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Seizures captured on a smartphone found diagnostic for epilepsy
WASHINGTON – Smartphone videos brought to the clinic by patients are valid tools for the diagnosis of epilepsy, according to a prospective blinded and multicenter study of 41 consecutive videos presented at the American Epilepsy Society annual meeting.
“These findings have global implications, because they suggest that smartphone videos are a cost effective tool that can accelerate the time to diagnosis even in places where video-EEG monitoring is not readily available,” reported William Tatum, DO, professor of neurology, Mayo Clinic, Jacksonville, Fla.
In addition to submitting a smartphone video, all patients in this study underwent a history and physical (H&P) and were evaluated with video-EEG monitoring. The smartphone videos underwent review by 10 epilepsy experts and 8 general neurology residents blinded to the video EEG findings. The latter group was selected to test the value of smartphone video in clinicians with general knowledge but no special expertise.
The final diagnosis was made on the basis of all the clinical information, including the video-EEG, which Dr. Tatum characterized as the gold standard for the diagnosis of epilepsy. Based on the video-EEG, 11 of the 41 patients (26.8%) had seizures, 26 (63.4%) had psychogenic nonepileptic seizures (PNES), 3 (7.4%) had physiologic nonepileptic events (PhysNEE), and 1 (2.4%) had both PhysNEE and PNES.
On the basis of the blinded smartphone video alone, the median correct diagnosis was 71.4% for experts and 66.7% for residents. Although this difference was not significant, Dr. Tatum reported that there was substantially less inter-rater variability among experts.
“Overall, smartphone video review correctly differentiated epilepsy from PNES in 68% of the videos evaluated by experts and 58% assessed by residents,” Dr. Tatum reported.
For experts, the smartphone video assessment yielded a specificity of 43% and sensitivity of 83% for epilepsy. For PNES, these figures were 80% and 54%, respectively. Among residents, the sensitivities and specificities for epilepsy (32% and 83%) and PNES (82% and 53%) were similar. Dr. Tatum noted that H&P predicted the definitive diagnosis in 75.6% of cases.
The rate of correct diagnoses with blinded smartphone video analysis in this study was respectable, but Dr. Tatum suggested that smartphone video should be an adjunctive tool that is reviewed in the context of H&P, which would be expected to further boost accuracy. Although he acknowledged that smartphone videos plus H&P will not completely supplant the need for video-EEG monitoring to reach a definitive diagnosis in all cases, he believes that it is accurate in many, and it accelerates the time to diagnosis.
“The median duration of the smartphone review was about a minute and a half. The median duration of H&P was 60 minutes, but the median time to a result with video-EEG was 2.54 days,” said Dr. Tatum, noting that this difference was highly significant (P lees than .001). If a diagnosis can be reached without video-EEG, it would also be expected to greatly reduce costs.
On a yes-no basis, 78% of those who evaluated the smartphone videos judged them to be adequate for a diagnosis. An analysis of those considered to be poor quality by expert and resident viewers was presented as a separate report. The most common reasons that smartphone videos were considered to have inadequate quality, according to this analysis, were inadequate duration, insufficient lighting, and poor audio. In other words, essentially all of the problems stemmed from inadequate technique, not technical limitations, reported Erin E. Coonan, an undergraduate research intern working with Dr. Tatum.
“We think that disseminating information to the general public about how to take an adequate quality smartphone video could increase the quality of these videos when they are brought to the clinic,” Ms. Coonan reported. She and Dr. Tatum believe that patient-submitted smartphone videos will be increasingly common tool in clinical medicine, making information about proper technique valuable.
Most U.S. adults now carry smartphones, and these are becoming increasingly common even in resource-poor areas of the world, according to Dr. Tatum. He said that clinical medicine should embrace this technology.
“The cost of a smartphone video is essentially zero, but our data suggest that they can be a useful adjunctive diagnostic tool,” Dr. Tatum said.
The presenters reported no potential conflicts of interest related to these studies.
SOURCE: Tatum W et al., AES 2017 abstract 3.161 and Coonan E et al., AES 2017 abstract 3.070
WASHINGTON – Smartphone videos brought to the clinic by patients are valid tools for the diagnosis of epilepsy, according to a prospective blinded and multicenter study of 41 consecutive videos presented at the American Epilepsy Society annual meeting.
