Poster hall at ASCO 2014

©ASCO/Todd Buchanan

CHICAGO—Infusion of autologous CD19-targeted chimeric antigen receptor (CAR)-modified T cells appears to have promising anti-tumor activity and be well-tolerated as a consolidation to frontline chemotherapy in patients with high-risk chronic lymphocytic leukemia (CLL), researchers report.

In a phase 1 trial, the modified T cells benefitted 43% of patients, including 1 who achieved a complete response and 2 who achieved marrow responses only.

Jae Park, MD, of Memorial Sloan-Kettering Cancer Center in New York, reported the findings at the 2014 ASCO Annual Meeting as abstract 7020.

Dr Park and colleagues enrolled 7 CLL patients who had detectable minimal residual disease after achieving either a partial or complete response following 6 cycles of pentostatin, cyclophosphamide, and rituximab.

Patients then received cyclophosphamide conditioning therapy, followed by 3 escalating doses of CAR T cells in 3 dose cohorts.

Six patients had unmutated IgHV, and 2 patients had del 11q. Four patients had palpable lymphadenopathy, including 1 patient with bulky lymph nodes, prior to T-cell infusion.

After a median follow-up of 11 months, 1 patient achieved a complete response, and 2 patients achieved complete responses in the bone marrow but had progressive disease in the lymph nodes.

Three patients achieved a partial response, and 1 patient had progressive disease, but this patient had rapidly rising absolute lymphocyte count at the time of T-cell infusion, Dr Park noted.

The investigators observed no dose-limiting toxicity. Mild and self-limiting cytokine release syndrome occurred in 3 patients.

“There was a positive correlation between the development of cytokine release syndrome and the CAR T-cell persistence,” Dr Park said.

“Our findings suggest that the CD19-targeted CAR T cells are more effective in eradicating disease in the marrow versus lymph nodes,” he added. “And further studies are being conducted to better understand the mechanism of resistance.”

ASCO discussant Veronika Bachanova, MD, of the University of Minnesota, noted that all previous studies of CAR T-cell therapy in CLL were conducted with relapsed/refractory patients.

“The novelty of this study,” she commented, “is the use of CAR T cells upfront.”

She noted that it can take as long as 8 months to develop the CAR T cells for therapy, adding that “the vector design is of critical importance, since inhibitory signals influence therapy.”

Poster hall at ASCO 2014

©ASCO/Todd Buchanan

CHICAGO—Infusion of autologous CD19-targeted chimeric antigen receptor (CAR)-modified T cells appears to have promising anti-tumor activity and be well-tolerated as a consolidation to frontline chemotherapy in patients with high-risk chronic lymphocytic leukemia (CLL), researchers report.

In a phase 1 trial, the modified T cells benefitted 43% of patients, including 1 who achieved a complete response and 2 who achieved marrow responses only.

Jae Park, MD, of Memorial Sloan-Kettering Cancer Center in New York, reported the findings at the 2014 ASCO Annual Meeting as abstract 7020.

Dr Park and colleagues enrolled 7 CLL patients who had detectable minimal residual disease after achieving either a partial or complete response following 6 cycles of pentostatin, cyclophosphamide, and rituximab.

Patients then received cyclophosphamide conditioning therapy, followed by 3 escalating doses of CAR T cells in 3 dose cohorts.

Six patients had unmutated IgHV, and 2 patients had del 11q. Four patients had palpable lymphadenopathy, including 1 patient with bulky lymph nodes, prior to T-cell infusion.

After a median follow-up of 11 months, 1 patient achieved a complete response, and 2 patients achieved complete responses in the bone marrow but had progressive disease in the lymph nodes.

Three patients achieved a partial response, and 1 patient had progressive disease, but this patient had rapidly rising absolute lymphocyte count at the time of T-cell infusion, Dr Park noted.

The investigators observed no dose-limiting toxicity. Mild and self-limiting cytokine release syndrome occurred in 3 patients.

“There was a positive correlation between the development of cytokine release syndrome and the CAR T-cell persistence,” Dr Park said.

“Our findings suggest that the CD19-targeted CAR T cells are more effective in eradicating disease in the marrow versus lymph nodes,” he added. “And further studies are being conducted to better understand the mechanism of resistance.”

ASCO discussant Veronika Bachanova, MD, of the University of Minnesota, noted that all previous studies of CAR T-cell therapy in CLL were conducted with relapsed/refractory patients.

“The novelty of this study,” she commented, “is the use of CAR T cells upfront.”

She noted that it can take as long as 8 months to develop the CAR T cells for therapy, adding that “the vector design is of critical importance, since inhibitory signals influence therapy.”

Poster hall at ASCO 2014

©ASCO/Todd Buchanan

CHICAGO—Infusion of autologous CD19-targeted chimeric antigen receptor (CAR)-modified T cells appears to have promising anti-tumor activity and be well-tolerated as a consolidation to frontline chemotherapy in patients with high-risk chronic lymphocytic leukemia (CLL), researchers report.

In a phase 1 trial, the modified T cells benefitted 43% of patients, including 1 who achieved a complete response and 2 who achieved marrow responses only.

Jae Park, MD, of Memorial Sloan-Kettering Cancer Center in New York, reported the findings at the 2014 ASCO Annual Meeting as abstract 7020.

Dr Park and colleagues enrolled 7 CLL patients who had detectable minimal residual disease after achieving either a partial or complete response following 6 cycles of pentostatin, cyclophosphamide, and rituximab.

Patients then received cyclophosphamide conditioning therapy, followed by 3 escalating doses of CAR T cells in 3 dose cohorts.

Six patients had unmutated IgHV, and 2 patients had del 11q. Four patients had palpable lymphadenopathy, including 1 patient with bulky lymph nodes, prior to T-cell infusion.

After a median follow-up of 11 months, 1 patient achieved a complete response, and 2 patients achieved complete responses in the bone marrow but had progressive disease in the lymph nodes.

Three patients achieved a partial response, and 1 patient had progressive disease, but this patient had rapidly rising absolute lymphocyte count at the time of T-cell infusion, Dr Park noted.

The investigators observed no dose-limiting toxicity. Mild and self-limiting cytokine release syndrome occurred in 3 patients.

“There was a positive correlation between the development of cytokine release syndrome and the CAR T-cell persistence,” Dr Park said.

“Our findings suggest that the CD19-targeted CAR T cells are more effective in eradicating disease in the marrow versus lymph nodes,” he added. “And further studies are being conducted to better understand the mechanism of resistance.”

ASCO discussant Veronika Bachanova, MD, of the University of Minnesota, noted that all previous studies of CAR T-cell therapy in CLL were conducted with relapsed/refractory patients.

“The novelty of this study,” she commented, “is the use of CAR T cells upfront.”

She noted that it can take as long as 8 months to develop the CAR T cells for therapy, adding that “the vector design is of critical importance, since inhibitory signals influence therapy.”

PARIS – Men with gout are significantly more likely to experience erectile dysfunction than are those without the disorder, Dr. Naomi Schlesinger said at the annual European Congress of Rheumatology.

In a survey of 201 men, erectile dysfunction (ED) occurred in 76% of 83 with gout and 52% of those without gout – a significant difference. In addition, 43% of those with gout and ED had severe erection difficulty – significantly more than those who had ED alone (30%).

Dr. Schlesinger, chief of rheumatology and connective tissue research at the Robert Wood Johnson Medical School, New Brunswick, N.J., said that ED can be a symptom of underlying cardiovascular disease. The small penile blood vessels can become atherosclerotic before the larger coronary vessels. The association between gout and ED remained significant even when she controlled for several cardiovascular risk factors: diabetes, hypertension, smoking, fasting glucose, and glomerular filtration rate.

Because of ED’s prevalence in this population – and because of its apparent association with cardiovascular disease – she advised that all men with gout be screened for sexual health.

"It’s not something physicians normally think to do" because of mutual embarrassment, she added.

[email protected]

On Twitter @alz_gal

PARIS – Men with gout are significantly more likely to experience erectile dysfunction than are those without the disorder, Dr. Naomi Schlesinger said at the annual European Congress of Rheumatology.

In a survey of 201 men, erectile dysfunction (ED) occurred in 76% of 83 with gout and 52% of those without gout – a significant difference. In addition, 43% of those with gout and ED had severe erection difficulty – significantly more than those who had ED alone (30%).

Dr. Schlesinger, chief of rheumatology and connective tissue research at the Robert Wood Johnson Medical School, New Brunswick, N.J., said that ED can be a symptom of underlying cardiovascular disease. The small penile blood vessels can become atherosclerotic before the larger coronary vessels. The association between gout and ED remained significant even when she controlled for several cardiovascular risk factors: diabetes, hypertension, smoking, fasting glucose, and glomerular filtration rate.

Because of ED’s prevalence in this population – and because of its apparent association with cardiovascular disease – she advised that all men with gout be screened for sexual health.

"It’s not something physicians normally think to do" because of mutual embarrassment, she added.

[email protected]

On Twitter @alz_gal

PARIS – Men with gout are significantly more likely to experience erectile dysfunction than are those without the disorder, Dr. Naomi Schlesinger said at the annual European Congress of Rheumatology.

In a survey of 201 men, erectile dysfunction (ED) occurred in 76% of 83 with gout and 52% of those without gout – a significant difference. In addition, 43% of those with gout and ED had severe erection difficulty – significantly more than those who had ED alone (30%).

Dr. Schlesinger, chief of rheumatology and connective tissue research at the Robert Wood Johnson Medical School, New Brunswick, N.J., said that ED can be a symptom of underlying cardiovascular disease. The small penile blood vessels can become atherosclerotic before the larger coronary vessels. The association between gout and ED remained significant even when she controlled for several cardiovascular risk factors: diabetes, hypertension, smoking, fasting glucose, and glomerular filtration rate.

Because of ED’s prevalence in this population – and because of its apparent association with cardiovascular disease – she advised that all men with gout be screened for sexual health.

"It’s not something physicians normally think to do" because of mutual embarrassment, she added.

[email protected]

On Twitter @alz_gal

Info booth at ASCO 2014

©ASCO/Scott Morgan

CHICAGO—Substituting lenalidomide for thalidomide in the standard treatment of newly diagnosed multiple myeloma (MM) improves quality of life and

lowers toxicity without significant loss of response, results of a phase 3 study suggest.

Combination melphalan, prednisone, and thalidomide (MPT) is considered a standard treatment option for transplant ineligible, newly diagnosed MM.

Early phase 1/2 studies suggested substituting lenalidomide for thalidomide might result in similar efficacy and less toxicity.

“However, neither feature can be confidently predicted, since long-term follow-up of the melphalan, prednisone, and lenalidomide (MPR) regimen is lacking, and myelosuppression may prove limiting, compromising drug dose and efficacy,” said A. Keith Stewart, MD, from the Mayo Clinic in Scottsdale, Arizona.

So Dr Stewart and his colleagues conducted a randomized, multicenter, phase 3 trial comparing MPT to MPR in untreated, symptomatic, transplant-ineligible MM patients. Dr Stewart presented the results at the 2014 ASCO Annual Meeting as abstract 8511.

The study included 306 patients with a median age of 76 years. The primary objective was to evaluate the  difference in progression-free survival (PFS) between patients receiving MPT and those treated with MPR.

Patients received melphalan at 9 mg/m² and prednisone at 100 mg orally on days 1-4, with thalidomide at 100 mg daily. Or they received melphalan at 5 mg/m² and prednisone at 100 mg orally on days 1-4, with lenalidomide at 10 mg orally on days 1-21.

MPT or MPR therapy was continued for twelve 28-day cycles, followed by thalidomide at 100 mg or lenalidomide at 10 mg daily until relapse. Patients were required to have aspirin prophylaxis.

Secondary study objectives included overall survival, toxicities, response rates, depth of response, and quality of life change. Treatment arms were balanced for age, ISS stage, and other major prognostic factors.

The median follow-up was 40.7 months. The median time on therapy was 12 months overall and 23 months for the 46% of patients on maintenance therapy, with no differences by arm. Some 7% of patients remained on treatment through cycle 60.

