GALEN safe and effective in relapsed and refractory follicular lymphoma

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– For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.

Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.

Neil Osterweil/Frontline Medical News
Dr. Franck Morschhauser
“I think we can say that the GALEN combination is highly effective in relapsed and refractory follicular lymphoma patients,” he said at the 14th International Conference on Malignant Lymphoma.

The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.

In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).

The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.

The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.

When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.

An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.

ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.

A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).

After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.

There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).

Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.

The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.

Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.

The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
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– For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.

Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.

Neil Osterweil/Frontline Medical News
Dr. Franck Morschhauser
“I think we can say that the GALEN combination is highly effective in relapsed and refractory follicular lymphoma patients,” he said at the 14th International Conference on Malignant Lymphoma.

The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.

In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).

The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.

The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.

When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.

An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.

ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.

A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).

After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.

There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).

Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.

The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.

Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.

The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.

 

– For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.

Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.

Neil Osterweil/Frontline Medical News
Dr. Franck Morschhauser
“I think we can say that the GALEN combination is highly effective in relapsed and refractory follicular lymphoma patients,” he said at the 14th International Conference on Malignant Lymphoma.

The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.

In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).

The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.

The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.

When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.

An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.

ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.

A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).

After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.

There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).

Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.

The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.

Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.

The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
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Key clinical point: A combination of lenalidomide and obinutuzumab was safe and effective in patients with relapsed/refractory follicular lymphoma.

Major finding: The overall response rate according to 1999 International Working Group criteria was 80.2%, including 39.5% CR/CRu.

Data source: Single-arm phase II study with 86 patients evaluable for efficacy and 88 evaluable for safety.

Disclosures: The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.

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Coconut oil and dairy fats pose similar CVD risk

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Are saturated fats good for you or not? A new American Heart Association presidential advisory says no.

In a mixed-effects meta-analysis of four core trials and six noncore trials, the AHA found that replacing saturated fats – particularly coconut oil and dairy fats – with vegetable oils rich in polyunsaturated fats, such as soybean oil, significantly lowered the risk of cardiovascular disease (CVD) by 29%. Because many foods that are high in saturated fats are also high in cholesterol, these dietary changes have the added benefit of improving cholesterol levels.

Dr. Frank M. Sacks
Coconut oil and butter in particular were singled out as high in LDL cholesterol and saturated fats. Despite the belief among 72% of Americans that coconut oil is a healthy food, the popular oil actually contains 82% saturated fat and should not be a preferred oil for food preparation, cautioned Frank M. Sacks, MD, professor of cardiovascular disease prevention at Harvard University, Boston, and his fellow researchers. Patients who replaced coconut oil or other saturated fat sources with safflower or soybean oil in the core trials saw improvements in CVD risk, according to the results of the meta-analysis.

On the other hand, replacing saturated fats with carbohydrates did not improve patients’ risk of CVD, according to the investigators, although further research into the effects of different types of carbohydrates is needed.

“Because coconut oil increases LDL cholesterol, a cause of CVD, and has no known offsetting favorable effects, we advise against the use of coconut oil” and other oils high in saturated fats, the researchers wrote.

Read more in Circulation (2017 Jun 15. doi: 10.1161/CIR.0000000000000510).

Dr. Sacks reported no relevant financial disclosures. Several researchers disclosed research grants from or consultant/advisory roles with a number of pharmaceutical and nutrition companies.
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Are saturated fats good for you or not? A new American Heart Association presidential advisory says no.

In a mixed-effects meta-analysis of four core trials and six noncore trials, the AHA found that replacing saturated fats – particularly coconut oil and dairy fats – with vegetable oils rich in polyunsaturated fats, such as soybean oil, significantly lowered the risk of cardiovascular disease (CVD) by 29%. Because many foods that are high in saturated fats are also high in cholesterol, these dietary changes have the added benefit of improving cholesterol levels.

Dr. Frank M. Sacks
Coconut oil and butter in particular were singled out as high in LDL cholesterol and saturated fats. Despite the belief among 72% of Americans that coconut oil is a healthy food, the popular oil actually contains 82% saturated fat and should not be a preferred oil for food preparation, cautioned Frank M. Sacks, MD, professor of cardiovascular disease prevention at Harvard University, Boston, and his fellow researchers. Patients who replaced coconut oil or other saturated fat sources with safflower or soybean oil in the core trials saw improvements in CVD risk, according to the results of the meta-analysis.

On the other hand, replacing saturated fats with carbohydrates did not improve patients’ risk of CVD, according to the investigators, although further research into the effects of different types of carbohydrates is needed.

“Because coconut oil increases LDL cholesterol, a cause of CVD, and has no known offsetting favorable effects, we advise against the use of coconut oil” and other oils high in saturated fats, the researchers wrote.

Read more in Circulation (2017 Jun 15. doi: 10.1161/CIR.0000000000000510).

Dr. Sacks reported no relevant financial disclosures. Several researchers disclosed research grants from or consultant/advisory roles with a number of pharmaceutical and nutrition companies.

 

Are saturated fats good for you or not? A new American Heart Association presidential advisory says no.

In a mixed-effects meta-analysis of four core trials and six noncore trials, the AHA found that replacing saturated fats – particularly coconut oil and dairy fats – with vegetable oils rich in polyunsaturated fats, such as soybean oil, significantly lowered the risk of cardiovascular disease (CVD) by 29%. Because many foods that are high in saturated fats are also high in cholesterol, these dietary changes have the added benefit of improving cholesterol levels.

Dr. Frank M. Sacks
Coconut oil and butter in particular were singled out as high in LDL cholesterol and saturated fats. Despite the belief among 72% of Americans that coconut oil is a healthy food, the popular oil actually contains 82% saturated fat and should not be a preferred oil for food preparation, cautioned Frank M. Sacks, MD, professor of cardiovascular disease prevention at Harvard University, Boston, and his fellow researchers. Patients who replaced coconut oil or other saturated fat sources with safflower or soybean oil in the core trials saw improvements in CVD risk, according to the results of the meta-analysis.

On the other hand, replacing saturated fats with carbohydrates did not improve patients’ risk of CVD, according to the investigators, although further research into the effects of different types of carbohydrates is needed.

“Because coconut oil increases LDL cholesterol, a cause of CVD, and has no known offsetting favorable effects, we advise against the use of coconut oil” and other oils high in saturated fats, the researchers wrote.

Read more in Circulation (2017 Jun 15. doi: 10.1161/CIR.0000000000000510).

Dr. Sacks reported no relevant financial disclosures. Several researchers disclosed research grants from or consultant/advisory roles with a number of pharmaceutical and nutrition companies.
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VIDEO: Dr. William J. Gradishar shares breast cancer take-aways from ASCO 2017

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– William J. Gradishar, MD, outlines key research on breast cancer treatment presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, discusses the take-home messages on pertuzumab for HER2+ breast cancer, PARP inhibitors for BRCA-mutated breast cancer, and CDK4/6 inhibitors for ER+ breast cancers.

 


In another video interview, Katherine O’Brien of the Metastatic Breast Cancer Network provides the patient advocate view on this years’ meeting.

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

 

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– William J. Gradishar, MD, outlines key research on breast cancer treatment presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, discusses the take-home messages on pertuzumab for HER2+ breast cancer, PARP inhibitors for BRCA-mutated breast cancer, and CDK4/6 inhibitors for ER+ breast cancers.

 


In another video interview, Katherine O’Brien of the Metastatic Breast Cancer Network provides the patient advocate view on this years’ meeting.

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

 

– William J. Gradishar, MD, outlines key research on breast cancer treatment presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, discusses the take-home messages on pertuzumab for HER2+ breast cancer, PARP inhibitors for BRCA-mutated breast cancer, and CDK4/6 inhibitors for ER+ breast cancers.

 


In another video interview, Katherine O’Brien of the Metastatic Breast Cancer Network provides the patient advocate view on this years’ meeting.

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

 

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Consider college immunization requirements when counseling about vaccines

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Clinicians who are counseling vaccine-hesitant parents about vaccination may want to consider adding immunization requirements of universities to their armamentarium, recommended Allison Noesekabel, a medical student at Wayne State University, Detroit, and Ada M. Fenick, MD, a pediatrician at Yale University, New Haven, Conn.

After identifying the 200 top-ranked U.S. universities in the US News and World Report 2014 National University rankings and sending a survey on university prematriculation immunization requirements (PIRs), the responding 124 universities spanned 44 states and the District of Columbia. Of those who responded, 94% had at least one PIR, 84% had at least two, 63% had at least three, and 16% required all the vaccines as required by any jurisdictional law for attendance at universities (hepatitis B, meningococcus, MMR, TdaP, and varicella). Only 6% of the universities had no immunization requirements.

Of the 121 universities with PIRs, 2% did not allow medical exemptions, 2% did not allow religious exemptions, and 46% did not allow philosophical belief exemptions. Medical exemptions were hardest to obtain for 24% of the 121 universities with PIRs, religious exemptions were the most difficult to obtain at 40%, and philosophical belief exemptions were hardest to obtain at 60% of the universities with PIRs. The most common administrative responses to lack of immunization were “the placement of a hold on registration of classes (89% of universities), additional registration fees (13%), and a hold on student housing (11%),” Ms. Noesekabel and Dr. Frenik reported.

Ms. Noesekabel and Dr. Frenik said they chose highly ranked universities for their study because these were likely to be desirable to vaccine-hesitant families, who tend to be highly educated and affluent. Therefore, the findings of this study may not be representative of all 4-year U.S. colleges, they said.

Read more at Vaccine (2017. doi: 10.1016/j.vaccine.2017.05.038).

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Clinicians who are counseling vaccine-hesitant parents about vaccination may want to consider adding immunization requirements of universities to their armamentarium, recommended Allison Noesekabel, a medical student at Wayne State University, Detroit, and Ada M. Fenick, MD, a pediatrician at Yale University, New Haven, Conn.

After identifying the 200 top-ranked U.S. universities in the US News and World Report 2014 National University rankings and sending a survey on university prematriculation immunization requirements (PIRs), the responding 124 universities spanned 44 states and the District of Columbia. Of those who responded, 94% had at least one PIR, 84% had at least two, 63% had at least three, and 16% required all the vaccines as required by any jurisdictional law for attendance at universities (hepatitis B, meningococcus, MMR, TdaP, and varicella). Only 6% of the universities had no immunization requirements.

Of the 121 universities with PIRs, 2% did not allow medical exemptions, 2% did not allow religious exemptions, and 46% did not allow philosophical belief exemptions. Medical exemptions were hardest to obtain for 24% of the 121 universities with PIRs, religious exemptions were the most difficult to obtain at 40%, and philosophical belief exemptions were hardest to obtain at 60% of the universities with PIRs. The most common administrative responses to lack of immunization were “the placement of a hold on registration of classes (89% of universities), additional registration fees (13%), and a hold on student housing (11%),” Ms. Noesekabel and Dr. Frenik reported.

Ms. Noesekabel and Dr. Frenik said they chose highly ranked universities for their study because these were likely to be desirable to vaccine-hesitant families, who tend to be highly educated and affluent. Therefore, the findings of this study may not be representative of all 4-year U.S. colleges, they said.

Read more at Vaccine (2017. doi: 10.1016/j.vaccine.2017.05.038).

 

Clinicians who are counseling vaccine-hesitant parents about vaccination may want to consider adding immunization requirements of universities to their armamentarium, recommended Allison Noesekabel, a medical student at Wayne State University, Detroit, and Ada M. Fenick, MD, a pediatrician at Yale University, New Haven, Conn.

After identifying the 200 top-ranked U.S. universities in the US News and World Report 2014 National University rankings and sending a survey on university prematriculation immunization requirements (PIRs), the responding 124 universities spanned 44 states and the District of Columbia. Of those who responded, 94% had at least one PIR, 84% had at least two, 63% had at least three, and 16% required all the vaccines as required by any jurisdictional law for attendance at universities (hepatitis B, meningococcus, MMR, TdaP, and varicella). Only 6% of the universities had no immunization requirements.

Of the 121 universities with PIRs, 2% did not allow medical exemptions, 2% did not allow religious exemptions, and 46% did not allow philosophical belief exemptions. Medical exemptions were hardest to obtain for 24% of the 121 universities with PIRs, religious exemptions were the most difficult to obtain at 40%, and philosophical belief exemptions were hardest to obtain at 60% of the universities with PIRs. The most common administrative responses to lack of immunization were “the placement of a hold on registration of classes (89% of universities), additional registration fees (13%), and a hold on student housing (11%),” Ms. Noesekabel and Dr. Frenik reported.

Ms. Noesekabel and Dr. Frenik said they chose highly ranked universities for their study because these were likely to be desirable to vaccine-hesitant families, who tend to be highly educated and affluent. Therefore, the findings of this study may not be representative of all 4-year U.S. colleges, they said.

Read more at Vaccine (2017. doi: 10.1016/j.vaccine.2017.05.038).

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Len plus anti-CD19 Mab MOR208 active against advanced DLBCL

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– Combining lenalidomide (Revlimid) with an anti-CD19 monoclonal antibody labeled MOR208 showed promising activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were ineligible for stem cell transplant and had poor prognosis, early interim results from a clinical study indicate.