“These findings have global implications, because they suggest that smartphone videos are a cost effective tool that can accelerate the time to diagnosis even in places where video-EEG monitoring is not readily available,” reported William Tatum, DO, professor of neurology, Mayo Clinic, Jacksonville, Fla.
In addition to submitting a smartphone video, all patients in this study underwent a history and physical (H&P) and were evaluated with video-EEG monitoring. The smartphone videos underwent review by 10 epilepsy experts and 8 general neurology residents blinded to the video EEG findings. The latter group was selected to test the value of smartphone video in clinicians with general knowledge but no special expertise.
The final diagnosis was made on the basis of all the clinical information, including the video-EEG, which Dr. Tatum characterized as the gold standard for the diagnosis of epilepsy. Based on the video-EEG, 11 of the 41 patients (26.8%) had seizures, 26 (63.4%) had psychogenic nonepileptic seizures (PNES), 3 (7.4%) had physiologic nonepileptic events (PhysNEE), and 1 (2.4%) had both PhysNEE and PNES.
On the basis of the blinded smartphone video alone, the median correct diagnosis was 71.4% for experts and 66.7% for residents. Although this difference was not significant, Dr. Tatum reported that there was substantially less inter-rater variability among experts.
“Overall, smartphone video review correctly differentiated epilepsy from PNES in 68% of the videos evaluated by experts and 58% assessed by residents,” Dr. Tatum reported.
For experts, the smartphone video assessment yielded a specificity of 43% and sensitivity of 83% for epilepsy. For PNES, these figures were 80% and 54%, respectively. Among residents, the sensitivities and specificities for epilepsy (32% and 83%) and PNES (82% and 53%) were similar. Dr. Tatum noted that H&P predicted the definitive diagnosis in 75.6% of cases.
The rate of correct diagnoses with blinded smartphone video analysis in this study was respectable, but Dr. Tatum suggested that smartphone video should be an adjunctive tool that is reviewed in the context of H&P, which would be expected to further boost accuracy. Although he acknowledged that smartphone videos plus H&P will not completely supplant the need for video-EEG monitoring to reach a definitive diagnosis in all cases, he believes that it is accurate in many, and it accelerates the time to diagnosis.
“The median duration of the smartphone review was about a minute and a half. The median duration of H&P was 60 minutes, but the median time to a result with video-EEG was 2.54 days,” said Dr. Tatum, noting that this difference was highly significant (P lees than .001). If a diagnosis can be reached without video-EEG, it would also be expected to greatly reduce costs.
On a yes-no basis, 78% of those who evaluated the smartphone videos judged them to be adequate for a diagnosis. An analysis of those considered to be poor quality by expert and resident viewers was presented as a separate report. The most common reasons that smartphone videos were considered to have inadequate quality, according to this analysis, were inadequate duration, insufficient lighting, and poor audio. In other words, essentially all of the problems stemmed from inadequate technique, not technical limitations, reported Erin E. Coonan, an undergraduate research intern working with Dr. Tatum.
“We think that disseminating information to the general public about how to take an adequate quality smartphone video could increase the quality of these videos when they are brought to the clinic,” Ms. Coonan reported. She and Dr. Tatum believe that patient-submitted smartphone videos will be increasingly common tool in clinical medicine, making information about proper technique valuable.
Most U.S. adults now carry smartphones, and these are becoming increasingly common even in resource-poor areas of the world, according to Dr. Tatum. He said that clinical medicine should embrace this technology.
“The cost of a smartphone video is essentially zero, but our data suggest that they can be a useful adjunctive diagnostic tool,” Dr. Tatum said.
The presenters reported no potential conflicts of interest related to these studies.
SOURCE: Tatum W et al., AES 2017 abstract 3.161 and Coonan E et al., AES 2017 abstract 3.070
WASHINGTON – Smartphone videos brought to the clinic by patients are valid tools for the diagnosis of epilepsy, according to a prospective blinded and multicenter study of 41 consecutive videos presented at the American Epilepsy Society annual meeting.
“These findings have global implications, because they suggest that smartphone videos are a cost effective tool that can accelerate the time to diagnosis even in places where video-EEG monitoring is not readily available,” reported William Tatum, DO, professor of neurology, Mayo Clinic, Jacksonville, Fla.
