370(15):1412-1421.

Study design

Randomized controlled trial (nonblinded)

Funding source

Government

Allocation

Concealed

Setting

Inpatient (ICU only)

Synopsis

Using concealed allocation, these investigators randomized adult patients in the intensive care unit (ICU) with severe sepsis within the previous 24 hours to receive either 300 mL of 20% albumin plus crystalloid solution or crystalloid solution alone. The treatment group received albumin daily from randomization through day 28 or until discharge from the ICU. Crystalloid solution was administered as clinically indicated in both groups. Baseline characteristics of the 2 groups were similar and analysis was by intention to treat. There were no significant differences detected in either 28-day or 90-day mortality between the groups, although a lower-than-expected mortality rate in the control group may have underpowered the study. Secondary outcomes were also similar, including number of new organ failures, hospital and ICU lengths of stay, and need for renal replacement therapy. The albumin group had a shorter time to suspension of vasopressor/inotropic agents (3 vs 4 days; P = .007), indicating a decreased use of these agents. Finally, a post-hoc subgroup analysis of those patients with confirmed septic shock suggested decreased mortality at 90 days in the albumin group. However, this type of analysis, since it is not prespecified, is very susceptible to bias.

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

Lately, I've been busy wading through a heavily publicized study that was published this month in the Lancet. In their paper, "Antipsychotics, mood stabilisers and risk of violent crime," Dr. Seena Fazel and his associates linked Swedish national registers to compare rates of violent crime among 82,647 male and female psychiatric patients to assess the effect of medication on this outcome.

The study made quite a splash in the news, because the outcome was almost too good to be true. There was a 64% reduction in violent crime among patients who had been prescribed any antipsychotic or mood stabilizer, compared with those taking other psychotropics. The reduction in violence for those taking neuroleptics and mood stabilizers was 45% and 24%, respectively. Selective serotonin reuptake inhibitors (SSRIs) had no apparent effect on crime (Lancet 2014 [doi:10.1016/S0140-6736(14)60379-2]).
Given our American anxiety over spree shooters and other high-profile crimes allegedly committed by untreated psychiatric patients, this study clearly deserves some scrutiny to thoroughly understand the findings, limitations, and other factors that could limit generalizability to the United States.

The authors compared mental health treatment registries with the national criminal history database. They looked at the rate and types of crimes committed by psychiatric patients when they were in and out of treatment. The "in-treatment" time interval was defined as the time between two or more prescriptions, as long as the prescriptions were no more than 4 months apart. Individuals who had only been given one script [prescription] were excluded. The outcome measure was any criminal conviction. The conviction outcome was based upon the date the offense took place, not the date of conviction. Individuals were excluded if the offense date was unknown.

A within-individual analysis showed significant reduction in all crimes, including violent crime, drug-related crime, and less severe crimes, during times when patients were prescribed medication, compared with medication-free intervals. When medicated, the rate of violent crime did not differ between patients with and without a history of violent offenses when diagnosis was not considered. When the analysis was limited to people with schizophrenia, bipolar disorder, or other psychotic disorders, the prescription of neuroleptics significantly reduced violent crime for both men and women.

For bipolar disorder, mood stabilizing medication reduced violent crime for men but not for women. The SSRI-medicated group was used as a control, to account for the general effect of contact with the mental health system and non-medication interventions related to this, and there was no effect on violent crime with this class of medication.

Now on to the limitations. Medication adherence was not assessed and could not be verified apart from patients given depot neuroleptics. The overall rate of violent crime was low, as would be expected. Only 6% of men and 1% of the women committed a violent crime. The numbers were so low that the study could not statistically assess the impact of violent crime history among patients diagnosed with psychosis. This is a small but crucial finding that did not make the traditional media coverage of this study.

Also, only 40% of those patients taking antipsychotics and mood stabilizers had a diagnosis of schizophrenia, other psychosis, or bipolar disorder, suggesting that, in Sweden, these medications might be prescribed for other indications such as characterologic low frustration tolerance or irritability. The analysis did not look at impact on violent crime by personality disorder diagnosis.