Among 34 patients evaluable for response, the preliminary objective response rate (ORR) was 56%, including complete responses in 32% of patients, reported Gilles Salles, MD, PhD, of the University of Lyon, France.

Dr. Gilles Salles
“The combination of MOR208 with lenalidomide showed, I would say, very encouraging activity,” Dr. Salles said at the International Congress on Malignant Lymphoma.

MOR208 is a humanized anti-CD19 monoclonal antibody with the Fc-antibody region enhanced to improve cytotoxicity. Its mechanisms of action include natural killer cell–mediated antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and direct cytotoxicity.

In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro, Dr. Salles said.

In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.

In an ongoing phase II, open-label study, Dr. Salles and his colleagues are enrolling transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.

Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other NHL histological subtypes, or central nervous system lymphoma involvement are excluded.

Patients receive MOR208 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally is delivered on days 1-21 of each cycle. Patients who have stable disease or better at the end of 12 cycles can be maintained on MOR208 at the same dose on days 1 and 15.

As of the data cutoff on March 6, 2017, 44 patients had been enrolled, and 34 were evaluable for response. The median patient age was 73 years (range, 47-82 years).

At the time of the data presentation, ORR, the primary endpoint, was 56%, consisting of 32% complete responses (11 patients), 24% partial responses (8), 12% stable disease (4), and 32% of patients who either had disease progression or had not yet had a postbaseline response assessment.

The median time to response was 1.8 months, with a median time to complete response of 3.4 months. Of 19 responders, 16 continue to have a response, including 10 of 11 patients with complete responses.

The most common grade 3 or 4 hematologic toxicities were neutropenia, anemia, and thrombocytopenia. Nonhematologic toxicities of any grade included rashes in 20% of patients, pyrexia in 16%, diarrhea in 16%, asthenia in 14%, and pneumonia, bronchitis, and nausea in 11% each.

There were no reported infusion-related reactions with the antibody. In all, 27% of patients required a lenalidomide dose reduction – to 20 mg/day in 20% of patients and to 15 mg/day in 7%.

Study accrual, follow-up of patients on therapy, investigations of cell origin, and subgroup analyses are ongoing.

MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor/consultant to many of the same companies.
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– Combining lenalidomide (Revlimid) with an anti-CD19 monoclonal antibody labeled MOR208 showed promising activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were ineligible for stem cell transplant and had poor prognosis, early interim results from a clinical study indicate.

Among 34 patients evaluable for response, the preliminary objective response rate (ORR) was 56%, including complete responses in 32% of patients, reported Gilles Salles, MD, PhD, of the University of Lyon, France.

Dr. Gilles Salles
“The combination of MOR208 with lenalidomide showed, I would say, very encouraging activity,” Dr. Salles said at the International Congress on Malignant Lymphoma.

MOR208 is a humanized anti-CD19 monoclonal antibody with the Fc-antibody region enhanced to improve cytotoxicity. Its mechanisms of action include natural killer cell–mediated antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and direct cytotoxicity.

In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro, Dr. Salles said.

In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.

In an ongoing phase II, open-label study, Dr. Salles and his colleagues are enrolling transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.

Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other NHL histological subtypes, or central nervous system lymphoma involvement are excluded.

Patients receive MOR208 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally is delivered on days 1-21 of each cycle. Patients who have stable disease or better at the end of 12 cycles can be maintained on MOR208 at the same dose on days 1 and 15.

As of the data cutoff on March 6, 2017, 44 patients had been enrolled, and 34 were evaluable for response. The median patient age was 73 years (range, 47-82 years).

At the time of the data presentation, ORR, the primary endpoint, was 56%, consisting of 32% complete responses (11 patients), 24% partial responses (8), 12% stable disease (4), and 32% of patients who either had disease progression or had not yet had a postbaseline response assessment.

The median time to response was 1.8 months, with a median time to complete response of 3.4 months. Of 19 responders, 16 continue to have a response, including 10 of 11 patients with complete responses.

The most common grade 3 or 4 hematologic toxicities were neutropenia, anemia, and thrombocytopenia. Nonhematologic toxicities of any grade included rashes in 20% of patients, pyrexia in 16%, diarrhea in 16%, asthenia in 14%, and pneumonia, bronchitis, and nausea in 11% each.

There were no reported infusion-related reactions with the antibody. In all, 27% of patients required a lenalidomide dose reduction – to 20 mg/day in 20% of patients and to 15 mg/day in 7%.

Study accrual, follow-up of patients on therapy, investigations of cell origin, and subgroup analyses are ongoing.

MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor/consultant to many of the same companies.

 

– Combining lenalidomide (Revlimid) with an anti-CD19 monoclonal antibody labeled MOR208 showed promising activity in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were ineligible for stem cell transplant and had poor prognosis, early interim results from a clinical study indicate.

Among 34 patients evaluable for response, the preliminary objective response rate (ORR) was 56%, including complete responses in 32% of patients, reported Gilles Salles, MD, PhD, of the University of Lyon, France.

Dr. Gilles Salles
“The combination of MOR208 with lenalidomide showed, I would say, very encouraging activity,” Dr. Salles said at the International Congress on Malignant Lymphoma.

MOR208 is a humanized anti-CD19 monoclonal antibody with the Fc-antibody region enhanced to improve cytotoxicity. Its mechanisms of action include natural killer cell–mediated antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and direct cytotoxicity.

In a preclinical study, a combination of MOR208 and lenalidomide showed synergistic antileukemic and antilymphoma activity both in vivo and in vitro, Dr. Salles said.

In addition, both lenalidomide and MOR208 have shown significant activity against relapsed, refractory B-cell non-Hodgkin lymphomas.

In an ongoing phase II, open-label study, Dr. Salles and his colleagues are enrolling transplant-ineligible patients 18 years and older with relapsed/refractory DLBCL, Eastern Cooperative Oncology Group status 0-2, and adequate organ function who had disease progression after 1-3 prior lines of therapy.

Patients with primary refractory DLBCL, double-hit or triple-hit DLBCL (i.e., mutations in Myc, BCL2, and/or BCL6), other NHL histological subtypes, or central nervous system lymphoma involvement are excluded.

Patients receive MOR208 12 mg/kg intravenously on days 1, 8, 15, and 22 for cycles 1-3 and on days 1 and 15 of cycles 4-12. Lenalidomide 25 mg orally is delivered on days 1-21 of each cycle. Patients who have stable disease or better at the end of 12 cycles can be maintained on MOR208 at the same dose on days 1 and 15.

As of the data cutoff on March 6, 2017, 44 patients had been enrolled, and 34 were evaluable for response. The median patient age was 73 years (range, 47-82 years).

At the time of the data presentation, ORR, the primary endpoint, was 56%, consisting of 32% complete responses (11 patients), 24% partial responses (8), 12% stable disease (4), and 32% of patients who either had disease progression or had not yet had a postbaseline response assessment.

The median time to response was 1.8 months, with a median time to complete response of 3.4 months. Of 19 responders, 16 continue to have a response, including 10 of 11 patients with complete responses.

The most common grade 3 or 4 hematologic toxicities were neutropenia, anemia, and thrombocytopenia. Nonhematologic toxicities of any grade included rashes in 20% of patients, pyrexia in 16%, diarrhea in 16%, asthenia in 14%, and pneumonia, bronchitis, and nausea in 11% each.

There were no reported infusion-related reactions with the antibody. In all, 27% of patients required a lenalidomide dose reduction – to 20 mg/day in 20% of patients and to 15 mg/day in 7%.

Study accrual, follow-up of patients on therapy, investigations of cell origin, and subgroup analyses are ongoing.

MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor/consultant to many of the same companies.
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Key clinical point: A combination of the anti-CD19 monoclonal antibody MOR208 and the immunomodulator lenalidomide has shown good activity against relapsed/refractory diffuse large B-cell lymphoma.

Major finding: The preliminary objective response rate was 56%, including 32% complete responses.

Data source: An ongoing open-label phase II study with 44 patients out of a planned 80 enrolled.

Disclosures: MorphoSys is sponsoring the study. Dr. Salles has received honoraria from Amgen, BMS, Celgene, Gilead, Janssen, Roche/Genentech, and Servier and is an advisor or consultant to many of the same companies.

Poll: How has the opioid crisis changed your practice?

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FFR stumbles in revascularization deferral decisions for ACS

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– One-year outcomes were significantly worse in patients with acute coronary syndrome whose revascularization was deferred based upon the results of fractional flow reserve than with instantaneous wave-free ratio, in the largest-ever study of patients whose revascularization decision was guided by physiologic measurements obtained via a pressure guidewire.

“The hypothesis that some authors have put forth – that in an ACS the hyperemic response of the myocardium is blunted by the ACS, and that this will affect the FFR hyperemic index – is now strengthened,” Javier Escaned, MD, said in presenting the study results at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

The study was a pooled, patient-level meta-analysis of the 4,529 participants with angiographically determined intermediate-risk stenoses in the previously reported randomized DEFINE FLAIR (N Engl J Med. 2017 May 11;376[19]:1824-34) and iFR SWEDEHEART (N Engl J Med. 2017 May 11;376[19]:1813-23) studies. The primary endpoint was the composite of death, nonfatal MI, or unplanned coronary revascularization within 12 months. And while the analysis brought unwelcome news for proponents of FFR with regard to the subset of patients with ACS, such patients comprised only 17% of the total study population.

Bruce Jancin/Frontline Medical News
Dr. Javier Escaned
Dr. Escaned opted for a glass-half-full approach. Stepping back to look at the big picture, he noted that in the entire population of 2,130 patients with deferred myocardial revascularization, 1-year event rates were low and virtually identical in the two study arms: 4.12% with iFR and 4.05% with FFR.

“I think that overall these results are very reassuring. The big finding is that we have dramatically improved the safety of deferral of revascularization using pressure guidewires. If you look at the MACE [major adverse cardiovascular event] rate in the deferred ACS group, it was about 6%, which is much less than the event rate at 1 year with deferral in patients with stable coronary disease in the pivotal DEFER trial [Circulation. 2001 Jun 19;103(24):2928-34], which was our former standard,” observed Dr. Escaned, an interventional cardiologist at San Carlos Hospital in Madrid and a DEFER coinvestigator.

He attributed these greatly improved outcomes of physiologically guided revascularization during the past 15 years to vastly improved stent technology and more effective optimal medical management.

Among the key findings of the combined analysis of DEFINE FLAIR and iFR SWEDEHEART:

•  More patients were deferred from PCI when iFR was used for decision-making: 50%, compared with 45% in the FFR arm. Yet 1-year outcomes were as good in the deferred iFR group as in the FFR group overall, and better than with FFR in the deferred ACS patients.

•  Event rates were significantly higher in deferred ACS patients overall than in deferred patients with stable coronary disease: 5.9% versus 3.6%. But the deferral tool made a difference: When iFR was utilized, the 1-year event rate was 5.4% in deferred ACS patients, not significantly different from the 3.8% rate in deferred patients with stable coronary disease. In contrast, the event rate in ACS patients with FFR-based deferral was 6.4%, significantly higher than the 3.4% rate in FFR-deferred patients with stable coronary disease.

Dr. Escaned noted that this finding is consistent with the cautionary results of several recent studies, including one, albeit tenfold smaller, in which ACS patients in whom revascularization was deferred based on FFR had a 25% rate of major adverse cardiovascular events at 3.4 years, compared with a 12% rate in patients with stable coronary disease (J Am Coll Cardiol. 2016 Sep 13;68[11]:1181-91).

Discussant Peter Jüni, MD, professor of medicine at the University of Toronto, said “the main results of your study show in a completely waterproof fashion that there is no signal of harm with the experimental strategy” of deferred revascularization based on physiologic measurements, at least in patients with stable ischemic coronary disease.

The results, however, also raise the question of whether physiology-based revascularization decision-making in ACS patients is the best strategy.

“Considering that the event rate in the deferred ACS group was nearly twice as high compared with stable patients, my question to you is: Should we ignore any functional testing in ACS patients and just say, ‘Let’s move forward with revascularization because this clinical presentation is a very good clinical characteristic for risk stratification?’ ”

Dr. Escaned rejected that option. He noted that both the European and U.S. guidelines now state that it’s inappropriate to base a revascularization decision solely on a coronary vessel’s angiographic appearance, because that has been shown to result in unnecessary treatment, which causes harm. Adoption of pressure guidewires to assist in revascularization decision making, whether by FFR or iFR, is still limited in interventional cardiology. The priority in the field now should be to encourage more widespread use of this technology, regardless of which method is selected, he argued.

“The biggest room in the world is the room for improvement,” the cardiologist mused.

“I think one of the real problems that’s impeding adoption of physiologic testing is that many physicians are still afraid of leaving a stenosis without treatment,” he continued. “It’s strange: If you perform angioplasty and it wasn’t indicated and there is a complication, physicians seem to have some type of peace of mind that they did their best and they were trying to help the patient. That’s why it’s so important to establish that deferring revascularization – not treating when it is not needed – is safe.”