The results showed similar response rates between the 2 arms. The partial response rate was 64% for the MPT group, compared with 60% for the MPR group, with no difference in very good partial response/complete response rates (18.8% vs 23%).

The median PFS was 21 months for patients receiving MPT and 18.7 months for those receiving MPR. The median overall survival was not significantly different between the arms—52.6% for the MPT arm and 47.7% for the MPR arm.

Toxicities of grade 3 or higher were significantly more likely in the MPT arm (73%) than in the MPR arm (58%), as was non-hematologic toxicity (59% and 40%, respectively).

The incidence of second primary malignancies was higher with MPT (3.47/100 person years) than with MPR (2.01/100 person years). And deep vein thrombosis or pulmonary embolism occurred in 8.8% of MPT patients and 6.7% MPR patients.

“The quality of life analysis favored MPR by induction end,” Dr Stewart said. “Response rates, PFS, and overall survival were similar between the 2 arms. However, there was significantly better quality of life at 12 months and lower toxicity with MPR.”

Dr Stewart noted, however, that in the US, “melphalan-based regimens are now seldom utilized due to availability of lenalidomide and bortezomib in newly diagnosed patients.”

Info booth at ASCO 2014

©ASCO/Scott Morgan

CHICAGO—Substituting lenalidomide for thalidomide in the standard treatment of newly diagnosed multiple myeloma (MM) improves quality of life and

lowers toxicity without significant loss of response, results of a phase 3 study suggest.

Combination melphalan, prednisone, and thalidomide (MPT) is considered a standard treatment option for transplant ineligible, newly diagnosed MM.

Early phase 1/2 studies suggested substituting lenalidomide for thalidomide might result in similar efficacy and less toxicity.

“However, neither feature can be confidently predicted, since long-term follow-up of the melphalan, prednisone, and lenalidomide (MPR) regimen is lacking, and myelosuppression may prove limiting, compromising drug dose and efficacy,” said A. Keith Stewart, MD, from the Mayo Clinic in Scottsdale, Arizona.

So Dr Stewart and his colleagues conducted a randomized, multicenter, phase 3 trial comparing MPT to MPR in untreated, symptomatic, transplant-ineligible MM patients. Dr Stewart presented the results at the 2014 ASCO Annual Meeting as abstract 8511.

The study included 306 patients with a median age of 76 years. The primary objective was to evaluate the  difference in progression-free survival (PFS) between patients receiving MPT and those treated with MPR.

Patients received melphalan at 9 mg/m² and prednisone at 100 mg orally on days 1-4, with thalidomide at 100 mg daily. Or they received melphalan at 5 mg/m² and prednisone at 100 mg orally on days 1-4, with lenalidomide at 10 mg orally on days 1-21.

MPT or MPR therapy was continued for twelve 28-day cycles, followed by thalidomide at 100 mg or lenalidomide at 10 mg daily until relapse. Patients were required to have aspirin prophylaxis.

Secondary study objectives included overall survival, toxicities, response rates, depth of response, and quality of life change. Treatment arms were balanced for age, ISS stage, and other major prognostic factors.

The median follow-up was 40.7 months. The median time on therapy was 12 months overall and 23 months for the 46% of patients on maintenance therapy, with no differences by arm. Some 7% of patients remained on treatment through cycle 60.

The results showed similar response rates between the 2 arms. The partial response rate was 64% for the MPT group, compared with 60% for the MPR group, with no difference in very good partial response/complete response rates (18.8% vs 23%).

The median PFS was 21 months for patients receiving MPT and 18.7 months for those receiving MPR. The median overall survival was not significantly different between the arms—52.6% for the MPT arm and 47.7% for the MPR arm.

Toxicities of grade 3 or higher were significantly more likely in the MPT arm (73%) than in the MPR arm (58%), as was non-hematologic toxicity (59% and 40%, respectively).

The incidence of second primary malignancies was higher with MPT (3.47/100 person years) than with MPR (2.01/100 person years). And deep vein thrombosis or pulmonary embolism occurred in 8.8% of MPT patients and 6.7% MPR patients.

“The quality of life analysis favored MPR by induction end,” Dr Stewart said. “Response rates, PFS, and overall survival were similar between the 2 arms. However, there was significantly better quality of life at 12 months and lower toxicity with MPR.”

Dr Stewart noted, however, that in the US, “melphalan-based regimens are now seldom utilized due to availability of lenalidomide and bortezomib in newly diagnosed patients.”

Info booth at ASCO 2014

©ASCO/Scott Morgan

CHICAGO—Substituting lenalidomide for thalidomide in the standard treatment of newly diagnosed multiple myeloma (MM) improves quality of life and

lowers toxicity without significant loss of response, results of a phase 3 study suggest.

Combination melphalan, prednisone, and thalidomide (MPT) is considered a standard treatment option for transplant ineligible, newly diagnosed MM.

Early phase 1/2 studies suggested substituting lenalidomide for thalidomide might result in similar efficacy and less toxicity.

“However, neither feature can be confidently predicted, since long-term follow-up of the melphalan, prednisone, and lenalidomide (MPR) regimen is lacking, and myelosuppression may prove limiting, compromising drug dose and efficacy,” said A. Keith Stewart, MD, from the Mayo Clinic in Scottsdale, Arizona.

So Dr Stewart and his colleagues conducted a randomized, multicenter, phase 3 trial comparing MPT to MPR in untreated, symptomatic, transplant-ineligible MM patients. Dr Stewart presented the results at the 2014 ASCO Annual Meeting as abstract 8511.

The study included 306 patients with a median age of 76 years. The primary objective was to evaluate the  difference in progression-free survival (PFS) between patients receiving MPT and those treated with MPR.

Patients received melphalan at 9 mg/m² and prednisone at 100 mg orally on days 1-4, with thalidomide at 100 mg daily. Or they received melphalan at 5 mg/m² and prednisone at 100 mg orally on days 1-4, with lenalidomide at 10 mg orally on days 1-21.

MPT or MPR therapy was continued for twelve 28-day cycles, followed by thalidomide at 100 mg or lenalidomide at 10 mg daily until relapse. Patients were required to have aspirin prophylaxis.

Secondary study objectives included overall survival, toxicities, response rates, depth of response, and quality of life change. Treatment arms were balanced for age, ISS stage, and other major prognostic factors.

The median follow-up was 40.7 months. The median time on therapy was 12 months overall and 23 months for the 46% of patients on maintenance therapy, with no differences by arm. Some 7% of patients remained on treatment through cycle 60.

The results showed similar response rates between the 2 arms. The partial response rate was 64% for the MPT group, compared with 60% for the MPR group, with no difference in very good partial response/complete response rates (18.8% vs 23%).

The median PFS was 21 months for patients receiving MPT and 18.7 months for those receiving MPR. The median overall survival was not significantly different between the arms—52.6% for the MPT arm and 47.7% for the MPR arm.

Toxicities of grade 3 or higher were significantly more likely in the MPT arm (73%) than in the MPR arm (58%), as was non-hematologic toxicity (59% and 40%, respectively).

The incidence of second primary malignancies was higher with MPT (3.47/100 person years) than with MPR (2.01/100 person years). And deep vein thrombosis or pulmonary embolism occurred in 8.8% of MPT patients and 6.7% MPR patients.

“The quality of life analysis favored MPR by induction end,” Dr Stewart said. “Response rates, PFS, and overall survival were similar between the 2 arms. However, there was significantly better quality of life at 12 months and lower toxicity with MPR.”

Dr Stewart noted, however, that in the US, “melphalan-based regimens are now seldom utilized due to availability of lenalidomide and bortezomib in newly diagnosed patients.”

PARIS – New international guidelines for polymyalgia rheumatica will focus on standardizing treatment practice across specialties.

When adopted, the proposed guidelines will succeed those published by the British Society of Rheumatology in 2009, according to Dr. Bhaskar Dasgupta, a primary author of the new guidelines and leader of the study group.

"This is the first transatlantic EULAR-ACR [European League against Rheumatism-American College of Rheumatology] guideline in rheumatology," he said at the annual European Congress of Rheumatology. "It is very patient-centered and was developed with patient input."

There has been a great need for a document such as this, he said. Primary care physicians are almost always on the front line of diagnosing polymyalgia rheumatica and often [the first] to treat these patients – with variable success, said Dr. Dasgupta, head of the Southend Hospital rheumatology department, Essex, England.

"This disorder is as common as – or more common than – rheumatoid arthritis, with a very high prevalence and incidence," he said. "It’s often diagnosed by general practitioners, with patients referred to nonrheumatologists. Yet there is a very wide variation in practice and a lot of uncertainty in the diagnosis. We are concerned that we have handed this over to primary care physicians when it needs so much clinical acumen to tease this out from other conditions.

The guidelines were developed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology and involving appraisal of 445 relevant publications in polymyalgia rheumatica (PMR), published since 1970. The document was reviewed on several occasions by an international panel that included 51 investigators from the United States and represented countries in Western and Eastern Europe, as well as Australia, New Zealand, Brazil, South America, Japan, and India. All recommendations were adopted unanimously without the need to vote, according to Dr. Dasgupta.

According to the proposed document, most patients are diagnosed and treated in primary care settings, but there are no well-elucidated referral algorithms for referral to specialty care. This can contribute to variability in treatment.

For instance, "a proportion of PMR patients do not adequately respond to glucocorticoid therapy and suffer frequent relapses and dependency on long-term high doses," according to the guidelines. "Prolonged glucocorticoid therapy is associated with considerable side effects especially when high doses are employed." Dr. Dasgupta said the proposed guidelines address groups that are at especially high risk for these problems. "While effective, steroids have the potential to cause serious side effects," he said. "It is important to know how to use them [steroids] correctly in PMR. The subgroups that are vulnerable to side effects – such as patients with diabetes, hypertension, osteoporosis, and glaucoma, and high disease activity should be recognized – female sex and those with peripheral arthritis or high inflammatory markers."

The guidelines are structured as a treatment algorithm, which begins with accurate diagnosis and patient assessment. They recommend that most patients be started on oral prednisone at the equivalent of 12.5-25 mg/day, or if the patient is at high risk of steroid-related side effects, to begin with intramuscular glucocorticoids.

If there is inadequate response, the guidelines recommend an increase in glucocorticoid dose or methotrexate for those at high risk of side effects, relapse, or prolonged therapy.

If there is improvement within 4 weeks, consider a gradual tapering of steroids. If not, a confirmation of the diagnosis is in order, the guidelines note. Patients who respond well to the taper will likely go into remission and may continue the taper. Patients who relapse should have a diagnostic confirmation and/or specialist referral.

"Ultimately, in order to be accepted, the guidelines will require confirmation of their usefulness in clinical practice. PMR recommendations endorsed by both the ACR and EULAR would have a significant impact on clinical decision making, would reduce practice variation, and would stimulate further research in areas where there is currently lack of adequate evidence."

In addition, he said, the role for early methotrexate in treatment of the condition is now emerging and will be included in the guidelines for consideration in special subgroups.

The guidelines must still be ratified by both the ACR and EULAR. Once that happens, they will be simultaneously published in both associations’ journals – no later than mid-2015, Dr. Dasgupta said.

Dr. Dasgupta disclosed that he has helped design clinical trials for a number of drug companies and has received remuneration for educational symposia from others.

[email protected]

On Twitter @alz_gal

PARIS – New international guidelines for polymyalgia rheumatica will focus on standardizing treatment practice across specialties.

When adopted, the proposed guidelines will succeed those published by the British Society of Rheumatology in 2009, according to Dr. Bhaskar Dasgupta, a primary author of the new guidelines and leader of the study group.

"This is the first transatlantic EULAR-ACR [European League against Rheumatism-American College of Rheumatology] guideline in rheumatology," he said at the annual European Congress of Rheumatology. "It is very patient-centered and was developed with patient input."

There has been a great need for a document such as this, he said. Primary care physicians are almost always on the front line of diagnosing polymyalgia rheumatica and often [the first] to treat these patients – with variable success, said Dr. Dasgupta, head of the Southend Hospital rheumatology department, Essex, England.