The authors acknowledged that their research could not prove a causal link between psychiatric illness and violence, another important conclusion that was not mentioned in traditional media coverage. In Sweden, mental illness cannot be used to prevent or mitigate a criminal conviction, so any connection between psychiatric symptoms and crime in this population can't be determined. The study also did not consider which subjects, if any, were taking medication or in treatment under court-mandated conditions.

As legislators and advocacy groups push to strengthen involuntary treatment laws, there is a risk that "bottom line" media coverage of research like this may inappropriately sway public opinion. Psychiatrists should be prepared to respond to proposed policies based on inaccurate interpretation of research.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson's employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Lately, I've been busy wading through a heavily publicized study that was published this month in the Lancet. In their paper, "Antipsychotics, mood stabilisers and risk of violent crime," Dr. Seena Fazel and his associates linked Swedish national registers to compare rates of violent crime among 82,647 male and female psychiatric patients to assess the effect of medication on this outcome.

The study made quite a splash in the news, because the outcome was almost too good to be true. There was a 64% reduction in violent crime among patients who had been prescribed any antipsychotic or mood stabilizer, compared with those taking other psychotropics. The reduction in violence for those taking neuroleptics and mood stabilizers was 45% and 24%, respectively. Selective serotonin reuptake inhibitors (SSRIs) had no apparent effect on crime (Lancet 2014 [doi:10.1016/S0140-6736(14)60379-2]).
Given our American anxiety over spree shooters and other high-profile crimes allegedly committed by untreated psychiatric patients, this study clearly deserves some scrutiny to thoroughly understand the findings, limitations, and other factors that could limit generalizability to the United States.

The authors compared mental health treatment registries with the national criminal history database. They looked at the rate and types of crimes committed by psychiatric patients when they were in and out of treatment. The "in-treatment" time interval was defined as the time between two or more prescriptions, as long as the prescriptions were no more than 4 months apart. Individuals who had only been given one script [prescription] were excluded. The outcome measure was any criminal conviction. The conviction outcome was based upon the date the offense took place, not the date of conviction. Individuals were excluded if the offense date was unknown.

A within-individual analysis showed significant reduction in all crimes, including violent crime, drug-related crime, and less severe crimes, during times when patients were prescribed medication, compared with medication-free intervals. When medicated, the rate of violent crime did not differ between patients with and without a history of violent offenses when diagnosis was not considered. When the analysis was limited to people with schizophrenia, bipolar disorder, or other psychotic disorders, the prescription of neuroleptics significantly reduced violent crime for both men and women.

For bipolar disorder, mood stabilizing medication reduced violent crime for men but not for women. The SSRI-medicated group was used as a control, to account for the general effect of contact with the mental health system and non-medication interventions related to this, and there was no effect on violent crime with this class of medication.

Now on to the limitations. Medication adherence was not assessed and could not be verified apart from patients given depot neuroleptics. The overall rate of violent crime was low, as would be expected. Only 6% of men and 1% of the women committed a violent crime. The numbers were so low that the study could not statistically assess the impact of violent crime history among patients diagnosed with psychosis. This is a small but crucial finding that did not make the traditional media coverage of this study.

Also, only 40% of those patients taking antipsychotics and mood stabilizers had a diagnosis of schizophrenia, other psychosis, or bipolar disorder, suggesting that, in Sweden, these medications might be prescribed for other indications such as characterologic low frustration tolerance or irritability. The analysis did not look at impact on violent crime by personality disorder diagnosis.

The authors acknowledged that their research could not prove a causal link between psychiatric illness and violence, another important conclusion that was not mentioned in traditional media coverage. In Sweden, mental illness cannot be used to prevent or mitigate a criminal conviction, so any connection between psychiatric symptoms and crime in this population can't be determined. The study also did not consider which subjects, if any, were taking medication or in treatment under court-mandated conditions.

As legislators and advocacy groups push to strengthen involuntary treatment laws, there is a risk that "bottom line" media coverage of research like this may inappropriately sway public opinion. Psychiatrists should be prepared to respond to proposed policies based on inaccurate interpretation of research.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson's employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Lately, I've been busy wading through a heavily publicized study that was published this month in the Lancet. In their paper, "Antipsychotics, mood stabilisers and risk of violent crime," Dr. Seena Fazel and his associates linked Swedish national registers to compare rates of violent crime among 82,647 male and female psychiatric patients to assess the effect of medication on this outcome.