The DEFINE FLAIR and iFR SWEDEHEART studies were funded by unrestricted grants from Philips Volcano. Dr. Escaned reported serving as a consultant to Abbott, AstraZeneca, Biosensors, Boston Scientific, Medtronic, OrbusNeich, and Philips Healthcare.

 

 

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– One-year outcomes were significantly worse in patients with acute coronary syndrome whose revascularization was deferred based upon the results of fractional flow reserve than with instantaneous wave-free ratio, in the largest-ever study of patients whose revascularization decision was guided by physiologic measurements obtained via a pressure guidewire.

“The hypothesis that some authors have put forth – that in an ACS the hyperemic response of the myocardium is blunted by the ACS, and that this will affect the FFR hyperemic index – is now strengthened,” Javier Escaned, MD, said in presenting the study results at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

The study was a pooled, patient-level meta-analysis of the 4,529 participants with angiographically determined intermediate-risk stenoses in the previously reported randomized DEFINE FLAIR (N Engl J Med. 2017 May 11;376[19]:1824-34) and iFR SWEDEHEART (N Engl J Med. 2017 May 11;376[19]:1813-23) studies. The primary endpoint was the composite of death, nonfatal MI, or unplanned coronary revascularization within 12 months. And while the analysis brought unwelcome news for proponents of FFR with regard to the subset of patients with ACS, such patients comprised only 17% of the total study population.

Bruce Jancin/Frontline Medical News
Dr. Javier Escaned
Dr. Escaned opted for a glass-half-full approach. Stepping back to look at the big picture, he noted that in the entire population of 2,130 patients with deferred myocardial revascularization, 1-year event rates were low and virtually identical in the two study arms: 4.12% with iFR and 4.05% with FFR.

“I think that overall these results are very reassuring. The big finding is that we have dramatically improved the safety of deferral of revascularization using pressure guidewires. If you look at the MACE [major adverse cardiovascular event] rate in the deferred ACS group, it was about 6%, which is much less than the event rate at 1 year with deferral in patients with stable coronary disease in the pivotal DEFER trial [Circulation. 2001 Jun 19;103(24):2928-34], which was our former standard,” observed Dr. Escaned, an interventional cardiologist at San Carlos Hospital in Madrid and a DEFER coinvestigator.

He attributed these greatly improved outcomes of physiologically guided revascularization during the past 15 years to vastly improved stent technology and more effective optimal medical management.

Among the key findings of the combined analysis of DEFINE FLAIR and iFR SWEDEHEART:

•  More patients were deferred from PCI when iFR was used for decision-making: 50%, compared with 45% in the FFR arm. Yet 1-year outcomes were as good in the deferred iFR group as in the FFR group overall, and better than with FFR in the deferred ACS patients.

•  Event rates were significantly higher in deferred ACS patients overall than in deferred patients with stable coronary disease: 5.9% versus 3.6%. But the deferral tool made a difference: When iFR was utilized, the 1-year event rate was 5.4% in deferred ACS patients, not significantly different from the 3.8% rate in deferred patients with stable coronary disease. In contrast, the event rate in ACS patients with FFR-based deferral was 6.4%, significantly higher than the 3.4% rate in FFR-deferred patients with stable coronary disease.

Dr. Escaned noted that this finding is consistent with the cautionary results of several recent studies, including one, albeit tenfold smaller, in which ACS patients in whom revascularization was deferred based on FFR had a 25% rate of major adverse cardiovascular events at 3.4 years, compared with a 12% rate in patients with stable coronary disease (J Am Coll Cardiol. 2016 Sep 13;68[11]:1181-91).

Discussant Peter Jüni, MD, professor of medicine at the University of Toronto, said “the main results of your study show in a completely waterproof fashion that there is no signal of harm with the experimental strategy” of deferred revascularization based on physiologic measurements, at least in patients with stable ischemic coronary disease.

The results, however, also raise the question of whether physiology-based revascularization decision-making in ACS patients is the best strategy.

“Considering that the event rate in the deferred ACS group was nearly twice as high compared with stable patients, my question to you is: Should we ignore any functional testing in ACS patients and just say, ‘Let’s move forward with revascularization because this clinical presentation is a very good clinical characteristic for risk stratification?’ ”

Dr. Escaned rejected that option. He noted that both the European and U.S. guidelines now state that it’s inappropriate to base a revascularization decision solely on a coronary vessel’s angiographic appearance, because that has been shown to result in unnecessary treatment, which causes harm. Adoption of pressure guidewires to assist in revascularization decision making, whether by FFR or iFR, is still limited in interventional cardiology. The priority in the field now should be to encourage more widespread use of this technology, regardless of which method is selected, he argued.

“The biggest room in the world is the room for improvement,” the cardiologist mused.

“I think one of the real problems that’s impeding adoption of physiologic testing is that many physicians are still afraid of leaving a stenosis without treatment,” he continued. “It’s strange: If you perform angioplasty and it wasn’t indicated and there is a complication, physicians seem to have some type of peace of mind that they did their best and they were trying to help the patient. That’s why it’s so important to establish that deferring revascularization – not treating when it is not needed – is safe.”

The DEFINE FLAIR and iFR SWEDEHEART studies were funded by unrestricted grants from Philips Volcano. Dr. Escaned reported serving as a consultant to Abbott, AstraZeneca, Biosensors, Boston Scientific, Medtronic, OrbusNeich, and Philips Healthcare.

 

 

 

– One-year outcomes were significantly worse in patients with acute coronary syndrome whose revascularization was deferred based upon the results of fractional flow reserve than with instantaneous wave-free ratio, in the largest-ever study of patients whose revascularization decision was guided by physiologic measurements obtained via a pressure guidewire.

“The hypothesis that some authors have put forth – that in an ACS the hyperemic response of the myocardium is blunted by the ACS, and that this will affect the FFR hyperemic index – is now strengthened,” Javier Escaned, MD, said in presenting the study results at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

The study was a pooled, patient-level meta-analysis of the 4,529 participants with angiographically determined intermediate-risk stenoses in the previously reported randomized DEFINE FLAIR (N Engl J Med. 2017 May 11;376[19]:1824-34) and iFR SWEDEHEART (N Engl J Med. 2017 May 11;376[19]:1813-23) studies. The primary endpoint was the composite of death, nonfatal MI, or unplanned coronary revascularization within 12 months. And while the analysis brought unwelcome news for proponents of FFR with regard to the subset of patients with ACS, such patients comprised only 17% of the total study population.

Bruce Jancin/Frontline Medical News
Dr. Javier Escaned
Dr. Escaned opted for a glass-half-full approach. Stepping back to look at the big picture, he noted that in the entire population of 2,130 patients with deferred myocardial revascularization, 1-year event rates were low and virtually identical in the two study arms: 4.12% with iFR and 4.05% with FFR.

“I think that overall these results are very reassuring. The big finding is that we have dramatically improved the safety of deferral of revascularization using pressure guidewires. If you look at the MACE [major adverse cardiovascular event] rate in the deferred ACS group, it was about 6%, which is much less than the event rate at 1 year with deferral in patients with stable coronary disease in the pivotal DEFER trial [Circulation. 2001 Jun 19;103(24):2928-34], which was our former standard,” observed Dr. Escaned, an interventional cardiologist at San Carlos Hospital in Madrid and a DEFER coinvestigator.

He attributed these greatly improved outcomes of physiologically guided revascularization during the past 15 years to vastly improved stent technology and more effective optimal medical management.

Among the key findings of the combined analysis of DEFINE FLAIR and iFR SWEDEHEART:

•  More patients were deferred from PCI when iFR was used for decision-making: 50%, compared with 45% in the FFR arm. Yet 1-year outcomes were as good in the deferred iFR group as in the FFR group overall, and better than with FFR in the deferred ACS patients.

•  Event rates were significantly higher in deferred ACS patients overall than in deferred patients with stable coronary disease: 5.9% versus 3.6%. But the deferral tool made a difference: When iFR was utilized, the 1-year event rate was 5.4% in deferred ACS patients, not significantly different from the 3.8% rate in deferred patients with stable coronary disease. In contrast, the event rate in ACS patients with FFR-based deferral was 6.4%, significantly higher than the 3.4% rate in FFR-deferred patients with stable coronary disease.

Dr. Escaned noted that this finding is consistent with the cautionary results of several recent studies, including one, albeit tenfold smaller, in which ACS patients in whom revascularization was deferred based on FFR had a 25% rate of major adverse cardiovascular events at 3.4 years, compared with a 12% rate in patients with stable coronary disease (J Am Coll Cardiol. 2016 Sep 13;68[11]:1181-91).

Discussant Peter Jüni, MD, professor of medicine at the University of Toronto, said “the main results of your study show in a completely waterproof fashion that there is no signal of harm with the experimental strategy” of deferred revascularization based on physiologic measurements, at least in patients with stable ischemic coronary disease.

The results, however, also raise the question of whether physiology-based revascularization decision-making in ACS patients is the best strategy.

“Considering that the event rate in the deferred ACS group was nearly twice as high compared with stable patients, my question to you is: Should we ignore any functional testing in ACS patients and just say, ‘Let’s move forward with revascularization because this clinical presentation is a very good clinical characteristic for risk stratification?’ ”

Dr. Escaned rejected that option. He noted that both the European and U.S. guidelines now state that it’s inappropriate to base a revascularization decision solely on a coronary vessel’s angiographic appearance, because that has been shown to result in unnecessary treatment, which causes harm. Adoption of pressure guidewires to assist in revascularization decision making, whether by FFR or iFR, is still limited in interventional cardiology. The priority in the field now should be to encourage more widespread use of this technology, regardless of which method is selected, he argued.

“The biggest room in the world is the room for improvement,” the cardiologist mused.

“I think one of the real problems that’s impeding adoption of physiologic testing is that many physicians are still afraid of leaving a stenosis without treatment,” he continued. “It’s strange: If you perform angioplasty and it wasn’t indicated and there is a complication, physicians seem to have some type of peace of mind that they did their best and they were trying to help the patient. That’s why it’s so important to establish that deferring revascularization – not treating when it is not needed – is safe.”

The DEFINE FLAIR and iFR SWEDEHEART studies were funded by unrestricted grants from Philips Volcano. Dr. Escaned reported serving as a consultant to Abbott, AstraZeneca, Biosensors, Boston Scientific, Medtronic, OrbusNeich, and Philips Healthcare.

 

 

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Key clinical point: Deferring revascularization on the basis of physiologic assessment, whether by fractional flow reserve or instantaneous wave-free ratio, is generally safe, particularly in patients with stable coronary disease.

Major finding: In patients with acute coronary syndrome, the 1-year adverse event rate in patients with FFR-based deferral was 6.4%, significantly higher than the 3.4% rate in patients with FFR-based deferral with stable coronary disease.

Data source: A pooled patient-level meta-analysis of the 4,529 participants with angiographically intermediate-risk stenoses in two previously reported randomized trials of physiologic assessment of lesions by fractional flow reserve or instantaneous wave-free ratio.

Disclosures: The DEFINE FLAIR and iFR SWEDEHEART studies were funded by unrestricted grants from Philips Volcano. The presenter reported serving as a consultant to Abbott, AstraZeneca, Biosensors, Boston Scientific, Medtronic, OrbusNeich, and Philips Healthcare.

Open Navicular Dislocation With Midfoot Dissociation in a 45-Year-Old Man

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Open Navicular Dislocation With Midfoot Dissociation in a 45-Year-Old Man

Take-Home Points

  • Stability of the foot is dependent on both the medial and lateral longitudinal columns; injuries to a single column alone are extremely rare.
  • Midfoot fractures that are recognized and treated early have generally favorable outcomes compared to those identified in a delayed fashion.
  • The most frequent complication of navicular dislocation is AVN, which is said to occur in as many as 25% of cases.
  • Many specialists agree that navicular dislocations are best treated with open reduction.
  • Ultimately, the goals of surgical intervention are to minimize pain and to establish stability of the plantigrade foot.

Traumatic dislocation of the tarsal navicular (especially without a navicular body fracture) is uncommon.1 The regional anatomy and ligamentous architecture confer stability to the midfoot.2-6 Navicular dislocation is part of a complex disruption involving structures in the adjacent column.6

Navicular dislocation has been associated with several bony and soft-tissue injury patterns, including comminuted intra-articular fracture of the calcaneus and associated calcaneocuboid joint subluxation; fracture and subluxation of the calcaneocuboid joint; fracture-dislocation of the calcaneocuboid joint with fractures of the third and fourth metatarsals; and a combination of fractures of the intermediate cuneiform, the second through fourth metatarsals, and the cuboid.4–11 In this article, we report a case of open complete navicular dislocation with talar head fracture and associated subtalar and calcaneocuboid subluxations in a 45-year-old man. The injury was managed with open reduction and stabilization with Kirschner wires (K-wires), which later required naviculocuneiform and intercuneiform fusion for posttraumatic avascular necrosis (AVN). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 45-year-old man sustained blunt trauma to the right foot in a high-speed head-on collision. He was hemodynamically stable with isolated complaints of pain in the foot. Physical examination revealed a grossly open 10-cm wound extending from the heel pad medially to the dorsal surface of the navicular. The navicular was clearly visible through the wound.