In addition to submitting a smartphone video, all patients in this study underwent a history and physical (H&P) and were evaluated with video-EEG monitoring. The smartphone videos underwent review by 10 epilepsy experts and 8 general neurology residents blinded to the video EEG findings. The latter group was selected to test the value of smartphone video in clinicians with general knowledge but no special expertise.
The final diagnosis was made on the basis of all the clinical information, including the video-EEG, which Dr. Tatum characterized as the gold standard for the diagnosis of epilepsy. Based on the video-EEG, 11 of the 41 patients (26.8%) had seizures, 26 (63.4%) had psychogenic nonepileptic seizures (PNES), 3 (7.4%) had physiologic nonepileptic events (PhysNEE), and 1 (2.4%) had both PhysNEE and PNES.
On the basis of the blinded smartphone video alone, the median correct diagnosis was 71.4% for experts and 66.7% for residents. Although this difference was not significant, Dr. Tatum reported that there was substantially less inter-rater variability among experts.
“Overall, smartphone video review correctly differentiated epilepsy from PNES in 68% of the videos evaluated by experts and 58% assessed by residents,” Dr. Tatum reported.
For experts, the smartphone video assessment yielded a specificity of 43% and sensitivity of 83% for epilepsy. For PNES, these figures were 80% and 54%, respectively. Among residents, the sensitivities and specificities for epilepsy (32% and 83%) and PNES (82% and 53%) were similar. Dr. Tatum noted that H&P predicted the definitive diagnosis in 75.6% of cases.
The rate of correct diagnoses with blinded smartphone video analysis in this study was respectable, but Dr. Tatum suggested that smartphone video should be an adjunctive tool that is reviewed in the context of H&P, which would be expected to further boost accuracy. Although he acknowledged that smartphone videos plus H&P will not completely supplant the need for video-EEG monitoring to reach a definitive diagnosis in all cases, he believes that it is accurate in many, and it accelerates the time to diagnosis.
“The median duration of the smartphone review was about a minute and a half. The median duration of H&P was 60 minutes, but the median time to a result with video-EEG was 2.54 days,” said Dr. Tatum, noting that this difference was highly significant (P lees than .001). If a diagnosis can be reached without video-EEG, it would also be expected to greatly reduce costs.
On a yes-no basis, 78% of those who evaluated the smartphone videos judged them to be adequate for a diagnosis. An analysis of those considered to be poor quality by expert and resident viewers was presented as a separate report. The most common reasons that smartphone videos were considered to have inadequate quality, according to this analysis, were inadequate duration, insufficient lighting, and poor audio. In other words, essentially all of the problems stemmed from inadequate technique, not technical limitations, reported Erin E. Coonan, an undergraduate research intern working with Dr. Tatum.
“We think that disseminating information to the general public about how to take an adequate quality smartphone video could increase the quality of these videos when they are brought to the clinic,” Ms. Coonan reported. She and Dr. Tatum believe that patient-submitted smartphone videos will be increasingly common tool in clinical medicine, making information about proper technique valuable.
Most U.S. adults now carry smartphones, and these are becoming increasingly common even in resource-poor areas of the world, according to Dr. Tatum. He said that clinical medicine should embrace this technology.
“The cost of a smartphone video is essentially zero, but our data suggest that they can be a useful adjunctive diagnostic tool,” Dr. Tatum said.
The presenters reported no potential conflicts of interest related to these studies.
SOURCE: Tatum W et al., AES 2017 abstract 3.161 and Coonan E et al., AES 2017 abstract 3.070
Key clinical point: Videos taken with a smartphone can contribute to the accurate diagnosis of epilepsy, according to results of a blinded study.
Major finding: Experts correctly differentiated epileptic seizures from psychogenic nonepileptic seizures with smartphone video in 68% of cases.
Data source: A multicenter, prospective blinded trial of 41 consecutive videos.
Disclosures: The presenters reported no potential conflicts of interest related to this topic.