The study made quite a splash in the news, because the outcome was almost too good to be true. There was a 64% reduction in violent crime among patients who had been prescribed any antipsychotic or mood stabilizer, compared with those taking other psychotropics. The reduction in violence for those taking neuroleptics and mood stabilizers was 45% and 24%, respectively. Selective serotonin reuptake inhibitors (SSRIs) had no apparent effect on crime (Lancet 2014 [doi:10.1016/S0140-6736(14)60379-2]).
Given our American anxiety over spree shooters and other high-profile crimes allegedly committed by untreated psychiatric patients, this study clearly deserves some scrutiny to thoroughly understand the findings, limitations, and other factors that could limit generalizability to the United States.

The authors compared mental health treatment registries with the national criminal history database. They looked at the rate and types of crimes committed by psychiatric patients when they were in and out of treatment. The "in-treatment" time interval was defined as the time between two or more prescriptions, as long as the prescriptions were no more than 4 months apart. Individuals who had only been given one script [prescription] were excluded. The outcome measure was any criminal conviction. The conviction outcome was based upon the date the offense took place, not the date of conviction. Individuals were excluded if the offense date was unknown.

A within-individual analysis showed significant reduction in all crimes, including violent crime, drug-related crime, and less severe crimes, during times when patients were prescribed medication, compared with medication-free intervals. When medicated, the rate of violent crime did not differ between patients with and without a history of violent offenses when diagnosis was not considered. When the analysis was limited to people with schizophrenia, bipolar disorder, or other psychotic disorders, the prescription of neuroleptics significantly reduced violent crime for both men and women.

For bipolar disorder, mood stabilizing medication reduced violent crime for men but not for women. The SSRI-medicated group was used as a control, to account for the general effect of contact with the mental health system and non-medication interventions related to this, and there was no effect on violent crime with this class of medication.

Now on to the limitations. Medication adherence was not assessed and could not be verified apart from patients given depot neuroleptics. The overall rate of violent crime was low, as would be expected. Only 6% of men and 1% of the women committed a violent crime. The numbers were so low that the study could not statistically assess the impact of violent crime history among patients diagnosed with psychosis. This is a small but crucial finding that did not make the traditional media coverage of this study.

Also, only 40% of those patients taking antipsychotics and mood stabilizers had a diagnosis of schizophrenia, other psychosis, or bipolar disorder, suggesting that, in Sweden, these medications might be prescribed for other indications such as characterologic low frustration tolerance or irritability. The analysis did not look at impact on violent crime by personality disorder diagnosis.

The authors acknowledged that their research could not prove a causal link between psychiatric illness and violence, another important conclusion that was not mentioned in traditional media coverage. In Sweden, mental illness cannot be used to prevent or mitigate a criminal conviction, so any connection between psychiatric symptoms and crime in this population can't be determined. The study also did not consider which subjects, if any, were taking medication or in treatment under court-mandated conditions.

As legislators and advocacy groups push to strengthen involuntary treatment laws, there is a risk that "bottom line" media coverage of research like this may inappropriately sway public opinion. Psychiatrists should be prepared to respond to proposed policies based on inaccurate interpretation of research.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson's employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

If you have patients who express interest in cosmetic procedures, and especially if you are a cosmetic dermatologist or a plastic surgeon, you might want to familiarize yourself with RealSelf.com. Founded in 2006, RealSelf is an online community for learning and sharing information about cosmetic surgery, dermatology, dentistry, and other elective treatments. In 2013, the site had 36 million unique visitors, and it is expected to grow.

Why might RealSelf be relevant for you? Simply put, it’s another channel to market you and your practice. It works by allowing physicians to answer users’ questions about cosmetic procedures ranging from rhinoplasty and liposuction to tattoo removal and Botox. Over time, your participation can lead to new consultations at your practice.

To ensure credibility, physicians must be board-certified in order to join RealSelf’s physician community. There is an element of game mechanics: The more active the physician, the more exposure his or her profile and practice receives. Similarly, paid subscriptions lead to more exposure than free subscriptions (more on this later.) Although this model does not appeal to some physicians, many of them do like the platform, and see it as a way to build a reputation as an expert and to market their practices.