Plain radiographs of the foot showed complete medial dislocation of the navicular with complete disruption of all 3 naviculocuneiform joints (Figures 1A-1C).

The subtalar and calcaneocuboid joints were subluxed but remained ligamentously stable on subsequent examination. There was marked subcutaneous soft-tissue swelling surrounding the injury.

On day of presentation, the patient was taken to the operating room for irrigation, débridement, reduction of the joints, and primary closure of the right foot wound. Minimal contamination was noted. Attempted gentle reduction maneuvers included distraction, adduction, and pronation of the forefoot with concomitant lateral pressure on the navicular. Initial reduction attempts were unsuccessful because of interposition of the flexor hallucis longus and peroneus longus tendons. Retraction of these plantar structures with the mentioned maneuvers resulted in a palpable and visible naviculocuneiform reduction. Intraoperative radiographs showed adequate reduction of the naviculocuneiform, with restoration of the normal subtalar and calcaneocuboid alignments. The naviculocuneiform joints remained grossly unstable, however, and would have readily dislocated in the absence of manual pressure. Therefore, two 0.062-inch K-wires were passed from the medial cuneiform across the talonavicular joint. Intraoperative radiographs (Figures 2A, 2B) and a postoperative radiograph (Figure 3) showed adequate alignment of the naviculocuneiform articulations.

An especially prominent medial navicular was noted on postreduction films. Initially, this suggested inadequate reduction of the naviculocuneiform joints, but, on close radiographic examination of each naviculocuneiform joint and imaging of the contralateral foot, we determined that the prominence represented a type III accessory navicular, also known as a cornuate navicular. Contralateral imaging showed an identical and asymptomatic medial prominence.

After surgery, the patient was made non-weight-bearing in a splint, received intravenous antibiotics for 48 hours, and was discharged shortly thereafter. Radiographs at 3 and 6 weeks after injury showed maintenance of the reduction. K-wires were removed at 6 weeks. The patient was advanced to partial weight-bearing at 6 weeks and to full weight-bearing at 3 months.

Over succeeding months, the patient developed pain accompanied by significant midfoot deformity and was found to have navicular collapse consistent with AVN and posttraumatic arthritis (Figures 4A, 4B). Ten months after the initial procedure, instrumented fusion of the naviculocuneiform and intercuneiform complex was performed, along with chondral decortication, navicular decompression, and iliac crest grafting. The patient was made non-weight-bearing in a cast for 6 weeks and was then slowly, progressively advanced.

Twenty-four months after fusion, the patient was fully ambulatory with no significant discomfort or disability. The most recent radiographs showed adequate alignment and bony fusion (Figures 5A, 5B).

 

 

Discussion

The naviculocuneiform joints are important for the dissipation of loading stresses on the midfoot but provide little motion. The plantar and dorsal ligaments are thick structures that stabilize these joints, predisposing the navicular to fracture rather than isolated dislocation. The stability of the foot is dependent on both the medial and lateral longitudinal columns, and it is thought impossible to injure one column without disrupting the other.6 Several patterns of associated lateral column disruptions have been documented, including 3 cases similar to our patient’s, involving navicular dislocation with associated calcaneocuboid joint injuries.5,6,10

Authors have proposed several mechanisms accounting for navicular dislocations. In the setting of acute trauma, the navicular displaces dorsally as the result of forefoot plantar flexion and axial loading.4 A severe abduction/pronation injury leading to a midtarsal dislocation followed by a spontaneous reduction can force the navicular to dislocate medially.6 This disruption of the naviculocuneiform joint and concurrent “nutcracker” injury to the lateral column can produce an associated disruption of the calcaneocuboid joint.6 Depending on the direction of the deforming force, the forefoot can dislocate superolaterally if the force is plantar or inferolaterally if the force is dorsal. The remaining soft-tissue attachments help determine the position of the navicular. A third postulated mechanism involves a complex wringing injury to the forefoot.10Most specialists agree that navicular dislocations are best treated with open reduction.4,6 The goal of surgical intervention is to establish a stable plantigrade foot and to minimize pain. The current literature supports using either wires or screws to maintain reduction of midfoot injuries. Wires can be used for both talonavicular and naviculocuneiform fixation. Screws can be placed across the naviculocuneiform joints, as there is little normal physiologic motion through these joints.4 The talonavicular joint and the cuboid-metatarsal joints provide most of the motion in the midfoot and should not be readily fused.5 Stabilization of both columns is considered necessary to avoid complications such as subluxation and midfoot deformity.Given the postreduction stability of the lateral column in the present case, bicolumnar stabilization was not considered necessary. It is possible that subsequent collapse of the midfoot may have been attenuated in the presence of lateral fixation, but this would not necessarily have prevented complications of AVN.

Midfoot fractures that are recognized and treated early have generally favorable outcomes,5-11 though chronic pain and subsequent deformity are not uncommon. Perhaps the most frequently reported complication of navicular dislocation is AVN, which is thought to occur in approximately 25% of cases.12 AVN is a well-recognized complication of hindfoot and midfoot trauma. In the tarsal navicular, blood supply to the central-third watershed region is marginal. Small branches of the posterior tibial and dorsalis pedis arteries that supply the medial and lateral areas are readily injured. Not surprisingly, the risk for AVN is high when the dislocated bone is severely displaced.6 In some circumstances, the shared blood supply of the posterior tibialis may be the only remaining osseous supply. The tendon and its soft-tissue attachments should therefore be carefully monitored during dissection and reduction.6 In most cases, AVN of the foot manifests clinically within the first 10 months after injury, as was the case with our patient.13 AVN can result in the Charcot-like collapse of the medial column, leading to progressive midfoot plantar deformities.4 Variations of midfoot fusion are often required.4,6AVN may be difficult to differentiate from posttraumatic arthritis. These conditions can have similar clinical presentations and appearances on plain radiographs. In such situations, magnetic resonance imaging or bone scintigraphy may determine the diagnosis. Damage to the articular surface at time of injury and residual articular displacement, instability, and joint subluxation after injury are considered risk factors for the development of posttraumatic arthritis in the foot and ankle.14 Reports suggest that the severity of the damage to the articular surface is directly proportional to the degree of arthritis.14 Such damage may not be initially visible, especially in axial impaction injuries, but latent deterioration of the articular surface can occur.15 For patients with significant dislocations of the naviculocuneiform joints, some authors advocate primary and early fusion15 instead of the more conservative approach used here. Primary fusions are argued to have minimal deleterious effects on function, secondary to the absence of normal physiologic motion through the affected joints.15 However, there is relatively little published evidence on long-term outcomes in primary versus secondary naviculocuneiform fusions.

Successful treatment of midfoot fractures and dislocations requires intimate knowledge of foot and ankle anatomy and mechanics. Surgeons must be able to anticipate, identify, and counsel patients about acute and delayed complications in these already challenging injuries.


Am J Orthop. 2017;46(3):E186-E189. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

References

1. Main BJ, Jowett RL. Injuries of the midtarsal joint. J Bone Jt Surg Br. 1975;57(1):89-97.

2. Pinney SJ, Sangeorzan BJ. Fractures of the tarsal bones. Orthop Clin North Am. 2001;32(1):21-33.

3. Vaishya R, Patrick JH. Isolated dorsal fracture-dislocation of tarsal navicular. Injury. 1991;22(1):47-48.

4. Early JS. Fractures and dislocations of the midfoot and forefoot. In: Bucholz WB, Heckman JD, Court-Brown C, et al, eds. Rockwood & Green’s Fractures in Adults. 6th ed. Philadelphia, PA: Lippincott; 2005:2337-2401.

5. Rao H. Complete open dislocation of the navicular: a case report. J Foot Ankle Surg. 2012;51(2):209-211.

6. Dhillon MS, Nagi ON. Total dislocation of the navicular: are they ever isolated injuries? J Bone Joint Surg Br. 1999;81(5):881-885.

7. Kollmannsberger A, De Boer P. Isolated calcaneo-cuboid dislocation: brief report. J Bone Joint Surg Br. 1989;71(2):323.

8. Randall RL, Hall RJ, Slabaugh P. An unusual midfoot dislocation: a case report. Am J Orthop. 1997;26(7):494-496.

9. Ruthman JC, Meyn NP. Isolated plantar midtarsal dislocation. Am J Emerg Med. 1988;6(6):599-601.

10. Pathria MN, Rosenstein A, Bjorkengren AG, Gershuni D, Resnick D. Isolated dislocation of the tarsal navicular: a case report. Foot Ankle. 1988;9(3):146-149.

11. Puente CA, Alaez JP, Marti DG. Tarsal fracture dislocation with plantar dislocation of the navicular: a case study. Foot Ankle Int. 1996;17(2):111-113.

12. Davis AT, Dann A, Kuldjanov D. Complete medial dislocation of the tarsal navicular without fracture: report of a rare injury. J Foot Ankle Surg. 2013;52(3):393-396.

13. Buchan CA, Pearce DH, Lau J, White LW. Imaging of postoperative avascular necrosis of the ankle and foot. Semin Musculoskelet Radiol. 2012;16(3):192-204.

14. Olson SA, Furman B, Guilak F. Joint injury and post-traumatic arthritis. HSS J. 2012;8(1):23-25.

15. Grambart S, Patel S, Schuberth JM. Naviculocuneiform dislocations treated with immediate arthrodesis: a report of 2 cases. J Foot Ankle Surg. 2005;44(3):228-235.

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Take-Home Points

  • Stability of the foot is dependent on both the medial and lateral longitudinal columns; injuries to a single column alone are extremely rare.
  • Midfoot fractures that are recognized and treated early have generally favorable outcomes compared to those identified in a delayed fashion.
  • The most frequent complication of navicular dislocation is AVN, which is said to occur in as many as 25% of cases.
  • Many specialists agree that navicular dislocations are best treated with open reduction.
  • Ultimately, the goals of surgical intervention are to minimize pain and to establish stability of the plantigrade foot.

Traumatic dislocation of the tarsal navicular (especially without a navicular body fracture) is uncommon.1 The regional anatomy and ligamentous architecture confer stability to the midfoot.2-6 Navicular dislocation is part of a complex disruption involving structures in the adjacent column.6

Navicular dislocation has been associated with several bony and soft-tissue injury patterns, including comminuted intra-articular fracture of the calcaneus and associated calcaneocuboid joint subluxation; fracture and subluxation of the calcaneocuboid joint; fracture-dislocation of the calcaneocuboid joint with fractures of the third and fourth metatarsals; and a combination of fractures of the intermediate cuneiform, the second through fourth metatarsals, and the cuboid.4–11 In this article, we report a case of open complete navicular dislocation with talar head fracture and associated subtalar and calcaneocuboid subluxations in a 45-year-old man. The injury was managed with open reduction and stabilization with Kirschner wires (K-wires), which later required naviculocuneiform and intercuneiform fusion for posttraumatic avascular necrosis (AVN). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 45-year-old man sustained blunt trauma to the right foot in a high-speed head-on collision. He was hemodynamically stable with isolated complaints of pain in the foot. Physical examination revealed a grossly open 10-cm wound extending from the heel pad medially to the dorsal surface of the navicular. The navicular was clearly visible through the wound.

Plain radiographs of the foot showed complete medial dislocation of the navicular with complete disruption of all 3 naviculocuneiform joints (Figures 1A-1C).

The subtalar and calcaneocuboid joints were subluxed but remained ligamentously stable on subsequent examination. There was marked subcutaneous soft-tissue swelling surrounding the injury.

On day of presentation, the patient was taken to the operating room for irrigation, débridement, reduction of the joints, and primary closure of the right foot wound. Minimal contamination was noted. Attempted gentle reduction maneuvers included distraction, adduction, and pronation of the forefoot with concomitant lateral pressure on the navicular. Initial reduction attempts were unsuccessful because of interposition of the flexor hallucis longus and peroneus longus tendons. Retraction of these plantar structures with the mentioned maneuvers resulted in a palpable and visible naviculocuneiform reduction. Intraoperative radiographs showed adequate reduction of the naviculocuneiform, with restoration of the normal subtalar and calcaneocuboid alignments. The naviculocuneiform joints remained grossly unstable, however, and would have readily dislocated in the absence of manual pressure. Therefore, two 0.062-inch K-wires were passed from the medial cuneiform across the talonavicular joint. Intraoperative radiographs (Figures 2A, 2B) and a postoperative radiograph (Figure 3) showed adequate alignment of the naviculocuneiform articulations.

An especially prominent medial navicular was noted on postreduction films. Initially, this suggested inadequate reduction of the naviculocuneiform joints, but, on close radiographic examination of each naviculocuneiform joint and imaging of the contralateral foot, we determined that the prominence represented a type III accessory navicular, also known as a cornuate navicular. Contralateral imaging showed an identical and asymptomatic medial prominence.

After surgery, the patient was made non-weight-bearing in a splint, received intravenous antibiotics for 48 hours, and was discharged shortly thereafter. Radiographs at 3 and 6 weeks after injury showed maintenance of the reduction. K-wires were removed at 6 weeks. The patient was advanced to partial weight-bearing at 6 weeks and to full weight-bearing at 3 months.