"This disorder is as common as – or more common than – rheumatoid arthritis, with a very high prevalence and incidence," he said. "It’s often diagnosed by general practitioners, with patients referred to nonrheumatologists. Yet there is a very wide variation in practice and a lot of uncertainty in the diagnosis. We are concerned that we have handed this over to primary care physicians when it needs so much clinical acumen to tease this out from other conditions.

The guidelines were developed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology and involving appraisal of 445 relevant publications in polymyalgia rheumatica (PMR), published since 1970. The document was reviewed on several occasions by an international panel that included 51 investigators from the United States and represented countries in Western and Eastern Europe, as well as Australia, New Zealand, Brazil, South America, Japan, and India. All recommendations were adopted unanimously without the need to vote, according to Dr. Dasgupta.

According to the proposed document, most patients are diagnosed and treated in primary care settings, but there are no well-elucidated referral algorithms for referral to specialty care. This can contribute to variability in treatment.

For instance, "a proportion of PMR patients do not adequately respond to glucocorticoid therapy and suffer frequent relapses and dependency on long-term high doses," according to the guidelines. "Prolonged glucocorticoid therapy is associated with considerable side effects especially when high doses are employed." Dr. Dasgupta said the proposed guidelines address groups that are at especially high risk for these problems. "While effective, steroids have the potential to cause serious side effects," he said. "It is important to know how to use them [steroids] correctly in PMR. The subgroups that are vulnerable to side effects – such as patients with diabetes, hypertension, osteoporosis, and glaucoma, and high disease activity should be recognized – female sex and those with peripheral arthritis or high inflammatory markers."

The guidelines are structured as a treatment algorithm, which begins with accurate diagnosis and patient assessment. They recommend that most patients be started on oral prednisone at the equivalent of 12.5-25 mg/day, or if the patient is at high risk of steroid-related side effects, to begin with intramuscular glucocorticoids.

If there is inadequate response, the guidelines recommend an increase in glucocorticoid dose or methotrexate for those at high risk of side effects, relapse, or prolonged therapy.

If there is improvement within 4 weeks, consider a gradual tapering of steroids. If not, a confirmation of the diagnosis is in order, the guidelines note. Patients who respond well to the taper will likely go into remission and may continue the taper. Patients who relapse should have a diagnostic confirmation and/or specialist referral.

"Ultimately, in order to be accepted, the guidelines will require confirmation of their usefulness in clinical practice. PMR recommendations endorsed by both the ACR and EULAR would have a significant impact on clinical decision making, would reduce practice variation, and would stimulate further research in areas where there is currently lack of adequate evidence."

In addition, he said, the role for early methotrexate in treatment of the condition is now emerging and will be included in the guidelines for consideration in special subgroups.

The guidelines must still be ratified by both the ACR and EULAR. Once that happens, they will be simultaneously published in both associations’ journals – no later than mid-2015, Dr. Dasgupta said.

Dr. Dasgupta disclosed that he has helped design clinical trials for a number of drug companies and has received remuneration for educational symposia from others.

[email protected]

On Twitter @alz_gal

PARIS – New international guidelines for polymyalgia rheumatica will focus on standardizing treatment practice across specialties.

When adopted, the proposed guidelines will succeed those published by the British Society of Rheumatology in 2009, according to Dr. Bhaskar Dasgupta, a primary author of the new guidelines and leader of the study group.

"This is the first transatlantic EULAR-ACR [European League against Rheumatism-American College of Rheumatology] guideline in rheumatology," he said at the annual European Congress of Rheumatology. "It is very patient-centered and was developed with patient input."

There has been a great need for a document such as this, he said. Primary care physicians are almost always on the front line of diagnosing polymyalgia rheumatica and often [the first] to treat these patients – with variable success, said Dr. Dasgupta, head of the Southend Hospital rheumatology department, Essex, England.

"This disorder is as common as – or more common than – rheumatoid arthritis, with a very high prevalence and incidence," he said. "It’s often diagnosed by general practitioners, with patients referred to nonrheumatologists. Yet there is a very wide variation in practice and a lot of uncertainty in the diagnosis. We are concerned that we have handed this over to primary care physicians when it needs so much clinical acumen to tease this out from other conditions.

The guidelines were developed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology and involving appraisal of 445 relevant publications in polymyalgia rheumatica (PMR), published since 1970. The document was reviewed on several occasions by an international panel that included 51 investigators from the United States and represented countries in Western and Eastern Europe, as well as Australia, New Zealand, Brazil, South America, Japan, and India. All recommendations were adopted unanimously without the need to vote, according to Dr. Dasgupta.

According to the proposed document, most patients are diagnosed and treated in primary care settings, but there are no well-elucidated referral algorithms for referral to specialty care. This can contribute to variability in treatment.

For instance, "a proportion of PMR patients do not adequately respond to glucocorticoid therapy and suffer frequent relapses and dependency on long-term high doses," according to the guidelines. "Prolonged glucocorticoid therapy is associated with considerable side effects especially when high doses are employed." Dr. Dasgupta said the proposed guidelines address groups that are at especially high risk for these problems. "While effective, steroids have the potential to cause serious side effects," he said. "It is important to know how to use them [steroids] correctly in PMR. The subgroups that are vulnerable to side effects – such as patients with diabetes, hypertension, osteoporosis, and glaucoma, and high disease activity should be recognized – female sex and those with peripheral arthritis or high inflammatory markers."

The guidelines are structured as a treatment algorithm, which begins with accurate diagnosis and patient assessment. They recommend that most patients be started on oral prednisone at the equivalent of 12.5-25 mg/day, or if the patient is at high risk of steroid-related side effects, to begin with intramuscular glucocorticoids.

If there is inadequate response, the guidelines recommend an increase in glucocorticoid dose or methotrexate for those at high risk of side effects, relapse, or prolonged therapy.

If there is improvement within 4 weeks, consider a gradual tapering of steroids. If not, a confirmation of the diagnosis is in order, the guidelines note. Patients who respond well to the taper will likely go into remission and may continue the taper. Patients who relapse should have a diagnostic confirmation and/or specialist referral.

"Ultimately, in order to be accepted, the guidelines will require confirmation of their usefulness in clinical practice. PMR recommendations endorsed by both the ACR and EULAR would have a significant impact on clinical decision making, would reduce practice variation, and would stimulate further research in areas where there is currently lack of adequate evidence."

In addition, he said, the role for early methotrexate in treatment of the condition is now emerging and will be included in the guidelines for consideration in special subgroups.

The guidelines must still be ratified by both the ACR and EULAR. Once that happens, they will be simultaneously published in both associations’ journals – no later than mid-2015, Dr. Dasgupta said.

Dr. Dasgupta disclosed that he has helped design clinical trials for a number of drug companies and has received remuneration for educational symposia from others.

[email protected]

On Twitter @alz_gal

In 2011, an article titled "Building a Successful Career: Advice From Leaders in Thoracic Surgery" was published in Thoracic Surgical Clinics of North America.¹ In developing this paper, Dr. Sean Grondin states, "I have been fortunate to have had mentors who have guided me through my surgical training and early years of practice," and he continues, "I realize how much I have learned from and been influenced by the experience and guidance of other surgeons."

Based on his experiences, Dr. Grondin selected a group of 20 outstanding leaders in thoracic surgery, and asked them to each write a short summary of what they deemed to be key elements for developing a successful thoracic surgical career. The inspiration for the paper was an appreciation for mentorship and a desire to further disseminate the influences of the greats in our field; it is both revealing and remarkably appropriate that, in their responses, the majority of the recognized leaders discussed the importance of cultivating strong mentorship relationships, with the word "mentor" mentioned 34 times in the article. The importance of having strong mentors to guide oneself in career development is highlighted over and over again.

In his comments, Dr. Douglas Mathisen states, "Residency training usually introduces you to the most important mentors in your life. They will be the ones who nurture you, educate you, and point you in the right direction. They are likely to bring out the desire in you to become an academic surgeon and educator."

Advice for success from Dr. Valerie Rusch included eight key points, one of which focused on mentorship: "Peer review and senior advice are frequently helpful, and most senior academic physicians are delighted to provide this. Mentors may be surgeons but are also often found in other specialties or even nonclinical settings." And, from the mentors’ perspective, Dr. F.G. Pearson remarks, "In a residency training program, the opportunity to act as a meaningful mentor is a gift and a rewarding opportunity."

For a cardiothoracic surgeon’s individual success, it is clear that having (and utilizing) the right mentors can make a significant impact. Further, when one considers the success of a group of individuals, it is equally important that mentorship relationships are present and strong. In the summer of 2011, the Senior Tour (a group of retired cardiothoracic surgeons committed to education and service for their profession) was asked by the Joint Council on Thoracic Surgery Education to visit 10 thoracic surgical training programs that were considered above average according to a poll taken of thoracic surgical residents in the fall of 2010 by the Thoracic Surgery Residents Association.²

As they summarized their findings, they noted that the top programs possessed many common features leading to superior training in cardiac and general thoracic surgery. The authors specifically noted seven key factors, and, among them, was "a significant emphasis on mentorship, with the program director playing the primary roles and with voluntary relationships between residents and other faculty and with mentorship also including involvement in job finding."

If mentorship is so important to success in this career path, exactly what opportunities exist for trainees seeking mentorship? A Google search for ["mentor" AND "thoracic surgery"] yields a number of results, with ultimate direction leading to essentially two organizations: the AATS and Women in Thoracic Surgery (WTS).

From the AATS website, there is a list of names and contact information for mentors who have been selected or self-nominated for prospective candidates for thoracic surgery residency. These mentors are available to offer guidance, recommendations, and research opportunities, as well as clinical rotations in cardiothoracic surgery (http://aats.org/TSR/contactsMentors.cgi).

A number of opportunities for mentorship are also available through WTS. There is a formal mentoring program, aiming to pair women interested in cardiothoracic surgical careers with established WTS members. Dr. Shanda Blackmon, the Mentoring Chair for the WTS, reflects on the program, stating, "Many surgeons think that mentorship has to be a formal relationship at the same institution. What we have learned at WTS is that mentorship relationships can be equally effective even when they are not formal and the mentor is not from the same institution." She continues, reporting that, "in the survey we conducted through WTS, we discovered that mentorship was one of the most important factors to young surgeons aspiring to start a career in thoracic surgery." It is for this reason that WTS places such emphasis on helping trainees find and sustain mentorship opportunities.

WTS specifically offers scholarships to the Society of Thoracic Surgeons meeting, the Scanlan/WTS Traveling Mentorship, the Carolyn Reed Award, a list of mentors online, and resident mentors. (Further details of all of these programs can be found at www.wtsnet.org.) WTS provides a number of opportunities for female trainees to connect with female mentors. But is it absolutely necessary to find mentors who are "like you"?

Dr. Jennifer Lawton, president of WTS, acknowledges that everyone needs mentoring, but urges that "mentoring of women and minorities is particularly important in order to take advantage of the vast array of benefits to be gained by ethnic, racial, and gender diversity in the workplace."

She continues: "If we don’t see others successful in a chosen field, we do not perceive the goal attainable for ourselves. I have seen this many times in cardiothoracic surgery and women. Women who are not exposed to female mentors have expressed concern that practice in the field is not possible for women (especially those who aspire to have a family)." And, further, she explains that "we are typically more comfortable in mentoring situations with others like ourselves (similar challenges, needs, concerns). Surveys demonstrate that medical students often choose fields of interest because of mentors. For these reasons, it is important for individuals to find mentors who are similar to themselves."

Additional formal mentoring programs exist, and include the Brooks Scholarship through the Southern Thoracic Surgical Association (STSA), the Society of Thoracic Surgeons Looking to the Future scholarship program, the AATS Member for a Day program, and more.

Exactly what should one hope to get out of a mentorship relationship? The truth is, it really depends on the stage of career and the specific needs of the mentee. Mentorship needs change over time, and even well-established mentoring relationships will evolve and adjust along with participants in the interaction.