Unlike doctor review sites that focus on the physician, RealSelf focuses on the procedure. For each procedure, users will find actual patient reviews and before and after photos, as well as Q&A’s with board-certified physicians. Users will also find licensed physicians in their area as well as the average cost for the procedure. RealSelf believes that patients value transparency, and including prices creates transparency.

Since most patients genuinely want to help other patients make informed medical decisions, the reviews tend to be thoughtful and thorough, and many of them contain multiple before-and-after photos. As a physician perusing the patient reviews, you’ll start to notice that most of them are reasonable. For example, customer satisfaction with laser treatment for melasma was 51%, whereas satisfaction for laser treatment for rosacea was 80%.

Patients and prospective patients are flocking to the site because it allows them to share their experiences, interact with other patients, and gain access to physician experts in the field. Many patients have difficulty making decisions about cosmetic procedures; RealSelf aims to alleviate their fears and help them "make confident health and beauty decisions." If a prospective patient wants to see a video of tattoo removal or Botox injections, he or she can. If a patient wants to ask physicians their opinions, he or she can. According to RealSelf, physicians have answered over 500,000 questions on the site.

Of course, all this isn’t free for physicians. RealSelf is a business. They have a tiered membership – free, pro, and spotlight. To obtain free membership, you simply visit the site and follow the prompts to "claim your profile." Once your profile is completed, you will have access to a "doctor advisor" who can help you "optimize your visibility on the site." Both "pro" and "spotlight" offer additional benefits, such as integrating patient reviews on your practice website, promotions on Facebook and Twitter, extended directory listings, and exposure in your local area. RealSelf does not discuss costs of membership until you have claimed your profile.

Only you can determine if RealSelf is beneficial to you and your practice. If, for example, you’re not looking for new patients, then you might find it unnecessary. But at the very least, you’ll know what RealSelf is the next time a fellow cosmetic physician brings it up at a conference. And it’s never a bad idea to be familiar with current social technologies that may affect your livelihood.

If you’ve used RealSelf, let us know what you think. For more information, visit RealSelf.com.

Disclaimer: I have no financial interest in RealSelf and am not an active member.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

If you have patients who express interest in cosmetic procedures, and especially if you are a cosmetic dermatologist or a plastic surgeon, you might want to familiarize yourself with RealSelf.com. Founded in 2006, RealSelf is an online community for learning and sharing information about cosmetic surgery, dermatology, dentistry, and other elective treatments. In 2013, the site had 36 million unique visitors, and it is expected to grow.

Why might RealSelf be relevant for you? Simply put, it’s another channel to market you and your practice. It works by allowing physicians to answer users’ questions about cosmetic procedures ranging from rhinoplasty and liposuction to tattoo removal and Botox. Over time, your participation can lead to new consultations at your practice.

To ensure credibility, physicians must be board-certified in order to join RealSelf’s physician community. There is an element of game mechanics: The more active the physician, the more exposure his or her profile and practice receives. Similarly, paid subscriptions lead to more exposure than free subscriptions (more on this later.) Although this model does not appeal to some physicians, many of them do like the platform, and see it as a way to build a reputation as an expert and to market their practices.

Unlike doctor review sites that focus on the physician, RealSelf focuses on the procedure. For each procedure, users will find actual patient reviews and before and after photos, as well as Q&A’s with board-certified physicians. Users will also find licensed physicians in their area as well as the average cost for the procedure. RealSelf believes that patients value transparency, and including prices creates transparency.

Since most patients genuinely want to help other patients make informed medical decisions, the reviews tend to be thoughtful and thorough, and many of them contain multiple before-and-after photos. As a physician perusing the patient reviews, you’ll start to notice that most of them are reasonable. For example, customer satisfaction with laser treatment for melasma was 51%, whereas satisfaction for laser treatment for rosacea was 80%.

Patients and prospective patients are flocking to the site because it allows them to share their experiences, interact with other patients, and gain access to physician experts in the field. Many patients have difficulty making decisions about cosmetic procedures; RealSelf aims to alleviate their fears and help them "make confident health and beauty decisions." If a prospective patient wants to see a video of tattoo removal or Botox injections, he or she can. If a patient wants to ask physicians their opinions, he or she can. According to RealSelf, physicians have answered over 500,000 questions on the site.