Over succeeding months, the patient developed pain accompanied by significant midfoot deformity and was found to have navicular collapse consistent with AVN and posttraumatic arthritis (Figures 4A, 4B). Ten months after the initial procedure, instrumented fusion of the naviculocuneiform and intercuneiform complex was performed, along with chondral decortication, navicular decompression, and iliac crest grafting. The patient was made non-weight-bearing in a cast for 6 weeks and was then slowly, progressively advanced.

Twenty-four months after fusion, the patient was fully ambulatory with no significant discomfort or disability. The most recent radiographs showed adequate alignment and bony fusion (Figures 5A, 5B).

 

 

Discussion

The naviculocuneiform joints are important for the dissipation of loading stresses on the midfoot but provide little motion. The plantar and dorsal ligaments are thick structures that stabilize these joints, predisposing the navicular to fracture rather than isolated dislocation. The stability of the foot is dependent on both the medial and lateral longitudinal columns, and it is thought impossible to injure one column without disrupting the other.6 Several patterns of associated lateral column disruptions have been documented, including 3 cases similar to our patient’s, involving navicular dislocation with associated calcaneocuboid joint injuries.5,6,10

Authors have proposed several mechanisms accounting for navicular dislocations. In the setting of acute trauma, the navicular displaces dorsally as the result of forefoot plantar flexion and axial loading.4 A severe abduction/pronation injury leading to a midtarsal dislocation followed by a spontaneous reduction can force the navicular to dislocate medially.6 This disruption of the naviculocuneiform joint and concurrent “nutcracker” injury to the lateral column can produce an associated disruption of the calcaneocuboid joint.6 Depending on the direction of the deforming force, the forefoot can dislocate superolaterally if the force is plantar or inferolaterally if the force is dorsal. The remaining soft-tissue attachments help determine the position of the navicular. A third postulated mechanism involves a complex wringing injury to the forefoot.10Most specialists agree that navicular dislocations are best treated with open reduction.4,6 The goal of surgical intervention is to establish a stable plantigrade foot and to minimize pain. The current literature supports using either wires or screws to maintain reduction of midfoot injuries. Wires can be used for both talonavicular and naviculocuneiform fixation. Screws can be placed across the naviculocuneiform joints, as there is little normal physiologic motion through these joints.4 The talonavicular joint and the cuboid-metatarsal joints provide most of the motion in the midfoot and should not be readily fused.5 Stabilization of both columns is considered necessary to avoid complications such as subluxation and midfoot deformity.Given the postreduction stability of the lateral column in the present case, bicolumnar stabilization was not considered necessary. It is possible that subsequent collapse of the midfoot may have been attenuated in the presence of lateral fixation, but this would not necessarily have prevented complications of AVN.

Midfoot fractures that are recognized and treated early have generally favorable outcomes,5-11 though chronic pain and subsequent deformity are not uncommon. Perhaps the most frequently reported complication of navicular dislocation is AVN, which is thought to occur in approximately 25% of cases.12 AVN is a well-recognized complication of hindfoot and midfoot trauma. In the tarsal navicular, blood supply to the central-third watershed region is marginal. Small branches of the posterior tibial and dorsalis pedis arteries that supply the medial and lateral areas are readily injured. Not surprisingly, the risk for AVN is high when the dislocated bone is severely displaced.6 In some circumstances, the shared blood supply of the posterior tibialis may be the only remaining osseous supply. The tendon and its soft-tissue attachments should therefore be carefully monitored during dissection and reduction.6 In most cases, AVN of the foot manifests clinically within the first 10 months after injury, as was the case with our patient.13 AVN can result in the Charcot-like collapse of the medial column, leading to progressive midfoot plantar deformities.4 Variations of midfoot fusion are often required.4,6AVN may be difficult to differentiate from posttraumatic arthritis. These conditions can have similar clinical presentations and appearances on plain radiographs. In such situations, magnetic resonance imaging or bone scintigraphy may determine the diagnosis. Damage to the articular surface at time of injury and residual articular displacement, instability, and joint subluxation after injury are considered risk factors for the development of posttraumatic arthritis in the foot and ankle.14 Reports suggest that the severity of the damage to the articular surface is directly proportional to the degree of arthritis.14 Such damage may not be initially visible, especially in axial impaction injuries, but latent deterioration of the articular surface can occur.15 For patients with significant dislocations of the naviculocuneiform joints, some authors advocate primary and early fusion15 instead of the more conservative approach used here. Primary fusions are argued to have minimal deleterious effects on function, secondary to the absence of normal physiologic motion through the affected joints.15 However, there is relatively little published evidence on long-term outcomes in primary versus secondary naviculocuneiform fusions.

Successful treatment of midfoot fractures and dislocations requires intimate knowledge of foot and ankle anatomy and mechanics. Surgeons must be able to anticipate, identify, and counsel patients about acute and delayed complications in these already challenging injuries.


Am J Orthop. 2017;46(3):E186-E189. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

  • Stability of the foot is dependent on both the medial and lateral longitudinal columns; injuries to a single column alone are extremely rare.
  • Midfoot fractures that are recognized and treated early have generally favorable outcomes compared to those identified in a delayed fashion.
  • The most frequent complication of navicular dislocation is AVN, which is said to occur in as many as 25% of cases.
  • Many specialists agree that navicular dislocations are best treated with open reduction.
  • Ultimately, the goals of surgical intervention are to minimize pain and to establish stability of the plantigrade foot.

Traumatic dislocation of the tarsal navicular (especially without a navicular body fracture) is uncommon.1 The regional anatomy and ligamentous architecture confer stability to the midfoot.2-6 Navicular dislocation is part of a complex disruption involving structures in the adjacent column.6

Navicular dislocation has been associated with several bony and soft-tissue injury patterns, including comminuted intra-articular fracture of the calcaneus and associated calcaneocuboid joint subluxation; fracture and subluxation of the calcaneocuboid joint; fracture-dislocation of the calcaneocuboid joint with fractures of the third and fourth metatarsals; and a combination of fractures of the intermediate cuneiform, the second through fourth metatarsals, and the cuboid.4–11 In this article, we report a case of open complete navicular dislocation with talar head fracture and associated subtalar and calcaneocuboid subluxations in a 45-year-old man. The injury was managed with open reduction and stabilization with Kirschner wires (K-wires), which later required naviculocuneiform and intercuneiform fusion for posttraumatic avascular necrosis (AVN). The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 45-year-old man sustained blunt trauma to the right foot in a high-speed head-on collision. He was hemodynamically stable with isolated complaints of pain in the foot. Physical examination revealed a grossly open 10-cm wound extending from the heel pad medially to the dorsal surface of the navicular. The navicular was clearly visible through the wound.

Plain radiographs of the foot showed complete medial dislocation of the navicular with complete disruption of all 3 naviculocuneiform joints (Figures 1A-1C).

The subtalar and calcaneocuboid joints were subluxed but remained ligamentously stable on subsequent examination. There was marked subcutaneous soft-tissue swelling surrounding the injury.

On day of presentation, the patient was taken to the operating room for irrigation, débridement, reduction of the joints, and primary closure of the right foot wound. Minimal contamination was noted. Attempted gentle reduction maneuvers included distraction, adduction, and pronation of the forefoot with concomitant lateral pressure on the navicular. Initial reduction attempts were unsuccessful because of interposition of the flexor hallucis longus and peroneus longus tendons. Retraction of these plantar structures with the mentioned maneuvers resulted in a palpable and visible naviculocuneiform reduction. Intraoperative radiographs showed adequate reduction of the naviculocuneiform, with restoration of the normal subtalar and calcaneocuboid alignments. The naviculocuneiform joints remained grossly unstable, however, and would have readily dislocated in the absence of manual pressure. Therefore, two 0.062-inch K-wires were passed from the medial cuneiform across the talonavicular joint. Intraoperative radiographs (Figures 2A, 2B) and a postoperative radiograph (Figure 3) showed adequate alignment of the naviculocuneiform articulations.

An especially prominent medial navicular was noted on postreduction films. Initially, this suggested inadequate reduction of the naviculocuneiform joints, but, on close radiographic examination of each naviculocuneiform joint and imaging of the contralateral foot, we determined that the prominence represented a type III accessory navicular, also known as a cornuate navicular. Contralateral imaging showed an identical and asymptomatic medial prominence.

After surgery, the patient was made non-weight-bearing in a splint, received intravenous antibiotics for 48 hours, and was discharged shortly thereafter. Radiographs at 3 and 6 weeks after injury showed maintenance of the reduction. K-wires were removed at 6 weeks. The patient was advanced to partial weight-bearing at 6 weeks and to full weight-bearing at 3 months.

Over succeeding months, the patient developed pain accompanied by significant midfoot deformity and was found to have navicular collapse consistent with AVN and posttraumatic arthritis (Figures 4A, 4B). Ten months after the initial procedure, instrumented fusion of the naviculocuneiform and intercuneiform complex was performed, along with chondral decortication, navicular decompression, and iliac crest grafting. The patient was made non-weight-bearing in a cast for 6 weeks and was then slowly, progressively advanced.

Twenty-four months after fusion, the patient was fully ambulatory with no significant discomfort or disability. The most recent radiographs showed adequate alignment and bony fusion (Figures 5A, 5B).

 

 

Discussion

The naviculocuneiform joints are important for the dissipation of loading stresses on the midfoot but provide little motion. The plantar and dorsal ligaments are thick structures that stabilize these joints, predisposing the navicular to fracture rather than isolated dislocation. The stability of the foot is dependent on both the medial and lateral longitudinal columns, and it is thought impossible to injure one column without disrupting the other.6 Several patterns of associated lateral column disruptions have been documented, including 3 cases similar to our patient’s, involving navicular dislocation with associated calcaneocuboid joint injuries.5,6,10

Authors have proposed several mechanisms accounting for navicular dislocations. In the setting of acute trauma, the navicular displaces dorsally as the result of forefoot plantar flexion and axial loading.4 A severe abduction/pronation injury leading to a midtarsal dislocation followed by a spontaneous reduction can force the navicular to dislocate medially.6 This disruption of the naviculocuneiform joint and concurrent “nutcracker” injury to the lateral column can produce an associated disruption of the calcaneocuboid joint.6 Depending on the direction of the deforming force, the forefoot can dislocate superolaterally if the force is plantar or inferolaterally if the force is dorsal. The remaining soft-tissue attachments help determine the position of the navicular. A third postulated mechanism involves a complex wringing injury to the forefoot.10Most specialists agree that navicular dislocations are best treated with open reduction.4,6 The goal of surgical intervention is to establish a stable plantigrade foot and to minimize pain. The current literature supports using either wires or screws to maintain reduction of midfoot injuries. Wires can be used for both talonavicular and naviculocuneiform fixation. Screws can be placed across the naviculocuneiform joints, as there is little normal physiologic motion through these joints.4 The talonavicular joint and the cuboid-metatarsal joints provide most of the motion in the midfoot and should not be readily fused.5 Stabilization of both columns is considered necessary to avoid complications such as subluxation and midfoot deformity.Given the postreduction stability of the lateral column in the present case, bicolumnar stabilization was not considered necessary. It is possible that subsequent collapse of the midfoot may have been attenuated in the presence of lateral fixation, but this would not necessarily have prevented complications of AVN.

Midfoot fractures that are recognized and treated early have generally favorable outcomes,5-11 though chronic pain and subsequent deformity are not uncommon. Perhaps the most frequently reported complication of navicular dislocation is AVN, which is thought to occur in approximately 25% of cases.12 AVN is a well-recognized complication of hindfoot and midfoot trauma. In the tarsal navicular, blood supply to the central-third watershed region is marginal. Small branches of the posterior tibial and dorsalis pedis arteries that supply the medial and lateral areas are readily injured. Not surprisingly, the risk for AVN is high when the dislocated bone is severely displaced.6 In some circumstances, the shared blood supply of the posterior tibialis may be the only remaining osseous supply. The tendon and its soft-tissue attachments should therefore be carefully monitored during dissection and reduction.6 In most cases, AVN of the foot manifests clinically within the first 10 months after injury, as was the case with our patient.13 AVN can result in the Charcot-like collapse of the medial column, leading to progressive midfoot plantar deformities.4 Variations of midfoot fusion are often required.4,6AVN may be difficult to differentiate from posttraumatic arthritis. These conditions can have similar clinical presentations and appearances on plain radiographs. In such situations, magnetic resonance imaging or bone scintigraphy may determine the diagnosis. Damage to the articular surface at time of injury and residual articular displacement, instability, and joint subluxation after injury are considered risk factors for the development of posttraumatic arthritis in the foot and ankle.14 Reports suggest that the severity of the damage to the articular surface is directly proportional to the degree of arthritis.14 Such damage may not be initially visible, especially in axial impaction injuries, but latent deterioration of the articular surface can occur.15 For patients with significant dislocations of the naviculocuneiform joints, some authors advocate primary and early fusion15 instead of the more conservative approach used here. Primary fusions are argued to have minimal deleterious effects on function, secondary to the absence of normal physiologic motion through the affected joints.15 However, there is relatively little published evidence on long-term outcomes in primary versus secondary naviculocuneiform fusions.