Sarah Schubert is a fourth-year medical student at Penn State, who has matched into the I-6 program at the University of Virginia and is the current recipient of the Scanlan/WTS scholarship. This award provides trainees with an opportunity to gain exposure to women cardiothoracic surgeon mentors by visiting a WTS member for an elective period. Ms. Schubert reports that she applied for the scholarship because she "wanted to work with and learn from a highly successful female cardiac surgeon in hopes of initiating and developing a professional relationship with a woman in the field."

As a medical student, she has fairly basic mentorship needs. She tells us that "right now, I need mentors who can serve as good role models – in the OR, with patients, with colleagues and trainees, and in their personal lives outside the hospital. As I prepare to enter residency, I anticipate that I will need to further develop my patient care skills and operative techniques, as well as skills to manage time and obligations. Knowing and working with people who have already figured out how to juggle those different obligations will be immensely helpful." Other medical students may be looking for advice on interviewing and ranking residency programs, and, like Ms. Schubert, may be interested in tips on how to get a great start in internship.

For individuals deep in the throes of cardiothoracic training, the needs are clearly different. Dr. Ryan Shelstad, a first-year fellow at the University of Colorado, states: "In my mind, the primary objective of clinical fellowship is acquisition of technical skills and clinical decision making in CT surgery. Thus, mentorship at this stage follows this objective." He continues, "CT fellowship is a relatively short time to achieve this goal as well as position oneself to successfully transition to a faculty position or private practice, which is the second objective—and area for mentoring."

Dr. Shelstad acknowledges and explains the transition in his mentorship needs, "I think earlier in training, mentorship focused on career choice, research, and transition to a fellowship. Much was focused on getting to the next step. While that is still important, now is the time to focus on the clinical aspects of CT surgery that I will use the rest of my career." And, certainly, the specific mentoring needs will continue to change with time.

Dr. Lawton, who holds the rank of professor at Washington University, St. Louis, states that, "after reaching full professor, surgeons need mentoring and sponsoring to reach goals such as dean positions, leadership positions, national organization officer positions, etc. We also all continually need mosaic mentoring that evolves over time (someone to mentor for research career aspects, managing work-life balance issues, family issues, teaching issues, financial issues, etc.). As we progress in our careers, we have the opportunity to also be mentored in other areas by younger generations."

Wait, did she just say that progressing surgeons can be mentored by younger generations? Yes, she did. And not only can seasoned surgeons be mentored by younger surgeons, they also stand to gain considerably from their own mentees. Dr. Lawton further states, "There is always reciprocal gain in a mentoring relationship for the mentor. There is no better joy than to see a mentee succeed and be fulfilled and happy in her chosen field. For some, this provides a rich legacy of trainees and mentees to provide continued enrichment, excitement, and a source of tremendous pride in later years." In the previously mentioned article by Grondin, Dr. Gail Darling states, "Academic careers are usually measured in papers published, grants awarded, invited lectures, and academic standing. Equally important are the students we teach and motivate toward careers in surgery, residents and fellows we have taught and mentored who will provide care to patients and who will go out and teach new generations of surgeons who will in turn provide care."

Once mentorship bonds have been established, it is critical to cultivate these relationships and to gain the most possible from these interactions. When asked how he has achieved these ends, Dr. Shelstad replies, "You and your mentors have the same goal: mutual success. Work hard for your mentors, and they will work hard for you. I would encourage explicit discussion of goals and expectations to ensure you and a potential mentor are on the same page. Mentorship is essential to success in cardiothoracic surgery."

Without a doubt, participation in mentorship relationships is a key element of success at every stage of the career and development of a cardiothoracic surgeon. Outstanding programs already exist to support modern trainees, and further efforts will certainly be met with great enthusiasm. Also apparent is the need for ongoing, career-long mentorship – and the paucity of formal programs to support it. This need may be a great opportunity for the establishment of future programming.

On a personal note, when reflecting on mentorship, I think of a statement made by Benjamin Franklin: "Tell me and I forget, teach me and I may remember, involve me and I learn." To those incredible individuals who have taken the time, effort, and interest to truly involve me, I have immense gratitude. I will aim for the rest of my career to make it worth your while, with hopes to bring you pride and inspire others as you have inspired me. To all who have taken time to truly involve any student, resident, or junior colleague – you have motivated us and given strength to the ongoing legacy of our amazing field.

Citations

1. Grondin SC. Building a Successful Career: Advice From Leaders in Thoracic Surgery. Thorac. Surg. Clin. 2011;21(3):395-415.

2. J. Thorac. Cardiovasc. Surg. 2014;147(1):15-17.

In 2011, an article titled "Building a Successful Career: Advice From Leaders in Thoracic Surgery" was published in Thoracic Surgical Clinics of North America.¹ In developing this paper, Dr. Sean Grondin states, "I have been fortunate to have had mentors who have guided me through my surgical training and early years of practice," and he continues, "I realize how much I have learned from and been influenced by the experience and guidance of other surgeons."

Based on his experiences, Dr. Grondin selected a group of 20 outstanding leaders in thoracic surgery, and asked them to each write a short summary of what they deemed to be key elements for developing a successful thoracic surgical career. The inspiration for the paper was an appreciation for mentorship and a desire to further disseminate the influences of the greats in our field; it is both revealing and remarkably appropriate that, in their responses, the majority of the recognized leaders discussed the importance of cultivating strong mentorship relationships, with the word "mentor" mentioned 34 times in the article. The importance of having strong mentors to guide oneself in career development is highlighted over and over again.

In his comments, Dr. Douglas Mathisen states, "Residency training usually introduces you to the most important mentors in your life. They will be the ones who nurture you, educate you, and point you in the right direction. They are likely to bring out the desire in you to become an academic surgeon and educator."

Advice for success from Dr. Valerie Rusch included eight key points, one of which focused on mentorship: "Peer review and senior advice are frequently helpful, and most senior academic physicians are delighted to provide this. Mentors may be surgeons but are also often found in other specialties or even nonclinical settings." And, from the mentors’ perspective, Dr. F.G. Pearson remarks, "In a residency training program, the opportunity to act as a meaningful mentor is a gift and a rewarding opportunity."

For a cardiothoracic surgeon’s individual success, it is clear that having (and utilizing) the right mentors can make a significant impact. Further, when one considers the success of a group of individuals, it is equally important that mentorship relationships are present and strong. In the summer of 2011, the Senior Tour (a group of retired cardiothoracic surgeons committed to education and service for their profession) was asked by the Joint Council on Thoracic Surgery Education to visit 10 thoracic surgical training programs that were considered above average according to a poll taken of thoracic surgical residents in the fall of 2010 by the Thoracic Surgery Residents Association.²

As they summarized their findings, they noted that the top programs possessed many common features leading to superior training in cardiac and general thoracic surgery. The authors specifically noted seven key factors, and, among them, was "a significant emphasis on mentorship, with the program director playing the primary roles and with voluntary relationships between residents and other faculty and with mentorship also including involvement in job finding."

If mentorship is so important to success in this career path, exactly what opportunities exist for trainees seeking mentorship? A Google search for ["mentor" AND "thoracic surgery"] yields a number of results, with ultimate direction leading to essentially two organizations: the AATS and Women in Thoracic Surgery (WTS).

From the AATS website, there is a list of names and contact information for mentors who have been selected or self-nominated for prospective candidates for thoracic surgery residency. These mentors are available to offer guidance, recommendations, and research opportunities, as well as clinical rotations in cardiothoracic surgery (http://aats.org/TSR/contactsMentors.cgi).

A number of opportunities for mentorship are also available through WTS. There is a formal mentoring program, aiming to pair women interested in cardiothoracic surgical careers with established WTS members. Dr. Shanda Blackmon, the Mentoring Chair for the WTS, reflects on the program, stating, "Many surgeons think that mentorship has to be a formal relationship at the same institution. What we have learned at WTS is that mentorship relationships can be equally effective even when they are not formal and the mentor is not from the same institution." She continues, reporting that, "in the survey we conducted through WTS, we discovered that mentorship was one of the most important factors to young surgeons aspiring to start a career in thoracic surgery." It is for this reason that WTS places such emphasis on helping trainees find and sustain mentorship opportunities.

WTS specifically offers scholarships to the Society of Thoracic Surgeons meeting, the Scanlan/WTS Traveling Mentorship, the Carolyn Reed Award, a list of mentors online, and resident mentors. (Further details of all of these programs can be found at www.wtsnet.org.) WTS provides a number of opportunities for female trainees to connect with female mentors. But is it absolutely necessary to find mentors who are "like you"?

Dr. Jennifer Lawton, president of WTS, acknowledges that everyone needs mentoring, but urges that "mentoring of women and minorities is particularly important in order to take advantage of the vast array of benefits to be gained by ethnic, racial, and gender diversity in the workplace."

She continues: "If we don’t see others successful in a chosen field, we do not perceive the goal attainable for ourselves. I have seen this many times in cardiothoracic surgery and women. Women who are not exposed to female mentors have expressed concern that practice in the field is not possible for women (especially those who aspire to have a family)." And, further, she explains that "we are typically more comfortable in mentoring situations with others like ourselves (similar challenges, needs, concerns). Surveys demonstrate that medical students often choose fields of interest because of mentors. For these reasons, it is important for individuals to find mentors who are similar to themselves."

Additional formal mentoring programs exist, and include the Brooks Scholarship through the Southern Thoracic Surgical Association (STSA), the Society of Thoracic Surgeons Looking to the Future scholarship program, the AATS Member for a Day program, and more.

Exactly what should one hope to get out of a mentorship relationship? The truth is, it really depends on the stage of career and the specific needs of the mentee. Mentorship needs change over time, and even well-established mentoring relationships will evolve and adjust along with participants in the interaction.

Sarah Schubert is a fourth-year medical student at Penn State, who has matched into the I-6 program at the University of Virginia and is the current recipient of the Scanlan/WTS scholarship. This award provides trainees with an opportunity to gain exposure to women cardiothoracic surgeon mentors by visiting a WTS member for an elective period. Ms. Schubert reports that she applied for the scholarship because she "wanted to work with and learn from a highly successful female cardiac surgeon in hopes of initiating and developing a professional relationship with a woman in the field."

As a medical student, she has fairly basic mentorship needs. She tells us that "right now, I need mentors who can serve as good role models – in the OR, with patients, with colleagues and trainees, and in their personal lives outside the hospital. As I prepare to enter residency, I anticipate that I will need to further develop my patient care skills and operative techniques, as well as skills to manage time and obligations. Knowing and working with people who have already figured out how to juggle those different obligations will be immensely helpful." Other medical students may be looking for advice on interviewing and ranking residency programs, and, like Ms. Schubert, may be interested in tips on how to get a great start in internship.

For individuals deep in the throes of cardiothoracic training, the needs are clearly different. Dr. Ryan Shelstad, a first-year fellow at the University of Colorado, states: "In my mind, the primary objective of clinical fellowship is acquisition of technical skills and clinical decision making in CT surgery. Thus, mentorship at this stage follows this objective." He continues, "CT fellowship is a relatively short time to achieve this goal as well as position oneself to successfully transition to a faculty position or private practice, which is the second objective—and area for mentoring."

Dr. Shelstad acknowledges and explains the transition in his mentorship needs, "I think earlier in training, mentorship focused on career choice, research, and transition to a fellowship. Much was focused on getting to the next step. While that is still important, now is the time to focus on the clinical aspects of CT surgery that I will use the rest of my career." And, certainly, the specific mentoring needs will continue to change with time.

Dr. Lawton, who holds the rank of professor at Washington University, St. Louis, states that, "after reaching full professor, surgeons need mentoring and sponsoring to reach goals such as dean positions, leadership positions, national organization officer positions, etc. We also all continually need mosaic mentoring that evolves over time (someone to mentor for research career aspects, managing work-life balance issues, family issues, teaching issues, financial issues, etc.). As we progress in our careers, we have the opportunity to also be mentored in other areas by younger generations."