Of course, all this isn’t free for physicians. RealSelf is a business. They have a tiered membership – free, pro, and spotlight. To obtain free membership, you simply visit the site and follow the prompts to "claim your profile." Once your profile is completed, you will have access to a "doctor advisor" who can help you "optimize your visibility on the site." Both "pro" and "spotlight" offer additional benefits, such as integrating patient reviews on your practice website, promotions on Facebook and Twitter, extended directory listings, and exposure in your local area. RealSelf does not discuss costs of membership until you have claimed your profile.

Only you can determine if RealSelf is beneficial to you and your practice. If, for example, you’re not looking for new patients, then you might find it unnecessary. But at the very least, you’ll know what RealSelf is the next time a fellow cosmetic physician brings it up at a conference. And it’s never a bad idea to be familiar with current social technologies that may affect your livelihood.

If you’ve used RealSelf, let us know what you think. For more information, visit RealSelf.com.

Disclaimer: I have no financial interest in RealSelf and am not an active member.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.

If you have patients who express interest in cosmetic procedures, and especially if you are a cosmetic dermatologist or a plastic surgeon, you might want to familiarize yourself with RealSelf.com. Founded in 2006, RealSelf is an online community for learning and sharing information about cosmetic surgery, dermatology, dentistry, and other elective treatments. In 2013, the site had 36 million unique visitors, and it is expected to grow.

Why might RealSelf be relevant for you? Simply put, it’s another channel to market you and your practice. It works by allowing physicians to answer users’ questions about cosmetic procedures ranging from rhinoplasty and liposuction to tattoo removal and Botox. Over time, your participation can lead to new consultations at your practice.

To ensure credibility, physicians must be board-certified in order to join RealSelf’s physician community. There is an element of game mechanics: The more active the physician, the more exposure his or her profile and practice receives. Similarly, paid subscriptions lead to more exposure than free subscriptions (more on this later.) Although this model does not appeal to some physicians, many of them do like the platform, and see it as a way to build a reputation as an expert and to market their practices.

Unlike doctor review sites that focus on the physician, RealSelf focuses on the procedure. For each procedure, users will find actual patient reviews and before and after photos, as well as Q&A’s with board-certified physicians. Users will also find licensed physicians in their area as well as the average cost for the procedure. RealSelf believes that patients value transparency, and including prices creates transparency.

Since most patients genuinely want to help other patients make informed medical decisions, the reviews tend to be thoughtful and thorough, and many of them contain multiple before-and-after photos. As a physician perusing the patient reviews, you’ll start to notice that most of them are reasonable. For example, customer satisfaction with laser treatment for melasma was 51%, whereas satisfaction for laser treatment for rosacea was 80%.

Patients and prospective patients are flocking to the site because it allows them to share their experiences, interact with other patients, and gain access to physician experts in the field. Many patients have difficulty making decisions about cosmetic procedures; RealSelf aims to alleviate their fears and help them "make confident health and beauty decisions." If a prospective patient wants to see a video of tattoo removal or Botox injections, he or she can. If a patient wants to ask physicians their opinions, he or she can. According to RealSelf, physicians have answered over 500,000 questions on the site.

Of course, all this isn’t free for physicians. RealSelf is a business. They have a tiered membership – free, pro, and spotlight. To obtain free membership, you simply visit the site and follow the prompts to "claim your profile." Once your profile is completed, you will have access to a "doctor advisor" who can help you "optimize your visibility on the site." Both "pro" and "spotlight" offer additional benefits, such as integrating patient reviews on your practice website, promotions on Facebook and Twitter, extended directory listings, and exposure in your local area. RealSelf does not discuss costs of membership until you have claimed your profile.

Only you can determine if RealSelf is beneficial to you and your practice. If, for example, you’re not looking for new patients, then you might find it unnecessary. But at the very least, you’ll know what RealSelf is the next time a fellow cosmetic physician brings it up at a conference. And it’s never a bad idea to be familiar with current social technologies that may affect your livelihood.

If you’ve used RealSelf, let us know what you think. For more information, visit RealSelf.com.

Disclaimer: I have no financial interest in RealSelf and am not an active member.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @Dermdoc on Twitter.