Successful treatment of midfoot fractures and dislocations requires intimate knowledge of foot and ankle anatomy and mechanics. Surgeons must be able to anticipate, identify, and counsel patients about acute and delayed complications in these already challenging injuries.


Am J Orthop. 2017;46(3):E186-E189. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

References

1. Main BJ, Jowett RL. Injuries of the midtarsal joint. J Bone Jt Surg Br. 1975;57(1):89-97.

2. Pinney SJ, Sangeorzan BJ. Fractures of the tarsal bones. Orthop Clin North Am. 2001;32(1):21-33.

3. Vaishya R, Patrick JH. Isolated dorsal fracture-dislocation of tarsal navicular. Injury. 1991;22(1):47-48.

4. Early JS. Fractures and dislocations of the midfoot and forefoot. In: Bucholz WB, Heckman JD, Court-Brown C, et al, eds. Rockwood & Green’s Fractures in Adults. 6th ed. Philadelphia, PA: Lippincott; 2005:2337-2401.

5. Rao H. Complete open dislocation of the navicular: a case report. J Foot Ankle Surg. 2012;51(2):209-211.

6. Dhillon MS, Nagi ON. Total dislocation of the navicular: are they ever isolated injuries? J Bone Joint Surg Br. 1999;81(5):881-885.

7. Kollmannsberger A, De Boer P. Isolated calcaneo-cuboid dislocation: brief report. J Bone Joint Surg Br. 1989;71(2):323.

8. Randall RL, Hall RJ, Slabaugh P. An unusual midfoot dislocation: a case report. Am J Orthop. 1997;26(7):494-496.

9. Ruthman JC, Meyn NP. Isolated plantar midtarsal dislocation. Am J Emerg Med. 1988;6(6):599-601.

10. Pathria MN, Rosenstein A, Bjorkengren AG, Gershuni D, Resnick D. Isolated dislocation of the tarsal navicular: a case report. Foot Ankle. 1988;9(3):146-149.

11. Puente CA, Alaez JP, Marti DG. Tarsal fracture dislocation with plantar dislocation of the navicular: a case study. Foot Ankle Int. 1996;17(2):111-113.

12. Davis AT, Dann A, Kuldjanov D. Complete medial dislocation of the tarsal navicular without fracture: report of a rare injury. J Foot Ankle Surg. 2013;52(3):393-396.

13. Buchan CA, Pearce DH, Lau J, White LW. Imaging of postoperative avascular necrosis of the ankle and foot. Semin Musculoskelet Radiol. 2012;16(3):192-204.

14. Olson SA, Furman B, Guilak F. Joint injury and post-traumatic arthritis. HSS J. 2012;8(1):23-25.

15. Grambart S, Patel S, Schuberth JM. Naviculocuneiform dislocations treated with immediate arthrodesis: a report of 2 cases. J Foot Ankle Surg. 2005;44(3):228-235.

References

1. Main BJ, Jowett RL. Injuries of the midtarsal joint. J Bone Jt Surg Br. 1975;57(1):89-97.

2. Pinney SJ, Sangeorzan BJ. Fractures of the tarsal bones. Orthop Clin North Am. 2001;32(1):21-33.

3. Vaishya R, Patrick JH. Isolated dorsal fracture-dislocation of tarsal navicular. Injury. 1991;22(1):47-48.

4. Early JS. Fractures and dislocations of the midfoot and forefoot. In: Bucholz WB, Heckman JD, Court-Brown C, et al, eds. Rockwood & Green’s Fractures in Adults. 6th ed. Philadelphia, PA: Lippincott; 2005:2337-2401.

5. Rao H. Complete open dislocation of the navicular: a case report. J Foot Ankle Surg. 2012;51(2):209-211.

6. Dhillon MS, Nagi ON. Total dislocation of the navicular: are they ever isolated injuries? J Bone Joint Surg Br. 1999;81(5):881-885.

7. Kollmannsberger A, De Boer P. Isolated calcaneo-cuboid dislocation: brief report. J Bone Joint Surg Br. 1989;71(2):323.

8. Randall RL, Hall RJ, Slabaugh P. An unusual midfoot dislocation: a case report. Am J Orthop. 1997;26(7):494-496.

9. Ruthman JC, Meyn NP. Isolated plantar midtarsal dislocation. Am J Emerg Med. 1988;6(6):599-601.

10. Pathria MN, Rosenstein A, Bjorkengren AG, Gershuni D, Resnick D. Isolated dislocation of the tarsal navicular: a case report. Foot Ankle. 1988;9(3):146-149.

11. Puente CA, Alaez JP, Marti DG. Tarsal fracture dislocation with plantar dislocation of the navicular: a case study. Foot Ankle Int. 1996;17(2):111-113.

12. Davis AT, Dann A, Kuldjanov D. Complete medial dislocation of the tarsal navicular without fracture: report of a rare injury. J Foot Ankle Surg. 2013;52(3):393-396.

13. Buchan CA, Pearce DH, Lau J, White LW. Imaging of postoperative avascular necrosis of the ankle and foot. Semin Musculoskelet Radiol. 2012;16(3):192-204.

14. Olson SA, Furman B, Guilak F. Joint injury and post-traumatic arthritis. HSS J. 2012;8(1):23-25.

15. Grambart S, Patel S, Schuberth JM. Naviculocuneiform dislocations treated with immediate arthrodesis: a report of 2 cases. J Foot Ankle Surg. 2005;44(3):228-235.

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Points/Counterpoint: Should surgeons operate on functional tricuspid regurgitation?

Article Type
Changed

 

Yes, functional TR is worth repairing (David H. Adams, MD)

Functional tricuspid regurgitation is a common finding in patients undergoing degenerative mitral valve repair. Severe tricuspid regurgitation is unusual, and clearly there is little debate on the merits of concomitant tricuspid repair for these patients. Moderate tricuspid regurgitation is identified preoperatively in around 15% of patients undergoing degenerative mitral repair (J Thorac Cardiovasc Surg. 2011;142:608-13), and concomitant tricuspid repair in these patients is certainly supported by both the American and European guidelines (J Am Coll Cardiol. 2017. doi: 10.1016/j.jacc.2017.03.011; Eur Heart J. 2012;33:2451-96).

What experience and evidence has led us to a more aggressive approach? One of the most important influences on our early adoption of tricuspid repair at the time of mitral surgery was linked to observations that tricuspid regurgitation (TR) sometimes progressed after isolated mitral valve repair (MVR), with some patients developing moderate or worse insufficiency. Certainly, the impact of significant tricuspid regurgitation on the quality and length of patients’ lives and the challenges of reoperation for isolated tricuspid regurgitation are well known to all surgeons.

Dr. David H. Adams
However, the first objective data supporting a more aggressive approach to abnormal tricuspid valve function was provided by Gilles Dreyfus, MD, and his team at Harefield Hospital in London, who reported significantly better symptomatic and echocardiographic outcomes after concomitant tricuspid repair for tricuspid annular dilatation (irrespective of the degree of tricuspid regurgitation), compared with patients who did not undergo tricuspid repair (Ann Thorac Surg. 1990;49:706-11).

Consequently, the importance of treating significant annular dilatation, even without significant tricuspid regurgitation, is supported by the guidelines. Our own experience with an aggressive approach to functional tricuspid regurgitation (FTR) at the time of mitral surgery put an exclamation point on this (J Am Coll Cardiol. 2015;65:1931-8). We found that concomitant tricuspid repair in patients who were worse off before surgery with more TR and higher rates of atrial fibrillation and right-sided dysfunction, actually did better during 5 years of follow-up than the isolated mitral repair patients who started with completely normal tricuspid valve anatomy and ventricular function.

Benign neglect is always an option (J Thorac Cardiovasc Surg. 2017;154:125-6), but we agree with Roberto Dion, MD – despite our friends’ opinions in Toronto and Rochester – we would much prefer to have minimal TR and a normal sized tricuspid valve after MVR. Ask yourself: would you rather have no TR and a normal sized tricuspid valve after you undergo a mitral operation, or a very dilated annulus and perhaps moderate FTR? I am pretty sure I know the answer, but if you are not sure, read our paper.

Dr. Adams is cardiac surgeon-in-chief, Mount Sinai Health System, and Marie-Josée and Henry R. Kravis Professor and Chairman, department of cardiovascular surgery, Icahn School of Medicine at Mount Sinai and The Mount Sinai Hospital, and president-elect of the American Association for Thoracic Surgery. He disclosed he is the national co-principal investigator for the Medtronic NeoChord trial, and receives royalties from Medtronic and Edwards Lifesciences. The Icahn School of Medicine at Mount Sinai receives royalty payments from Edwards Lifesciences and Medtronic for intellectual property related to Dr. Adams’ involvement in the development of 2 mitral valve repair rings and 1 tricuspid valve repair ring.​

No, a patient with FTR does not necessarily need repair (Tirone David, MD)

In our clinic, a patient who undergoes MVR and has FTR generally goes home without an annuloplasty. We now have 12 years or more of follow-up in these patients, and they do not develop TR if their MVR is competent. We have reported that preoperative TR in patients who had MVR is associated with mitral valve disease and often improves after the operation (J Thorac Cardiovasc Surg. 2017;154:110-22). New postoperative TR is uncommon.

Ninety percent of my mitral valve repair patients today have no symptoms. Of those patients, a small proportion have moderate TR.

Dr. Tirone David
Predicting severe FTR is difficult in these patients. For reasons that we don’t know, when you perform mitral valve repair in a patient with ejection fraction less than 40%, ultimately the tricuspid valve begins to leak 10 or 15 years later. Longstanding atrial fibrillation also causes TR. The data published to date on tricuspid annuloplasty show that at 10 years, 30% had recurrent TR regardless of whether or not they’ve had mitral valve repair (Circulation. 2006;114(suppl);I577-81).

Dr. David is a professor of surgery at Toronto General Hospital. He reported no financial relationships.

Yes, but repair of FTR requires caution (Gilles Dreyfus, MD)

The controversy surrounding the legitimacy of concomitant tricuspid annuloplasty for functional TR during MVR begs for a clinical trial, but before we can conduct a clinical trial, we must define the primary and secondary endpoints. We’ve seen recent prospective, randomized trials that have reported faulty conclusions because the primary endpoints were wrong.

 

 

We need a strong debate to agree on those endpoints. Mortality as an endpoint will probably take a very long time to arrive at.

We’re mixing up many different factors. We’re mixing up TR grading, and we know that grading is unreliable. We have all seen patients with full-fledged TR, and after we put them on Lasix (furosemide, Sanofi), 3 days later they have mild TR. So the same patient with no treatment becomes let’s say a “Dreyfus indication,” and then suddenly in 3 days the patient doesn’t need surgery. At any further stage of his life this patient can experience severe TR again; tricuspid annuloplasty will prevent that from happening.

Dr. Gilles Dreyfus
It is a big mistake to rely only on grading to determine the need for surgery to treat FTR. We are superimposing the assessment of the right ventricle (RV) to the left one, but that is mixing apples and pears. The left ventricle (LV) is working against resistances and its volume does not change; the RV supplies only the pulmonary system and is volume-dependent. You can double the size of the RV without changing its function whatsoever, and that’s when TR may appear if all the features are present: annular dilatation and RV dilatation. Any changes in preload such as severe renal failure, as well as any changes in afterload such as moderate LV impairment or mild/moderate MR after MVR, may modify RV size and TR grading.

Moderate TR according to the common definition does not exist. If you look at the reports in echocardiography and if you ask any cardiologist, everything between no TR and severe TR is considered moderate. We have proposed a new staging system for evaluating FTR that uses three factors: TR severity; annular dilatation; and extent of tethering, or mode of leaflet coaptation (J Am Coll Cardiol. 2015;65:2331-6).

Dr. Dreyfus is director of the medical and surgical team at the Cardiothoracic Centre of Monaco in Monte Carlo and professor of cardiothoracic surgery at Paris V University and the Imperial College of London. He disclosed receiving speaker fees from Edwards Lifesciences, LivaNova, and Medtronic.

No, few FTR patients at risk after MVR (Hartzell Schaff, MD)

Echocardiography can provide a great deal of information about when concomitant repair for TR is indicated during MVR. We’ve found that if the patient has no right-sided signs, has normal right atrial pressure, and has mild or mild/moderate TR at the time of repair to the journey mitral valve, the chance of him returning for a tricuspid valve procedure is near zero.

A few patients do return after MVR. They develop atrial fibrillation and may need a pacemaker, but we see very few patients return for tricuspid surgery.

Dr. Hartzell Schaff
There is a hierarchy of valves: the tricuspid valve; the pulmonary; the aortic valve; and the mitral valve. You can do without the pulmonary valve and live. In fact you can do without a tricuspid valve and live; there was a surgeon that used to do tricuspid valvectomies for endocarditis. You don’t live well; you’ll eventually have to have the tricuspid valve replaced. But you cannot live without a mitral valve and you cannot live without an aortic valve.

It’s fair to say we cannot demonstrate any benefit of correcting functional mitral regurgitation. Why would we think there’s a benefit of correcting FTR? We can say we’re going to look at grade of TR down the road, or we could look at some other endpoint, but think about it this way: If we cannot prove that correcting functional mitral regurgitation is helpful, why is correcting FTR going to help?