Wait, did she just say that progressing surgeons can be mentored by younger generations? Yes, she did. And not only can seasoned surgeons be mentored by younger surgeons, they also stand to gain considerably from their own mentees. Dr. Lawton further states, "There is always reciprocal gain in a mentoring relationship for the mentor. There is no better joy than to see a mentee succeed and be fulfilled and happy in her chosen field. For some, this provides a rich legacy of trainees and mentees to provide continued enrichment, excitement, and a source of tremendous pride in later years." In the previously mentioned article by Grondin, Dr. Gail Darling states, "Academic careers are usually measured in papers published, grants awarded, invited lectures, and academic standing. Equally important are the students we teach and motivate toward careers in surgery, residents and fellows we have taught and mentored who will provide care to patients and who will go out and teach new generations of surgeons who will in turn provide care."

Once mentorship bonds have been established, it is critical to cultivate these relationships and to gain the most possible from these interactions. When asked how he has achieved these ends, Dr. Shelstad replies, "You and your mentors have the same goal: mutual success. Work hard for your mentors, and they will work hard for you. I would encourage explicit discussion of goals and expectations to ensure you and a potential mentor are on the same page. Mentorship is essential to success in cardiothoracic surgery."

Without a doubt, participation in mentorship relationships is a key element of success at every stage of the career and development of a cardiothoracic surgeon. Outstanding programs already exist to support modern trainees, and further efforts will certainly be met with great enthusiasm. Also apparent is the need for ongoing, career-long mentorship – and the paucity of formal programs to support it. This need may be a great opportunity for the establishment of future programming.

On a personal note, when reflecting on mentorship, I think of a statement made by Benjamin Franklin: "Tell me and I forget, teach me and I may remember, involve me and I learn." To those incredible individuals who have taken the time, effort, and interest to truly involve me, I have immense gratitude. I will aim for the rest of my career to make it worth your while, with hopes to bring you pride and inspire others as you have inspired me. To all who have taken time to truly involve any student, resident, or junior colleague – you have motivated us and given strength to the ongoing legacy of our amazing field.

Citations

1. Grondin SC. Building a Successful Career: Advice From Leaders in Thoracic Surgery. Thorac. Surg. Clin. 2011;21(3):395-415.

2. J. Thorac. Cardiovasc. Surg. 2014;147(1):15-17.

In 2011, an article titled "Building a Successful Career: Advice From Leaders in Thoracic Surgery" was published in Thoracic Surgical Clinics of North America.¹ In developing this paper, Dr. Sean Grondin states, "I have been fortunate to have had mentors who have guided me through my surgical training and early years of practice," and he continues, "I realize how much I have learned from and been influenced by the experience and guidance of other surgeons."

Based on his experiences, Dr. Grondin selected a group of 20 outstanding leaders in thoracic surgery, and asked them to each write a short summary of what they deemed to be key elements for developing a successful thoracic surgical career. The inspiration for the paper was an appreciation for mentorship and a desire to further disseminate the influences of the greats in our field; it is both revealing and remarkably appropriate that, in their responses, the majority of the recognized leaders discussed the importance of cultivating strong mentorship relationships, with the word "mentor" mentioned 34 times in the article. The importance of having strong mentors to guide oneself in career development is highlighted over and over again.

In his comments, Dr. Douglas Mathisen states, "Residency training usually introduces you to the most important mentors in your life. They will be the ones who nurture you, educate you, and point you in the right direction. They are likely to bring out the desire in you to become an academic surgeon and educator."

Advice for success from Dr. Valerie Rusch included eight key points, one of which focused on mentorship: "Peer review and senior advice are frequently helpful, and most senior academic physicians are delighted to provide this. Mentors may be surgeons but are also often found in other specialties or even nonclinical settings." And, from the mentors’ perspective, Dr. F.G. Pearson remarks, "In a residency training program, the opportunity to act as a meaningful mentor is a gift and a rewarding opportunity."

For a cardiothoracic surgeon’s individual success, it is clear that having (and utilizing) the right mentors can make a significant impact. Further, when one considers the success of a group of individuals, it is equally important that mentorship relationships are present and strong. In the summer of 2011, the Senior Tour (a group of retired cardiothoracic surgeons committed to education and service for their profession) was asked by the Joint Council on Thoracic Surgery Education to visit 10 thoracic surgical training programs that were considered above average according to a poll taken of thoracic surgical residents in the fall of 2010 by the Thoracic Surgery Residents Association.²

As they summarized their findings, they noted that the top programs possessed many common features leading to superior training in cardiac and general thoracic surgery. The authors specifically noted seven key factors, and, among them, was "a significant emphasis on mentorship, with the program director playing the primary roles and with voluntary relationships between residents and other faculty and with mentorship also including involvement in job finding."

If mentorship is so important to success in this career path, exactly what opportunities exist for trainees seeking mentorship? A Google search for ["mentor" AND "thoracic surgery"] yields a number of results, with ultimate direction leading to essentially two organizations: the AATS and Women in Thoracic Surgery (WTS).

From the AATS website, there is a list of names and contact information for mentors who have been selected or self-nominated for prospective candidates for thoracic surgery residency. These mentors are available to offer guidance, recommendations, and research opportunities, as well as clinical rotations in cardiothoracic surgery (http://aats.org/TSR/contactsMentors.cgi).

A number of opportunities for mentorship are also available through WTS. There is a formal mentoring program, aiming to pair women interested in cardiothoracic surgical careers with established WTS members. Dr. Shanda Blackmon, the Mentoring Chair for the WTS, reflects on the program, stating, "Many surgeons think that mentorship has to be a formal relationship at the same institution. What we have learned at WTS is that mentorship relationships can be equally effective even when they are not formal and the mentor is not from the same institution." She continues, reporting that, "in the survey we conducted through WTS, we discovered that mentorship was one of the most important factors to young surgeons aspiring to start a career in thoracic surgery." It is for this reason that WTS places such emphasis on helping trainees find and sustain mentorship opportunities.

WTS specifically offers scholarships to the Society of Thoracic Surgeons meeting, the Scanlan/WTS Traveling Mentorship, the Carolyn Reed Award, a list of mentors online, and resident mentors. (Further details of all of these programs can be found at www.wtsnet.org.) WTS provides a number of opportunities for female trainees to connect with female mentors. But is it absolutely necessary to find mentors who are "like you"?

Dr. Jennifer Lawton, president of WTS, acknowledges that everyone needs mentoring, but urges that "mentoring of women and minorities is particularly important in order to take advantage of the vast array of benefits to be gained by ethnic, racial, and gender diversity in the workplace."

She continues: "If we don’t see others successful in a chosen field, we do not perceive the goal attainable for ourselves. I have seen this many times in cardiothoracic surgery and women. Women who are not exposed to female mentors have expressed concern that practice in the field is not possible for women (especially those who aspire to have a family)." And, further, she explains that "we are typically more comfortable in mentoring situations with others like ourselves (similar challenges, needs, concerns). Surveys demonstrate that medical students often choose fields of interest because of mentors. For these reasons, it is important for individuals to find mentors who are similar to themselves."

Additional formal mentoring programs exist, and include the Brooks Scholarship through the Southern Thoracic Surgical Association (STSA), the Society of Thoracic Surgeons Looking to the Future scholarship program, the AATS Member for a Day program, and more.

Exactly what should one hope to get out of a mentorship relationship? The truth is, it really depends on the stage of career and the specific needs of the mentee. Mentorship needs change over time, and even well-established mentoring relationships will evolve and adjust along with participants in the interaction.

Sarah Schubert is a fourth-year medical student at Penn State, who has matched into the I-6 program at the University of Virginia and is the current recipient of the Scanlan/WTS scholarship. This award provides trainees with an opportunity to gain exposure to women cardiothoracic surgeon mentors by visiting a WTS member for an elective period. Ms. Schubert reports that she applied for the scholarship because she "wanted to work with and learn from a highly successful female cardiac surgeon in hopes of initiating and developing a professional relationship with a woman in the field."

As a medical student, she has fairly basic mentorship needs. She tells us that "right now, I need mentors who can serve as good role models – in the OR, with patients, with colleagues and trainees, and in their personal lives outside the hospital. As I prepare to enter residency, I anticipate that I will need to further develop my patient care skills and operative techniques, as well as skills to manage time and obligations. Knowing and working with people who have already figured out how to juggle those different obligations will be immensely helpful." Other medical students may be looking for advice on interviewing and ranking residency programs, and, like Ms. Schubert, may be interested in tips on how to get a great start in internship.

For individuals deep in the throes of cardiothoracic training, the needs are clearly different. Dr. Ryan Shelstad, a first-year fellow at the University of Colorado, states: "In my mind, the primary objective of clinical fellowship is acquisition of technical skills and clinical decision making in CT surgery. Thus, mentorship at this stage follows this objective." He continues, "CT fellowship is a relatively short time to achieve this goal as well as position oneself to successfully transition to a faculty position or private practice, which is the second objective—and area for mentoring."

Dr. Shelstad acknowledges and explains the transition in his mentorship needs, "I think earlier in training, mentorship focused on career choice, research, and transition to a fellowship. Much was focused on getting to the next step. While that is still important, now is the time to focus on the clinical aspects of CT surgery that I will use the rest of my career." And, certainly, the specific mentoring needs will continue to change with time.

Dr. Lawton, who holds the rank of professor at Washington University, St. Louis, states that, "after reaching full professor, surgeons need mentoring and sponsoring to reach goals such as dean positions, leadership positions, national organization officer positions, etc. We also all continually need mosaic mentoring that evolves over time (someone to mentor for research career aspects, managing work-life balance issues, family issues, teaching issues, financial issues, etc.). As we progress in our careers, we have the opportunity to also be mentored in other areas by younger generations."

Wait, did she just say that progressing surgeons can be mentored by younger generations? Yes, she did. And not only can seasoned surgeons be mentored by younger surgeons, they also stand to gain considerably from their own mentees. Dr. Lawton further states, "There is always reciprocal gain in a mentoring relationship for the mentor. There is no better joy than to see a mentee succeed and be fulfilled and happy in her chosen field. For some, this provides a rich legacy of trainees and mentees to provide continued enrichment, excitement, and a source of tremendous pride in later years." In the previously mentioned article by Grondin, Dr. Gail Darling states, "Academic careers are usually measured in papers published, grants awarded, invited lectures, and academic standing. Equally important are the students we teach and motivate toward careers in surgery, residents and fellows we have taught and mentored who will provide care to patients and who will go out and teach new generations of surgeons who will in turn provide care."

Once mentorship bonds have been established, it is critical to cultivate these relationships and to gain the most possible from these interactions. When asked how he has achieved these ends, Dr. Shelstad replies, "You and your mentors have the same goal: mutual success. Work hard for your mentors, and they will work hard for you. I would encourage explicit discussion of goals and expectations to ensure you and a potential mentor are on the same page. Mentorship is essential to success in cardiothoracic surgery."

Without a doubt, participation in mentorship relationships is a key element of success at every stage of the career and development of a cardiothoracic surgeon. Outstanding programs already exist to support modern trainees, and further efforts will certainly be met with great enthusiasm. Also apparent is the need for ongoing, career-long mentorship – and the paucity of formal programs to support it. This need may be a great opportunity for the establishment of future programming.

On a personal note, when reflecting on mentorship, I think of a statement made by Benjamin Franklin: "Tell me and I forget, teach me and I may remember, involve me and I learn." To those incredible individuals who have taken the time, effort, and interest to truly involve me, I have immense gratitude. I will aim for the rest of my career to make it worth your while, with hopes to bring you pride and inspire others as you have inspired me. To all who have taken time to truly involve any student, resident, or junior colleague – you have motivated us and given strength to the ongoing legacy of our amazing field.

Citations

1. Grondin SC. Building a Successful Career: Advice From Leaders in Thoracic Surgery. Thorac. Surg. Clin. 2011;21(3):395-415.