Dr. Schaff is a cardiothoracic surgeon at Mayo Clinic Foundation, Rochester, Minn. He reported no financial relationships.
 

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Yes, functional TR is worth repairing (David H. Adams, MD)

Functional tricuspid regurgitation is a common finding in patients undergoing degenerative mitral valve repair. Severe tricuspid regurgitation is unusual, and clearly there is little debate on the merits of concomitant tricuspid repair for these patients. Moderate tricuspid regurgitation is identified preoperatively in around 15% of patients undergoing degenerative mitral repair (J Thorac Cardiovasc Surg. 2011;142:608-13), and concomitant tricuspid repair in these patients is certainly supported by both the American and European guidelines (J Am Coll Cardiol. 2017. doi: 10.1016/j.jacc.2017.03.011; Eur Heart J. 2012;33:2451-96).

What experience and evidence has led us to a more aggressive approach? One of the most important influences on our early adoption of tricuspid repair at the time of mitral surgery was linked to observations that tricuspid regurgitation (TR) sometimes progressed after isolated mitral valve repair (MVR), with some patients developing moderate or worse insufficiency. Certainly, the impact of significant tricuspid regurgitation on the quality and length of patients’ lives and the challenges of reoperation for isolated tricuspid regurgitation are well known to all surgeons.

Dr. David H. Adams
However, the first objective data supporting a more aggressive approach to abnormal tricuspid valve function was provided by Gilles Dreyfus, MD, and his team at Harefield Hospital in London, who reported significantly better symptomatic and echocardiographic outcomes after concomitant tricuspid repair for tricuspid annular dilatation (irrespective of the degree of tricuspid regurgitation), compared with patients who did not undergo tricuspid repair (Ann Thorac Surg. 1990;49:706-11).

Consequently, the importance of treating significant annular dilatation, even without significant tricuspid regurgitation, is supported by the guidelines. Our own experience with an aggressive approach to functional tricuspid regurgitation (FTR) at the time of mitral surgery put an exclamation point on this (J Am Coll Cardiol. 2015;65:1931-8). We found that concomitant tricuspid repair in patients who were worse off before surgery with more TR and higher rates of atrial fibrillation and right-sided dysfunction, actually did better during 5 years of follow-up than the isolated mitral repair patients who started with completely normal tricuspid valve anatomy and ventricular function.

Benign neglect is always an option (J Thorac Cardiovasc Surg. 2017;154:125-6), but we agree with Roberto Dion, MD – despite our friends’ opinions in Toronto and Rochester – we would much prefer to have minimal TR and a normal sized tricuspid valve after MVR. Ask yourself: would you rather have no TR and a normal sized tricuspid valve after you undergo a mitral operation, or a very dilated annulus and perhaps moderate FTR? I am pretty sure I know the answer, but if you are not sure, read our paper.

Dr. Adams is cardiac surgeon-in-chief, Mount Sinai Health System, and Marie-Josée and Henry R. Kravis Professor and Chairman, department of cardiovascular surgery, Icahn School of Medicine at Mount Sinai and The Mount Sinai Hospital, and president-elect of the American Association for Thoracic Surgery. He disclosed he is the national co-principal investigator for the Medtronic NeoChord trial, and receives royalties from Medtronic and Edwards Lifesciences. The Icahn School of Medicine at Mount Sinai receives royalty payments from Edwards Lifesciences and Medtronic for intellectual property related to Dr. Adams’ involvement in the development of 2 mitral valve repair rings and 1 tricuspid valve repair ring.​

No, a patient with FTR does not necessarily need repair (Tirone David, MD)

In our clinic, a patient who undergoes MVR and has FTR generally goes home without an annuloplasty. We now have 12 years or more of follow-up in these patients, and they do not develop TR if their MVR is competent. We have reported that preoperative TR in patients who had MVR is associated with mitral valve disease and often improves after the operation (J Thorac Cardiovasc Surg. 2017;154:110-22). New postoperative TR is uncommon.

Ninety percent of my mitral valve repair patients today have no symptoms. Of those patients, a small proportion have moderate TR.

Dr. Tirone David
Predicting severe FTR is difficult in these patients. For reasons that we don’t know, when you perform mitral valve repair in a patient with ejection fraction less than 40%, ultimately the tricuspid valve begins to leak 10 or 15 years later. Longstanding atrial fibrillation also causes TR. The data published to date on tricuspid annuloplasty show that at 10 years, 30% had recurrent TR regardless of whether or not they’ve had mitral valve repair (Circulation. 2006;114(suppl);I577-81).

Dr. David is a professor of surgery at Toronto General Hospital. He reported no financial relationships.

Yes, but repair of FTR requires caution (Gilles Dreyfus, MD)

The controversy surrounding the legitimacy of concomitant tricuspid annuloplasty for functional TR during MVR begs for a clinical trial, but before we can conduct a clinical trial, we must define the primary and secondary endpoints. We’ve seen recent prospective, randomized trials that have reported faulty conclusions because the primary endpoints were wrong.

 

 

We need a strong debate to agree on those endpoints. Mortality as an endpoint will probably take a very long time to arrive at.

We’re mixing up many different factors. We’re mixing up TR grading, and we know that grading is unreliable. We have all seen patients with full-fledged TR, and after we put them on Lasix (furosemide, Sanofi), 3 days later they have mild TR. So the same patient with no treatment becomes let’s say a “Dreyfus indication,” and then suddenly in 3 days the patient doesn’t need surgery. At any further stage of his life this patient can experience severe TR again; tricuspid annuloplasty will prevent that from happening.

Dr. Gilles Dreyfus
It is a big mistake to rely only on grading to determine the need for surgery to treat FTR. We are superimposing the assessment of the right ventricle (RV) to the left one, but that is mixing apples and pears. The left ventricle (LV) is working against resistances and its volume does not change; the RV supplies only the pulmonary system and is volume-dependent. You can double the size of the RV without changing its function whatsoever, and that’s when TR may appear if all the features are present: annular dilatation and RV dilatation. Any changes in preload such as severe renal failure, as well as any changes in afterload such as moderate LV impairment or mild/moderate MR after MVR, may modify RV size and TR grading.

Moderate TR according to the common definition does not exist. If you look at the reports in echocardiography and if you ask any cardiologist, everything between no TR and severe TR is considered moderate. We have proposed a new staging system for evaluating FTR that uses three factors: TR severity; annular dilatation; and extent of tethering, or mode of leaflet coaptation (J Am Coll Cardiol. 2015;65:2331-6).

Dr. Dreyfus is director of the medical and surgical team at the Cardiothoracic Centre of Monaco in Monte Carlo and professor of cardiothoracic surgery at Paris V University and the Imperial College of London. He disclosed receiving speaker fees from Edwards Lifesciences, LivaNova, and Medtronic.

No, few FTR patients at risk after MVR (Hartzell Schaff, MD)

Echocardiography can provide a great deal of information about when concomitant repair for TR is indicated during MVR. We’ve found that if the patient has no right-sided signs, has normal right atrial pressure, and has mild or mild/moderate TR at the time of repair to the journey mitral valve, the chance of him returning for a tricuspid valve procedure is near zero.

A few patients do return after MVR. They develop atrial fibrillation and may need a pacemaker, but we see very few patients return for tricuspid surgery.

Dr. Hartzell Schaff
There is a hierarchy of valves: the tricuspid valve; the pulmonary; the aortic valve; and the mitral valve. You can do without the pulmonary valve and live. In fact you can do without a tricuspid valve and live; there was a surgeon that used to do tricuspid valvectomies for endocarditis. You don’t live well; you’ll eventually have to have the tricuspid valve replaced. But you cannot live without a mitral valve and you cannot live without an aortic valve.

It’s fair to say we cannot demonstrate any benefit of correcting functional mitral regurgitation. Why would we think there’s a benefit of correcting FTR? We can say we’re going to look at grade of TR down the road, or we could look at some other endpoint, but think about it this way: If we cannot prove that correcting functional mitral regurgitation is helpful, why is correcting FTR going to help?

Dr. Schaff is a cardiothoracic surgeon at Mayo Clinic Foundation, Rochester, Minn. He reported no financial relationships.
 

 

Yes, functional TR is worth repairing (David H. Adams, MD)

Functional tricuspid regurgitation is a common finding in patients undergoing degenerative mitral valve repair. Severe tricuspid regurgitation is unusual, and clearly there is little debate on the merits of concomitant tricuspid repair for these patients. Moderate tricuspid regurgitation is identified preoperatively in around 15% of patients undergoing degenerative mitral repair (J Thorac Cardiovasc Surg. 2011;142:608-13), and concomitant tricuspid repair in these patients is certainly supported by both the American and European guidelines (J Am Coll Cardiol. 2017. doi: 10.1016/j.jacc.2017.03.011; Eur Heart J. 2012;33:2451-96).

What experience and evidence has led us to a more aggressive approach? One of the most important influences on our early adoption of tricuspid repair at the time of mitral surgery was linked to observations that tricuspid regurgitation (TR) sometimes progressed after isolated mitral valve repair (MVR), with some patients developing moderate or worse insufficiency. Certainly, the impact of significant tricuspid regurgitation on the quality and length of patients’ lives and the challenges of reoperation for isolated tricuspid regurgitation are well known to all surgeons.

Dr. David H. Adams
However, the first objective data supporting a more aggressive approach to abnormal tricuspid valve function was provided by Gilles Dreyfus, MD, and his team at Harefield Hospital in London, who reported significantly better symptomatic and echocardiographic outcomes after concomitant tricuspid repair for tricuspid annular dilatation (irrespective of the degree of tricuspid regurgitation), compared with patients who did not undergo tricuspid repair (Ann Thorac Surg. 1990;49:706-11).

Consequently, the importance of treating significant annular dilatation, even without significant tricuspid regurgitation, is supported by the guidelines. Our own experience with an aggressive approach to functional tricuspid regurgitation (FTR) at the time of mitral surgery put an exclamation point on this (J Am Coll Cardiol. 2015;65:1931-8). We found that concomitant tricuspid repair in patients who were worse off before surgery with more TR and higher rates of atrial fibrillation and right-sided dysfunction, actually did better during 5 years of follow-up than the isolated mitral repair patients who started with completely normal tricuspid valve anatomy and ventricular function.

Benign neglect is always an option (J Thorac Cardiovasc Surg. 2017;154:125-6), but we agree with Roberto Dion, MD – despite our friends’ opinions in Toronto and Rochester – we would much prefer to have minimal TR and a normal sized tricuspid valve after MVR. Ask yourself: would you rather have no TR and a normal sized tricuspid valve after you undergo a mitral operation, or a very dilated annulus and perhaps moderate FTR? I am pretty sure I know the answer, but if you are not sure, read our paper.

Dr. Adams is cardiac surgeon-in-chief, Mount Sinai Health System, and Marie-Josée and Henry R. Kravis Professor and Chairman, department of cardiovascular surgery, Icahn School of Medicine at Mount Sinai and The Mount Sinai Hospital, and president-elect of the American Association for Thoracic Surgery. He disclosed he is the national co-principal investigator for the Medtronic NeoChord trial, and receives royalties from Medtronic and Edwards Lifesciences. The Icahn School of Medicine at Mount Sinai receives royalty payments from Edwards Lifesciences and Medtronic for intellectual property related to Dr. Adams’ involvement in the development of 2 mitral valve repair rings and 1 tricuspid valve repair ring.​

No, a patient with FTR does not necessarily need repair (Tirone David, MD)

In our clinic, a patient who undergoes MVR and has FTR generally goes home without an annuloplasty. We now have 12 years or more of follow-up in these patients, and they do not develop TR if their MVR is competent. We have reported that preoperative TR in patients who had MVR is associated with mitral valve disease and often improves after the operation (J Thorac Cardiovasc Surg. 2017;154:110-22). New postoperative TR is uncommon.

Ninety percent of my mitral valve repair patients today have no symptoms. Of those patients, a small proportion have moderate TR.

Dr. Tirone David
Predicting severe FTR is difficult in these patients. For reasons that we don’t know, when you perform mitral valve repair in a patient with ejection fraction less than 40%, ultimately the tricuspid valve begins to leak 10 or 15 years later. Longstanding atrial fibrillation also causes TR. The data published to date on tricuspid annuloplasty show that at 10 years, 30% had recurrent TR regardless of whether or not they’ve had mitral valve repair (Circulation. 2006;114(suppl);I577-81).

Dr. David is a professor of surgery at Toronto General Hospital. He reported no financial relationships.

Yes, but repair of FTR requires caution (Gilles Dreyfus, MD)

The controversy surrounding the legitimacy of concomitant tricuspid annuloplasty for functional TR during MVR begs for a clinical trial, but before we can conduct a clinical trial, we must define the primary and secondary endpoints. We’ve seen recent prospective, randomized trials that have reported faulty conclusions because the primary endpoints were wrong.

 

 

We need a strong debate to agree on those endpoints. Mortality as an endpoint will probably take a very long time to arrive at.

We’re mixing up many different factors. We’re mixing up TR grading, and we know that grading is unreliable. We have all seen patients with full-fledged TR, and after we put them on Lasix (furosemide, Sanofi), 3 days later they have mild TR. So the same patient with no treatment becomes let’s say a “Dreyfus indication,” and then suddenly in 3 days the patient doesn’t need surgery. At any further stage of his life this patient can experience severe TR again; tricuspid annuloplasty will prevent that from happening.

Dr. Gilles Dreyfus
It is a big mistake to rely only on grading to determine the need for surgery to treat FTR. We are superimposing the assessment of the right ventricle (RV) to the left one, but that is mixing apples and pears. The left ventricle (LV) is working against resistances and its volume does not change; the RV supplies only the pulmonary system and is volume-dependent. You can double the size of the RV without changing its function whatsoever, and that’s when TR may appear if all the features are present: annular dilatation and RV dilatation. Any changes in preload such as severe renal failure, as well as any changes in afterload such as moderate LV impairment or mild/moderate MR after MVR, may modify RV size and TR grading.

Moderate TR according to the common definition does not exist. If you look at the reports in echocardiography and if you ask any cardiologist, everything between no TR and severe TR is considered moderate. We have proposed a new staging system for evaluating FTR that uses three factors: TR severity; annular dilatation; and extent of tethering, or mode of leaflet coaptation (J Am Coll Cardiol. 2015;65:2331-6).

Dr. Dreyfus is director of the medical and surgical team at the Cardiothoracic Centre of Monaco in Monte Carlo and professor of cardiothoracic surgery at Paris V University and the Imperial College of London. He disclosed receiving speaker fees from Edwards Lifesciences, LivaNova, and Medtronic.

No, few FTR patients at risk after MVR (Hartzell Schaff, MD)

Echocardiography can provide a great deal of information about when concomitant repair for TR is indicated during MVR. We’ve found that if the patient has no right-sided signs, has normal right atrial pressure, and has mild or mild/moderate TR at the time of repair to the journey mitral valve, the chance of him returning for a tricuspid valve procedure is near zero.

A few patients do return after MVR. They develop atrial fibrillation and may need a pacemaker, but we see very few patients return for tricuspid surgery.

Dr. Hartzell Schaff
There is a hierarchy of valves: the tricuspid valve; the pulmonary; the aortic valve; and the mitral valve. You can do without the pulmonary valve and live. In fact you can do without a tricuspid valve and live; there was a surgeon that used to do tricuspid valvectomies for endocarditis. You don’t live well; you’ll eventually have to have the tricuspid valve replaced. But you cannot live without a mitral valve and you cannot live without an aortic valve.

It’s fair to say we cannot demonstrate any benefit of correcting functional mitral regurgitation. Why would we think there’s a benefit of correcting FTR? We can say we’re going to look at grade of TR down the road, or we could look at some other endpoint, but think about it this way: If we cannot prove that correcting functional mitral regurgitation is helpful, why is correcting FTR going to help?

Dr. Schaff is a cardiothoracic surgeon at Mayo Clinic Foundation, Rochester, Minn. He reported no financial relationships.
 

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Apomorphine pump dramatically decreases ‘off’ time in Parkinson’s

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BOSTON – The most rigorous study of its kind suggests that apomorphine subcutaneous infusion (APO) via pump can substantially reduce ‘off’ time when conventional therapy fails to control dyskinesias in patients with Parkinson’s disease.

tupungato/Thinkstock
Dr. Katzenschlager presented the findings of the industry-funded phase III TOLEDO study at the annual meeting of the American Academy of Neurology.

According to the study authors, previous open-label research has supported the use of apomorphine to reduce dyskinesias, off time, and the need for levodopa.

For the new study, researchers recruited 106 patients aged at least 30 years with a diagnosis of idiopathic Parkinson’s disease and motor fluctuations that were not adequately controlled by medication. They all were taking L-dopa and had an average off time of at least 3 hours a day.

The subjects, who came from 23 centers in seven countries, were randomly assigned to receive apomorphine infusion while they were awake (16 hours; 8 or less mg/hour) or placebo saline infusion.

“Apomorphine is administered via bespoke pumps, which are produced by several manufacturers,” Dr. Katzenschlager said. “The pump used in the trial is a mechanical delivery system and has been in clinical use in Europe for many years for this purpose. The pump is worn outside the body; no surgical procedure is required. It delivers the drug continuously into the subcutaneous fatty tissue, usually abdomen or thighs, via a tube and a thin metal or Teflon needle.”

The pump is about the size of a mobile phone, Dr. Katzenschlager said, and typically worn in a pouch attached to a belt.

The study abstract does not note the dose of apomorphine, and Dr. Katzenschlager declined to say how much of the drug is given to patients. The trial information on clinicaltrials.gov states only that a 5-mg/mL solution of APO-go was to be provided via prefilled syringe. The hourly flow rate of apomorphine and dosages of other Parkinson’s disease medications were adjusted during the first 4 weeks of the trial for efficacy and tolerability purposes.

Researchers report that daily off time declined over the 12-week trial (–0.58 hours for placebo vs. –2.47 hours for apomorphine), accounting for a difference of –1.89 hours (95% CI, –3.16 to –0.62; P = .0025).

“This was highly statistically significant. This degree of improvement has been proven to be clinically relevant to the patients,” Dr. Katzenschlager said. “This was reflected in the patients’ own assessment of the overall treatment effect in the study.”

The study examined Patient Global Impression of Change in apomorphine vs. placebo. The abstract released at the AAN meeting does not report the full results but says that the apomorphine patients had higher scores at the end of the study (P less than .001).

Why might this infusion approach work? “Apomorphine infusion achieves more than injections, which are intended as a rescue therapy for off periods in addition to the patients’ oral medication,” Dr. Katzenschlager said. “The continuous delivery of apomorphine resembles the natural state of dopamine levels in the brain in persons without Parkinson’s disease, where this is mostly stable. The administration via the pump system usually enables oral drugs to be reduced. This may contribute to the improvement in dyskinesias often observed and is a benefit to the patients in itself.”

The study authors noted that apomorphine “was generally well tolerated and no unexpected adverse events were observed.” Dr. Katzenschlager declined to discuss cost.

Britannia Pharmaceuticals, which manufactures APO-go, funded the study. Dr. Katzenschlager reports multiple disclosures, including research support and speaking/consulting fees from Brittania Pharmaceuticals.

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BOSTON – The most rigorous study of its kind suggests that apomorphine subcutaneous infusion (APO) via pump can substantially reduce ‘off’ time when conventional therapy fails to control dyskinesias in patients with Parkinson’s disease.

tupungato/Thinkstock
Dr. Katzenschlager presented the findings of the industry-funded phase III TOLEDO study at the annual meeting of the American Academy of Neurology.

According to the study authors, previous open-label research has supported the use of apomorphine to reduce dyskinesias, off time, and the need for levodopa.

For the new study, researchers recruited 106 patients aged at least 30 years with a diagnosis of idiopathic Parkinson’s disease and motor fluctuations that were not adequately controlled by medication. They all were taking L-dopa and had an average off time of at least 3 hours a day.

The subjects, who came from 23 centers in seven countries, were randomly assigned to receive apomorphine infusion while they were awake (16 hours; 8 or less mg/hour) or placebo saline infusion.

“Apomorphine is administered via bespoke pumps, which are produced by several manufacturers,” Dr. Katzenschlager said. “The pump used in the trial is a mechanical delivery system and has been in clinical use in Europe for many years for this purpose. The pump is worn outside the body; no surgical procedure is required. It delivers the drug continuously into the subcutaneous fatty tissue, usually abdomen or thighs, via a tube and a thin metal or Teflon needle.”

The pump is about the size of a mobile phone, Dr. Katzenschlager said, and typically worn in a pouch attached to a belt.

The study abstract does not note the dose of apomorphine, and Dr. Katzenschlager declined to say how much of the drug is given to patients. The trial information on clinicaltrials.gov states only that a 5-mg/mL solution of APO-go was to be provided via prefilled syringe. The hourly flow rate of apomorphine and dosages of other Parkinson’s disease medications were adjusted during the first 4 weeks of the trial for efficacy and tolerability purposes.

Researchers report that daily off time declined over the 12-week trial (–0.58 hours for placebo vs. –2.47 hours for apomorphine), accounting for a difference of –1.89 hours (95% CI, –3.16 to –0.62; P = .0025).

“This was highly statistically significant. This degree of improvement has been proven to be clinically relevant to the patients,” Dr. Katzenschlager said. “This was reflected in the patients’ own assessment of the overall treatment effect in the study.”

The study examined Patient Global Impression of Change in apomorphine vs. placebo. The abstract released at the AAN meeting does not report the full results but says that the apomorphine patients had higher scores at the end of the study (P less than .001).

Why might this infusion approach work? “Apomorphine infusion achieves more than injections, which are intended as a rescue therapy for off periods in addition to the patients’ oral medication,” Dr. Katzenschlager said. “The continuous delivery of apomorphine resembles the natural state of dopamine levels in the brain in persons without Parkinson’s disease, where this is mostly stable. The administration via the pump system usually enables oral drugs to be reduced. This may contribute to the improvement in dyskinesias often observed and is a benefit to the patients in itself.”

The study authors noted that apomorphine “was generally well tolerated and no unexpected adverse events were observed.” Dr. Katzenschlager declined to discuss cost.

Britannia Pharmaceuticals, which manufactures APO-go, funded the study. Dr. Katzenschlager reports multiple disclosures, including research support and speaking/consulting fees from Brittania Pharmaceuticals.

 

BOSTON – The most rigorous study of its kind suggests that apomorphine subcutaneous infusion (APO) via pump can substantially reduce ‘off’ time when conventional therapy fails to control dyskinesias in patients with Parkinson’s disease.

tupungato/Thinkstock
Dr. Katzenschlager presented the findings of the industry-funded phase III TOLEDO study at the annual meeting of the American Academy of Neurology.

According to the study authors, previous open-label research has supported the use of apomorphine to reduce dyskinesias, off time, and the need for levodopa.

For the new study, researchers recruited 106 patients aged at least 30 years with a diagnosis of idiopathic Parkinson’s disease and motor fluctuations that were not adequately controlled by medication. They all were taking L-dopa and had an average off time of at least 3 hours a day.

The subjects, who came from 23 centers in seven countries, were randomly assigned to receive apomorphine infusion while they were awake (16 hours; 8 or less mg/hour) or placebo saline infusion.

“Apomorphine is administered via bespoke pumps, which are produced by several manufacturers,” Dr. Katzenschlager said. “The pump used in the trial is a mechanical delivery system and has been in clinical use in Europe for many years for this purpose. The pump is worn outside the body; no surgical procedure is required. It delivers the drug continuously into the subcutaneous fatty tissue, usually abdomen or thighs, via a tube and a thin metal or Teflon needle.”

The pump is about the size of a mobile phone, Dr. Katzenschlager said, and typically worn in a pouch attached to a belt.

The study abstract does not note the dose of apomorphine, and Dr. Katzenschlager declined to say how much of the drug is given to patients. The trial information on clinicaltrials.gov states only that a 5-mg/mL solution of APO-go was to be provided via prefilled syringe. The hourly flow rate of apomorphine and dosages of other Parkinson’s disease medications were adjusted during the first 4 weeks of the trial for efficacy and tolerability purposes.

Researchers report that daily off time declined over the 12-week trial (–0.58 hours for placebo vs. –2.47 hours for apomorphine), accounting for a difference of –1.89 hours (95% CI, –3.16 to –0.62; P = .0025).

“This was highly statistically significant. This degree of improvement has been proven to be clinically relevant to the patients,” Dr. Katzenschlager said. “This was reflected in the patients’ own assessment of the overall treatment effect in the study.”

The study examined Patient Global Impression of Change in apomorphine vs. placebo. The abstract released at the AAN meeting does not report the full results but says that the apomorphine patients had higher scores at the end of the study (P less than .001).

Why might this infusion approach work? “Apomorphine infusion achieves more than injections, which are intended as a rescue therapy for off periods in addition to the patients’ oral medication,” Dr. Katzenschlager said. “The continuous delivery of apomorphine resembles the natural state of dopamine levels in the brain in persons without Parkinson’s disease, where this is mostly stable. The administration via the pump system usually enables oral drugs to be reduced. This may contribute to the improvement in dyskinesias often observed and is a benefit to the patients in itself.”

The study authors noted that apomorphine “was generally well tolerated and no unexpected adverse events were observed.” Dr. Katzenschlager declined to discuss cost.

Britannia Pharmaceuticals, which manufactures APO-go, funded the study. Dr. Katzenschlager reports multiple disclosures, including research support and speaking/consulting fees from Brittania Pharmaceuticals.

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Key clinical point: Apomorphine subcutaneous infusion via pump dramatically decreases ‘off’ time in Parkinson’s patients whose muscle movements are not well controlled by medication.

Major finding: Daily ‘off’ time declined over 12 weeks by –0.58 hours for placebo vs. –2.47 hours for apomorphine, accounting for a difference of –1.89 hours (95% CI, –3.16 to –0.62; P = .0025).

Data source: Double-blind, randomized, placebo-controlled, phase III study of 106 Parkinson’s disease patients.

Disclosures: Britannia Pharmaceuticals, which manufactures APO-go, funded the study.