2. J. Thorac. Cardiovasc. Surg. 2014;147(1):15-17.

Adults in poor cardiovascular health were more likely to develop cognitive problems such as learning and memory impairment, compared with healthier peers, according to a large prospective study published online June 11 in the Journal of the American Heart Association.

But top scorers on the cardiovascular health (CVH) measure used in the study were not more protected against incident mental impairment than were intermediate scorers, reported Evan Thacker, Ph.D., of Brigham Young University in Provo, Utah, and his associates.

"This pattern suggests that even intermediate levels of CVH are preferable to low levels of CVH," the investigators said. "This is an encouraging message for population health promotion, because intermediate CVH is a more realistic target than ideal CVH for many individuals."

The investigators used the American Heart Association Life’s Simple 7 score to classify the cardiovascular health of 17,761 black and white adults in the United States aged 45 years and older (J. Am. Heart Assoc. 2014 June 11 [doi: 10.1161/JAHA.113.000635]). Individuals were participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. The Six-Item Screener was used assess baseline global cognitive status; and a three-test measure of verbal learning, memory, and fluency was used to assess mental function at subsequent 2-year intervals. In all, 56% of individuals resided in "stroke belt" states, including Arkansas, Alabama, Louisiana, Georgia, Mississippi, North and South Carolina, and Tennessee, the investigators said. All study participants had normal cognitive function and no stroke history at the outset.

After adjustment for age, sex, race, and education, 4.6% of individuals with the worst CVH scores developed cognitive impairment after baseline (95% confidence interval, 4.0%-5.2%), compared with only 2.7% of those with intermediate scores (95% CI, 2.3%-3.1%) and 2.6% of those with the best scores (95% CI, 2.1%-3.1%), Dr. Thacker and his associates reported. Therefore, the odds of incident cognitive impairment were 35%-37% lower in the intermediate- and high-CVH groups than in the low-CVH group, the researchers added (odds ratios, 0.65 and 0.63; 95% CIs, 0.52-0.81 and 0.51-0.79, respectively).

"Rather than a dose-response pattern across the range of Life’s Simple 7 scores, we observed that associations with [incident clinical impairment] were the same for the highest tertile of Life’s Simple 7 score and the middle tertile, relative to the lowest tertile," the researchers wrote. "Based on these findings, we hypothesize that the AHA’s strategic efforts to improve CVH from poor to intermediate or higher levels could lead to reductions in cognitive decline, and we believe further research addressing this hypothesis is warranted."

The National Institute of Neurological Disorders and Stroke funded the study. The authors reported no conflicts of interest.

Adults in poor cardiovascular health were more likely to develop cognitive problems such as learning and memory impairment, compared with healthier peers, according to a large prospective study published online June 11 in the Journal of the American Heart Association.

But top scorers on the cardiovascular health (CVH) measure used in the study were not more protected against incident mental impairment than were intermediate scorers, reported Evan Thacker, Ph.D., of Brigham Young University in Provo, Utah, and his associates.

"This pattern suggests that even intermediate levels of CVH are preferable to low levels of CVH," the investigators said. "This is an encouraging message for population health promotion, because intermediate CVH is a more realistic target than ideal CVH for many individuals."

The investigators used the American Heart Association Life’s Simple 7 score to classify the cardiovascular health of 17,761 black and white adults in the United States aged 45 years and older (J. Am. Heart Assoc. 2014 June 11 [doi: 10.1161/JAHA.113.000635]). Individuals were participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. The Six-Item Screener was used assess baseline global cognitive status; and a three-test measure of verbal learning, memory, and fluency was used to assess mental function at subsequent 2-year intervals. In all, 56% of individuals resided in "stroke belt" states, including Arkansas, Alabama, Louisiana, Georgia, Mississippi, North and South Carolina, and Tennessee, the investigators said. All study participants had normal cognitive function and no stroke history at the outset.

After adjustment for age, sex, race, and education, 4.6% of individuals with the worst CVH scores developed cognitive impairment after baseline (95% confidence interval, 4.0%-5.2%), compared with only 2.7% of those with intermediate scores (95% CI, 2.3%-3.1%) and 2.6% of those with the best scores (95% CI, 2.1%-3.1%), Dr. Thacker and his associates reported. Therefore, the odds of incident cognitive impairment were 35%-37% lower in the intermediate- and high-CVH groups than in the low-CVH group, the researchers added (odds ratios, 0.65 and 0.63; 95% CIs, 0.52-0.81 and 0.51-0.79, respectively).

"Rather than a dose-response pattern across the range of Life’s Simple 7 scores, we observed that associations with [incident clinical impairment] were the same for the highest tertile of Life’s Simple 7 score and the middle tertile, relative to the lowest tertile," the researchers wrote. "Based on these findings, we hypothesize that the AHA’s strategic efforts to improve CVH from poor to intermediate or higher levels could lead to reductions in cognitive decline, and we believe further research addressing this hypothesis is warranted."

The National Institute of Neurological Disorders and Stroke funded the study. The authors reported no conflicts of interest.

Adults in poor cardiovascular health were more likely to develop cognitive problems such as learning and memory impairment, compared with healthier peers, according to a large prospective study published online June 11 in the Journal of the American Heart Association.

But top scorers on the cardiovascular health (CVH) measure used in the study were not more protected against incident mental impairment than were intermediate scorers, reported Evan Thacker, Ph.D., of Brigham Young University in Provo, Utah, and his associates.

"This pattern suggests that even intermediate levels of CVH are preferable to low levels of CVH," the investigators said. "This is an encouraging message for population health promotion, because intermediate CVH is a more realistic target than ideal CVH for many individuals."

The investigators used the American Heart Association Life’s Simple 7 score to classify the cardiovascular health of 17,761 black and white adults in the United States aged 45 years and older (J. Am. Heart Assoc. 2014 June 11 [doi: 10.1161/JAHA.113.000635]). Individuals were participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. The Six-Item Screener was used assess baseline global cognitive status; and a three-test measure of verbal learning, memory, and fluency was used to assess mental function at subsequent 2-year intervals. In all, 56% of individuals resided in "stroke belt" states, including Arkansas, Alabama, Louisiana, Georgia, Mississippi, North and South Carolina, and Tennessee, the investigators said. All study participants had normal cognitive function and no stroke history at the outset.

After adjustment for age, sex, race, and education, 4.6% of individuals with the worst CVH scores developed cognitive impairment after baseline (95% confidence interval, 4.0%-5.2%), compared with only 2.7% of those with intermediate scores (95% CI, 2.3%-3.1%) and 2.6% of those with the best scores (95% CI, 2.1%-3.1%), Dr. Thacker and his associates reported. Therefore, the odds of incident cognitive impairment were 35%-37% lower in the intermediate- and high-CVH groups than in the low-CVH group, the researchers added (odds ratios, 0.65 and 0.63; 95% CIs, 0.52-0.81 and 0.51-0.79, respectively).

"Rather than a dose-response pattern across the range of Life’s Simple 7 scores, we observed that associations with [incident clinical impairment] were the same for the highest tertile of Life’s Simple 7 score and the middle tertile, relative to the lowest tertile," the researchers wrote. "Based on these findings, we hypothesize that the AHA’s strategic efforts to improve CVH from poor to intermediate or higher levels could lead to reductions in cognitive decline, and we believe further research addressing this hypothesis is warranted."

The National Institute of Neurological Disorders and Stroke funded the study. The authors reported no conflicts of interest.

TORONTO – In academic medical centers, attending cardiothoracic surgeons often perform simultaneous procedures in different operating rooms as a means of increasing training opportunities for surgical fellows and to decrease hospital costs. However, the practice of running simultaneous operating rooms did not appear to affect perioperative timing or negatively affect patient outcomes, according to the results of a single institution review by Dr. Kenan W. Yount.

He and his colleagues at the University of Virginia, Charlottesville, wanted to examine their own data in guiding hospital policy as several major centers have recently proposed implementing a 1:1 ratio of attending surgeon-to-operating room.

Martin Allred/Frontline Medical News

In his presentation, Dr. Yount discussed the results of their review study, which categorized 1,377 cardiac and 1,682 general thoracic operations performed from July 2011 to July 2013 by attending, case type, and whether the attending was simultaneously supervising two surgeries. "Our institution adheres to a strict policy of attending surgeon oversight of and involvement in the critical and key portions of all operations," said Dr. Yount.

They compared operative duration, starting and closing times, postoperative complications, and 30-day mortality in each category. They also compared rates postoperative complications, hospital length of stay, and operative mortality in each category.

Interestingly, timing effects varied between the two overall types of surgery. Running two rooms had no effect on room start times, but thoracic rooms finished 16 minutes later than scheduled. Across six surgeons and 15 operation types, however, there were no differences in operative times.

"Furthermore, running two rooms was not associated with any differences in operative duration, morbidity, or mortality in our multivariate regression analyses, and there were no statistically significant differences in observed outcomes in any category," Dr. Yount said.

"In academic cardiothoracic surgical centers that rely on surgical support from fellowship training, the practice of running simultaneous operating rooms can be efficient and does not appear to negatively impact patient outcomes," said Dr. Yount. "In addition, the practice did not significantly increase operative duration or dramatically [affect] operating room starting or closing times," he concluded.

In discussing the implications of these results, he said, "Obviously, there are caveats: Attendings must be intimately involved in operations and scrubbed for every key and critical portion of the operation; also operations being scheduled in separate rooms must be done so with reasonable foresight."

As long as institutions are following these practices, he concluded, "It would appear that lens of current policy efforts is too narrow by focusing on perception. The debate should be refocused by challenging training programs to strengthen attending involvement and ensure the requisite competence of their trainees."

Dr. Yount reported no relevant disclosures.

[email protected]

TORONTO – In academic medical centers, attending cardiothoracic surgeons often perform simultaneous procedures in different operating rooms as a means of increasing training opportunities for surgical fellows and to decrease hospital costs. However, the practice of running simultaneous operating rooms did not appear to affect perioperative timing or negatively affect patient outcomes, according to the results of a single institution review by Dr. Kenan W. Yount.

He and his colleagues at the University of Virginia, Charlottesville, wanted to examine their own data in guiding hospital policy as several major centers have recently proposed implementing a 1:1 ratio of attending surgeon-to-operating room.

Martin Allred/Frontline Medical News

In his presentation, Dr. Yount discussed the results of their review study, which categorized 1,377 cardiac and 1,682 general thoracic operations performed from July 2011 to July 2013 by attending, case type, and whether the attending was simultaneously supervising two surgeries. "Our institution adheres to a strict policy of attending surgeon oversight of and involvement in the critical and key portions of all operations," said Dr. Yount.

They compared operative duration, starting and closing times, postoperative complications, and 30-day mortality in each category. They also compared rates postoperative complications, hospital length of stay, and operative mortality in each category.

Interestingly, timing effects varied between the two overall types of surgery. Running two rooms had no effect on room start times, but thoracic rooms finished 16 minutes later than scheduled. Across six surgeons and 15 operation types, however, there were no differences in operative times.

"Furthermore, running two rooms was not associated with any differences in operative duration, morbidity, or mortality in our multivariate regression analyses, and there were no statistically significant differences in observed outcomes in any category," Dr. Yount said.

"In academic cardiothoracic surgical centers that rely on surgical support from fellowship training, the practice of running simultaneous operating rooms can be efficient and does not appear to negatively impact patient outcomes," said Dr. Yount. "In addition, the practice did not significantly increase operative duration or dramatically [affect] operating room starting or closing times," he concluded.

In discussing the implications of these results, he said, "Obviously, there are caveats: Attendings must be intimately involved in operations and scrubbed for every key and critical portion of the operation; also operations being scheduled in separate rooms must be done so with reasonable foresight."

As long as institutions are following these practices, he concluded, "It would appear that lens of current policy efforts is too narrow by focusing on perception. The debate should be refocused by challenging training programs to strengthen attending involvement and ensure the requisite competence of their trainees."

Dr. Yount reported no relevant disclosures.

[email protected]

TORONTO – In academic medical centers, attending cardiothoracic surgeons often perform simultaneous procedures in different operating rooms as a means of increasing training opportunities for surgical fellows and to decrease hospital costs. However, the practice of running simultaneous operating rooms did not appear to affect perioperative timing or negatively affect patient outcomes, according to the results of a single institution review by Dr. Kenan W. Yount.

He and his colleagues at the University of Virginia, Charlottesville, wanted to examine their own data in guiding hospital policy as several major centers have recently proposed implementing a 1:1 ratio of attending surgeon-to-operating room.

Martin Allred/Frontline Medical News

In his presentation, Dr. Yount discussed the results of their review study, which categorized 1,377 cardiac and 1,682 general thoracic operations performed from July 2011 to July 2013 by attending, case type, and whether the attending was simultaneously supervising two surgeries. "Our institution adheres to a strict policy of attending surgeon oversight of and involvement in the critical and key portions of all operations," said Dr. Yount.

They compared operative duration, starting and closing times, postoperative complications, and 30-day mortality in each category. They also compared rates postoperative complications, hospital length of stay, and operative mortality in each category.

Interestingly, timing effects varied between the two overall types of surgery. Running two rooms had no effect on room start times, but thoracic rooms finished 16 minutes later than scheduled. Across six surgeons and 15 operation types, however, there were no differences in operative times.

"Furthermore, running two rooms was not associated with any differences in operative duration, morbidity, or mortality in our multivariate regression analyses, and there were no statistically significant differences in observed outcomes in any category," Dr. Yount said.

"In academic cardiothoracic surgical centers that rely on surgical support from fellowship training, the practice of running simultaneous operating rooms can be efficient and does not appear to negatively impact patient outcomes," said Dr. Yount. "In addition, the practice did not significantly increase operative duration or dramatically [affect] operating room starting or closing times," he concluded.

In discussing the implications of these results, he said, "Obviously, there are caveats: Attendings must be intimately involved in operations and scrubbed for every key and critical portion of the operation; also operations being scheduled in separate rooms must be done so with reasonable foresight."

As long as institutions are following these practices, he concluded, "It would appear that lens of current policy efforts is too narrow by focusing on perception. The debate should be refocused by challenging training programs to strengthen attending involvement and ensure the requisite competence of their trainees."

Dr. Yount reported no relevant disclosures.

[email protected]

Introduction

All children learn to say "no" and want to experiment with asserting their will, but children who frequently refuse to comply are extremely challenging, making oppositional behavior one of the most common presentations to pediatricians and child psychiatrists.

Case summary

A 4-and-a-half-year-old boy whose parents have been divorced for 2 years presents with a 2-year history of aggression toward other kids in day care, biting and kicking, and tantrums and defiance when he doesn’t want to do something, especially transition from one activity to another. These episodes are brief but have been increasing in frequency and severity, and recently, he has been hitting his mother when it is time to leave the playground. His parents have tried reasoning with him, providing warnings, time-outs, and counting to 3. "Nothing works." He argues constantly and gets irritable easily. He also has a high energy level and short attention span and sometimes gets anxious over small issues.

Discussion

Psychologists who systematically observe families that struggle with this kind of behavior often see a cycle of child refusal and parental frustration and desperate attempts to force the child to comply by finding the right punishment. Parents often repeat their instructions over and over without success, getting increasingly frustrated, sometimes yelling or hitting. When parents achieve success after yelling, they may end up thinking that it is only verbal, or even physical, aggression that will force the child to comply. Parents may also give up at other times, teaching the child that sometimes their refusals will help him to avoid a task. There can be gradual escalation in tantrums, yelling, or physical aggression on the part of both parents and the child over the years.

There are often underlying aspects of the child’s temperament and genetic make-up that contribute to this cycle. Aspects of temperament such as difficulties with transitions to new activities, quick negative emotional responses, and stubbornness contribute. Attention deficit/hyperactivity disorder (ADHD) and language difficulties are also common factors. Parents’ own personalities, emotional, and behavioral issues, and outside stressors affecting the family also increase the chance of entering this distressing cycle. In this case, the child’s behavior seemed to start or worsen after the stressor of the divorce, and he has some symptoms suggestive of ADHD as well as irritability and anxiety, which might be an adjustment response to the divorce, an aspect of his temperament, or a more clinical mood disorder.

When facing a complex picture such as this, it can be helpful to obtain general behavioral rating scales such as the Child Behavior Checklist (CBCL) or Behavior Assessment System for Children (BASC) from parents and teachers to assess how severe differing components of the presentation are in comparison to other children of the same age and sex. Developmental assessments including information from schools can help clarify cognitive and language issues that may play a role

In addition to addressing any underlying issues, the intervention best supported by evidence is training parents in behavioral skills to address the oppositional and impulsive behavior. Teaching parents specific skills to notice and reinforce good behaviors while decreasing reinforcement for bad behaviors improves the relationship and motivates children to behave better. The second part of this type of program involves replacing yelling and harsh punishments with mild consequences that are delivered calmly and very consistently.

These skills may sound simple but can be challenging to put in place. Specific programs that give parents abundant opportunities to practice and master the skills through practice with their child in session and role plays have repeatedly been demonstrated to improve compliance and relationships with the child. Specific, very-well-researched programs include Helping the Noncompliant Child, Parent Child Interaction Therapy, The Incredible Years, Triple P, Parent Management Training Oregon, Parent Management Training (Kazdin), and The Defiant Teen and The Defiant Child.

It can sometimes be difficult to find therapists experienced with these programs. It is worth inquiring about the specific programs therapists use or even encouraging therapists to get trained in a specific program. Manuals are readily available for Helping the Noncompliant Child, Parent Management Training (Kazdin), and The Defiant Child and The Defiant Teen among others. The Yale Parenting Center offers online or phone consultation. Information about training in all of the above programs is available online.

How we talk to parents about the complex factors that play into oppositional behavior sets the stage for treatment. Parents often feel overwhelmed, guilty, and defensive. I stress that the difficulties do not originate with the parent but are a mix of the stresses the family experiences, the child’s temperament and genetic make-up, and the parent’s own temperament, and parenting style. I emphasize how challenging children can be and that it is not obvious how to respond to these behaviors. And I stress that we want to address the issue in as many ways as we can and that parents are the most important people in their children’s lives. In the end, such programs often help parents feel empowered and closer to their children.

Dr. Hall is an assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She provides periodic trainings in Helping the Noncompliant Child and the use of the manual Parent Management Training by Alan Kazdin but has no financial conflicts relevant to this article.

Introduction

All children learn to say "no" and want to experiment with asserting their will, but children who frequently refuse to comply are extremely challenging, making oppositional behavior one of the most common presentations to pediatricians and child psychiatrists.

Case summary

A 4-and-a-half-year-old boy whose parents have been divorced for 2 years presents with a 2-year history of aggression toward other kids in day care, biting and kicking, and tantrums and defiance when he doesn’t want to do something, especially transition from one activity to another. These episodes are brief but have been increasing in frequency and severity, and recently, he has been hitting his mother when it is time to leave the playground. His parents have tried reasoning with him, providing warnings, time-outs, and counting to 3. "Nothing works." He argues constantly and gets irritable easily. He also has a high energy level and short attention span and sometimes gets anxious over small issues.

Discussion

Psychologists who systematically observe families that struggle with this kind of behavior often see a cycle of child refusal and parental frustration and desperate attempts to force the child to comply by finding the right punishment. Parents often repeat their instructions over and over without success, getting increasingly frustrated, sometimes yelling or hitting. When parents achieve success after yelling, they may end up thinking that it is only verbal, or even physical, aggression that will force the child to comply. Parents may also give up at other times, teaching the child that sometimes their refusals will help him to avoid a task. There can be gradual escalation in tantrums, yelling, or physical aggression on the part of both parents and the child over the years.

There are often underlying aspects of the child’s temperament and genetic make-up that contribute to this cycle. Aspects of temperament such as difficulties with transitions to new activities, quick negative emotional responses, and stubbornness contribute. Attention deficit/hyperactivity disorder (ADHD) and language difficulties are also common factors. Parents’ own personalities, emotional, and behavioral issues, and outside stressors affecting the family also increase the chance of entering this distressing cycle. In this case, the child’s behavior seemed to start or worsen after the stressor of the divorce, and he has some symptoms suggestive of ADHD as well as irritability and anxiety, which might be an adjustment response to the divorce, an aspect of his temperament, or a more clinical mood disorder.

When facing a complex picture such as this, it can be helpful to obtain general behavioral rating scales such as the Child Behavior Checklist (CBCL) or Behavior Assessment System for Children (BASC) from parents and teachers to assess how severe differing components of the presentation are in comparison to other children of the same age and sex. Developmental assessments including information from schools can help clarify cognitive and language issues that may play a role

In addition to addressing any underlying issues, the intervention best supported by evidence is training parents in behavioral skills to address the oppositional and impulsive behavior. Teaching parents specific skills to notice and reinforce good behaviors while decreasing reinforcement for bad behaviors improves the relationship and motivates children to behave better. The second part of this type of program involves replacing yelling and harsh punishments with mild consequences that are delivered calmly and very consistently.

These skills may sound simple but can be challenging to put in place. Specific programs that give parents abundant opportunities to practice and master the skills through practice with their child in session and role plays have repeatedly been demonstrated to improve compliance and relationships with the child. Specific, very-well-researched programs include Helping the Noncompliant Child, Parent Child Interaction Therapy, The Incredible Years, Triple P, Parent Management Training Oregon, Parent Management Training (Kazdin), and The Defiant Teen and The Defiant Child.

It can sometimes be difficult to find therapists experienced with these programs. It is worth inquiring about the specific programs therapists use or even encouraging therapists to get trained in a specific program. Manuals are readily available for Helping the Noncompliant Child, Parent Management Training (Kazdin), and The Defiant Child and The Defiant Teen among others. The Yale Parenting Center offers online or phone consultation. Information about training in all of the above programs is available online.

How we talk to parents about the complex factors that play into oppositional behavior sets the stage for treatment. Parents often feel overwhelmed, guilty, and defensive. I stress that the difficulties do not originate with the parent but are a mix of the stresses the family experiences, the child’s temperament and genetic make-up, and the parent’s own temperament, and parenting style. I emphasize how challenging children can be and that it is not obvious how to respond to these behaviors. And I stress that we want to address the issue in as many ways as we can and that parents are the most important people in their children’s lives. In the end, such programs often help parents feel empowered and closer to their children.

Dr. Hall is an assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She provides periodic trainings in Helping the Noncompliant Child and the use of the manual Parent Management Training by Alan Kazdin but has no financial conflicts relevant to this article.

Introduction

All children learn to say "no" and want to experiment with asserting their will, but children who frequently refuse to comply are extremely challenging, making oppositional behavior one of the most common presentations to pediatricians and child psychiatrists.

Case summary

A 4-and-a-half-year-old boy whose parents have been divorced for 2 years presents with a 2-year history of aggression toward other kids in day care, biting and kicking, and tantrums and defiance when he doesn’t want to do something, especially transition from one activity to another. These episodes are brief but have been increasing in frequency and severity, and recently, he has been hitting his mother when it is time to leave the playground. His parents have tried reasoning with him, providing warnings, time-outs, and counting to 3. "Nothing works." He argues constantly and gets irritable easily. He also has a high energy level and short attention span and sometimes gets anxious over small issues.

Discussion

Psychologists who systematically observe families that struggle with this kind of behavior often see a cycle of child refusal and parental frustration and desperate attempts to force the child to comply by finding the right punishment. Parents often repeat their instructions over and over without success, getting increasingly frustrated, sometimes yelling or hitting. When parents achieve success after yelling, they may end up thinking that it is only verbal, or even physical, aggression that will force the child to comply. Parents may also give up at other times, teaching the child that sometimes their refusals will help him to avoid a task. There can be gradual escalation in tantrums, yelling, or physical aggression on the part of both parents and the child over the years.

There are often underlying aspects of the child’s temperament and genetic make-up that contribute to this cycle. Aspects of temperament such as difficulties with transitions to new activities, quick negative emotional responses, and stubbornness contribute. Attention deficit/hyperactivity disorder (ADHD) and language difficulties are also common factors. Parents’ own personalities, emotional, and behavioral issues, and outside stressors affecting the family also increase the chance of entering this distressing cycle. In this case, the child’s behavior seemed to start or worsen after the stressor of the divorce, and he has some symptoms suggestive of ADHD as well as irritability and anxiety, which might be an adjustment response to the divorce, an aspect of his temperament, or a more clinical mood disorder.

When facing a complex picture such as this, it can be helpful to obtain general behavioral rating scales such as the Child Behavior Checklist (CBCL) or Behavior Assessment System for Children (BASC) from parents and teachers to assess how severe differing components of the presentation are in comparison to other children of the same age and sex. Developmental assessments including information from schools can help clarify cognitive and language issues that may play a role

In addition to addressing any underlying issues, the intervention best supported by evidence is training parents in behavioral skills to address the oppositional and impulsive behavior. Teaching parents specific skills to notice and reinforce good behaviors while decreasing reinforcement for bad behaviors improves the relationship and motivates children to behave better. The second part of this type of program involves replacing yelling and harsh punishments with mild consequences that are delivered calmly and very consistently.

These skills may sound simple but can be challenging to put in place. Specific programs that give parents abundant opportunities to practice and master the skills through practice with their child in session and role plays have repeatedly been demonstrated to improve compliance and relationships with the child. Specific, very-well-researched programs include Helping the Noncompliant Child, Parent Child Interaction Therapy, The Incredible Years, Triple P, Parent Management Training Oregon, Parent Management Training (Kazdin), and The Defiant Teen and The Defiant Child.

It can sometimes be difficult to find therapists experienced with these programs. It is worth inquiring about the specific programs therapists use or even encouraging therapists to get trained in a specific program. Manuals are readily available for Helping the Noncompliant Child, Parent Management Training (Kazdin), and The Defiant Child and The Defiant Teen among others. The Yale Parenting Center offers online or phone consultation. Information about training in all of the above programs is available online.

How we talk to parents about the complex factors that play into oppositional behavior sets the stage for treatment. Parents often feel overwhelmed, guilty, and defensive. I stress that the difficulties do not originate with the parent but are a mix of the stresses the family experiences, the child’s temperament and genetic make-up, and the parent’s own temperament, and parenting style. I emphasize how challenging children can be and that it is not obvious how to respond to these behaviors. And I stress that we want to address the issue in as many ways as we can and that parents are the most important people in their children’s lives. In the end, such programs often help parents feel empowered and closer to their children.

Dr. Hall is an assistant professor of psychiatry and pediatrics at the University of Vermont, Burlington. She provides periodic trainings in Helping the Noncompliant Child and the use of the manual Parent Management Training by Alan Kazdin but has no financial conflicts relevant to this article.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

 

 

Lobby view at ASCO 2014

©ASCO/Rodney White

 

CHICAGO—The novel, oral selective inhibitor of nuclear transport known as selinexor (KPT-330) can safely be given as monotherapy to patients with heavily pretreated non-Hodgkin lymphoma (NHL), according to a presentation at the 2014 ASCO Annual Meeting.

“Selinexor has favorable pharmacokinetic and pharmacodynamic characteristics,” said presenter Martin Gutierrez, MD, of the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey.

Selinexor is a slowly reversible, selective inhibitor of nuclear transport that inhibits XPO1, which is elevated in NHL, chronic lymphocytic leukemia (CLL), and other malignances.

“It shows single-agent anti-tumor activity across all NHL types, with durable cancer control of more than 9 months [and] marked activity across germ cell B (GCB), non-germ cell B, and double-hit diffuse large B-cell lymphoma (DLBCL),” Dr Gutierrez said.

He provided an update of the ongoing phase 1 dose-escalation study at the meeting as abstract 8518.

The study now includes 51 patients, half of whom have NHL. Their median age is 60 years.

The patients received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m². Dosing at 60 mg/m² twice weekly is ongoing, and the maximum-tolerated dose has not been reached.

Among the 43 evaluable patients, the disease control rate was 74%, the overall response rate was 28%, and the complete response rate was 5%.

“All patients who had their disease controlled had a reduction in lymph nodes and some degree of activity across all dose levels,” Dr Gutierrez said. “GCB and non-GCB patients responded similarly.”

The length of response was up to 632 days in the DLBCL group.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

The investigators found a higher incidence of side effects in the first treatment cycle. The dosing schedule was interrupted and reduced to maintain steady state levels.

“The results suggest that an intermittent dosing schedule optimally induces a steady state with maximal induction of XPO1 mRNA,” Dr Gutierrez said.

There were 3 dose-limiting toxicities, including 1 multiple myeloma patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

ASCO discussant Owen O’Connor, MD, from Columbia University Medical Center in New York, commented, “These clinical data are interesting with a provocative target. I applaud the investigators for doing a trial across a diversity of B- and T-cell lymphomas . . . . The results suggest a potential effect in a rare subset of lymphoma patients that have little treatment options.”

Frontline trials of selinexor are planned, including patients with Richter transformation and follicular lymphoma.

Selinexor recently received orphan drug status from the US Food and Drug Administration for the treatment of DLBCL.

Eukaryotic cytoskeleton; actin

filaments (red), microtubules

(green), and nuclei (blue)

National Institutes of Health

A new technique allows scientists to view the cell cytoskeleton with “unprecedented resolution,” according to a paper published in Nature Methods.

A group of researchers exploited the properties of a fluorescent molecule they developed to generate 2 probes for imaging the cytoskeleton.

The team said these probes can easily enter live cells, are non-toxic, have long-lasting signals, and offer better image resolution than current imaging techniques.

This research began when Kai Johnsson, PhD, of École Polytechnique Fédérale de Lausanne in Switzerland, and his colleagues developed a fluorescent molecule called silicon-rhodamine (SiR).

The molecule switches “on” only when it binds to the charged surface of a protein like those found on the cytoskeleton. When SiR switches on, it emits light at far-red wavelengths.

The challenge was getting SiR to bind specifically to the cytoskeleton’s proteins, actin and tubulin. To achieve this, the researchers fused SiR molecules with compounds that bind tubulin or actin.

The resulting hybrid molecules consist of a SiR molecule, which provides the fluorescent signal, and a molecule of a natural compound that can bind the target protein.

One such compound was docetaxel, an anticancer drug that binds tubulin, and the other was jasplakinolide, which specifically binds the cytoskeletal form of actin. Both compounds, which are used here in very low, non-toxic concentrations, can easily pass through the cell’s membrane and into the cell itself.

The probes, called SiR-tubulin and SiR-actin, were used to visualize the dynamics of the cytoskeleton in human skin cells. Because the light signal of the probes is emitted in the far-red spectrum, it is easy to isolate from background noise, which generates images of unprecedented resolution when used with super-resolution microscopy.

An additional advantage of the probes, according to the researchers, is their practicality.

“You just add them directly into your cell culture, and they are taken up by the cells,” Dr Johnsson said.

The probes don’t require any washing or preparation of the cells before administration or any subsequent washing steps, which helps in maintaining the stability of their environment and their natural biological functions.

“Up to now, no probes were available that would allow you to get high-quality images of microtubules and microfilaments in living cells without some kind of genetic modification,” Dr Johnsson said.

“With this work, we provide the biological community with 2 high-performing, high-contrast fluorogenic probes that emit in the non-phototoxic part of the light spectrum, and can be even used in tissues like whole-blood samples.”

Eukaryotic cytoskeleton; actin

filaments (red), microtubules

(green), and nuclei (blue)

National Institutes of Health

A new technique allows scientists to view the cell cytoskeleton with “unprecedented resolution,” according to a paper published in Nature Methods.

A group of researchers exploited the properties of a fluorescent molecule they developed to generate 2 probes for imaging the cytoskeleton.

The team said these probes can easily enter live cells, are non-toxic, have long-lasting signals, and offer better image resolution than current imaging techniques.

This research began when Kai Johnsson, PhD, of École Polytechnique Fédérale de Lausanne in Switzerland, and his colleagues developed a fluorescent molecule called silicon-rhodamine (SiR).

The molecule switches “on” only when it binds to the charged surface of a protein like those found on the cytoskeleton. When SiR switches on, it emits light at far-red wavelengths.

The challenge was getting SiR to bind specifically to the cytoskeleton’s proteins, actin and tubulin. To achieve this, the researchers fused SiR molecules with compounds that bind tubulin or actin.

The resulting hybrid molecules consist of a SiR molecule, which provides the fluorescent signal, and a molecule of a natural compound that can bind the target protein.

One such compound was docetaxel, an anticancer drug that binds tubulin, and the other was jasplakinolide, which specifically binds the cytoskeletal form of actin. Both compounds, which are used here in very low, non-toxic concentrations, can easily pass through the cell’s membrane and into the cell itself.

The probes, called SiR-tubulin and SiR-actin, were used to visualize the dynamics of the cytoskeleton in human skin cells. Because the light signal of the probes is emitted in the far-red spectrum, it is easy to isolate from background noise, which generates images of unprecedented resolution when used with super-resolution microscopy.

An additional advantage of the probes, according to the researchers, is their practicality.

“You just add them directly into your cell culture, and they are taken up by the cells,” Dr Johnsson said.

The probes don’t require any washing or preparation of the cells before administration or any subsequent washing steps, which helps in maintaining the stability of their environment and their natural biological functions.

“Up to now, no probes were available that would allow you to get high-quality images of microtubules and microfilaments in living cells without some kind of genetic modification,” Dr Johnsson said.

“With this work, we provide the biological community with 2 high-performing, high-contrast fluorogenic probes that emit in the non-phototoxic part of the light spectrum, and can be even used in tissues like whole-blood samples.”

Eukaryotic cytoskeleton; actin

filaments (red), microtubules

(green), and nuclei (blue)

National Institutes of Health

A new technique allows scientists to view the cell cytoskeleton with “unprecedented resolution,” according to a paper published in Nature Methods.

A group of researchers exploited the properties of a fluorescent molecule they developed to generate 2 probes for imaging the cytoskeleton.

The team said these probes can easily enter live cells, are non-toxic, have long-lasting signals, and offer better image resolution than current imaging techniques.

This research began when Kai Johnsson, PhD, of École Polytechnique Fédérale de Lausanne in Switzerland, and his colleagues developed a fluorescent molecule called silicon-rhodamine (SiR).

The molecule switches “on” only when it binds to the charged surface of a protein like those found on the cytoskeleton. When SiR switches on, it emits light at far-red wavelengths.

The challenge was getting SiR to bind specifically to the cytoskeleton’s proteins, actin and tubulin. To achieve this, the researchers fused SiR molecules with compounds that bind tubulin or actin.

The resulting hybrid molecules consist of a SiR molecule, which provides the fluorescent signal, and a molecule of a natural compound that can bind the target protein.

One such compound was docetaxel, an anticancer drug that binds tubulin, and the other was jasplakinolide, which specifically binds the cytoskeletal form of actin. Both compounds, which are used here in very low, non-toxic concentrations, can easily pass through the cell’s membrane and into the cell itself.

The probes, called SiR-tubulin and SiR-actin, were used to visualize the dynamics of the cytoskeleton in human skin cells. Because the light signal of the probes is emitted in the far-red spectrum, it is easy to isolate from background noise, which generates images of unprecedented resolution when used with super-resolution microscopy.

An additional advantage of the probes, according to the researchers, is their practicality.

“You just add them directly into your cell culture, and they are taken up by the cells,” Dr Johnsson said.

The probes don’t require any washing or preparation of the cells before administration or any subsequent washing steps, which helps in maintaining the stability of their environment and their natural biological functions.

“Up to now, no probes were available that would allow you to get high-quality images of microtubules and microfilaments in living cells without some kind of genetic modification,” Dr Johnsson said.

“With this work, we provide the biological community with 2 high-performing, high-contrast fluorogenic probes that emit in the non-phototoxic part of the light spectrum, and can be even used in tissues like whole-blood samples.”