Source: Tatum W et al., AES 2017 abstract 3.161 and Coonan E et al., AES 2017 abstract 3.070
FDA okays dosing software for hemophilia A
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The free, web-based software estimates a patient’s pharmokinetic curve using age, body weight, and local laboratory FVIII one-stage clotting activity measurements and allows physicians to estimate a full pharmokinetic curve with just two measurable blood samples, according to Shire, the software’s manufacturer. That’s much lower than the 9-11 blood samples recommendation from the International Society on Thrombosis and Haemostasis.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The free, web-based software estimates a patient’s pharmokinetic curve using age, body weight, and local laboratory FVIII one-stage clotting activity measurements and allows physicians to estimate a full pharmokinetic curve with just two measurable blood samples, according to Shire, the software’s manufacturer. That’s much lower than the 9-11 blood samples recommendation from the International Society on Thrombosis and Haemostasis.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The free, web-based software estimates a patient’s pharmokinetic curve using age, body weight, and local laboratory FVIII one-stage clotting activity measurements and allows physicians to estimate a full pharmokinetic curve with just two measurable blood samples, according to Shire, the software’s manufacturer. That’s much lower than the 9-11 blood samples recommendation from the International Society on Thrombosis and Haemostasis.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
FDA: Gadolinium retention prompts new GBCA class warning, safety measures
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.
The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.
Specifically, the agency will require that patients receiving GBCAs first receive a Medication Guide and that GBCA manufacturers conduct human and animal studies to further assess GBCA safety. At this time, the only known adverse health effect of gadolinium retention is nephrogenic systemic fibrosis, which affects a small subgroup of patients with pre-existing kidney failure. No causal association has been established between gadolinium retention and reported adverse events in those with normal kidney function.
The FDA recommended that health care professionals consider the retention characteristics of GBCAs for patients who may be at higher risk for retention, including those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions, but stressed that, although repeated GBCA imaging studies should be minimized when possible, they should not be avoided or deferred when they are necessary. In the safety alert, the FDA noted that administration of the GBCAs Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol) produce the lowest gadolinium levels in the body, and the three agents leave similar gadolinium levels in the body.
The agency encourages reports of adverse events or side effects related to the use of GBCAs to its MedWatch Safety information and Adverse Event Reporting Program. Reports can be submitted online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a preaddressed form that can be mailed or faxed to 1-800-FDA-0178.
Gene mutations tied to viral skin infection in pediatric AD patients
Filaggrin (FLG) polymorphism appears to be linked with Molluscum contagiosum virus skin infection in children with atopic dermatitis (AD), reported Sara Manti, MD, of the University of Messina (Italy), and her associates.
“To the best of our knowledge, this is the first study” to describe this association, they said.
In an Italian study of 100 children with AD and 97 healthy children who served as controls, both clinical and laboratory data showed that FLG gene mutations were linked to early AD onset, a more severe clinical course of disease, and a significantly higher risk of Molluscum contagiosum virus (MCV)–associated skin infection.
The data “suggest that FLG gene may serve as a potential biomarker to screen the atopic population, identifying patients at high risk of AD, to adopt preventive measures that can restore the barrier function of the skin and reduce patients’ susceptibility to recurrent skin infection,” they wrote. “Our findings also indicate that the identified SNPs [single-nucleotide polymorphisms] might have clinically relevant implications with respect to a major MCV [M. contagiosum virus] colonization of skin, also permitting the identification of a new AD phenotype in children. However, to date, because of the existence of controversial data, we believe that further and needed insights into AD pathophysiology may also be gained by studying people with the FLG gene who do not have atopic predisposition and/or AD. Thus, a large population-based study is necessary to further validate these early interpretations and to gain detailed information about the role of FLG variants,” Dr. Manti and her coinvestigators concluded.
Read more in Manti S et al. Ann Allergy Asthma Immunol. 2017;119:446-51.
Filaggrin (FLG) polymorphism appears to be linked with Molluscum contagiosum virus skin infection in children with atopic dermatitis (AD), reported Sara Manti, MD, of the University of Messina (Italy), and her associates.
“To the best of our knowledge, this is the first study” to describe this association, they said.
In an Italian study of 100 children with AD and 97 healthy children who served as controls, both clinical and laboratory data showed that FLG gene mutations were linked to early AD onset, a more severe clinical course of disease, and a significantly higher risk of Molluscum contagiosum virus (MCV)–associated skin infection.
The data “suggest that FLG gene may serve as a potential biomarker to screen the atopic population, identifying patients at high risk of AD, to adopt preventive measures that can restore the barrier function of the skin and reduce patients’ susceptibility to recurrent skin infection,” they wrote. “Our findings also indicate that the identified SNPs [single-nucleotide polymorphisms] might have clinically relevant implications with respect to a major MCV [M. contagiosum virus] colonization of skin, also permitting the identification of a new AD phenotype in children. However, to date, because of the existence of controversial data, we believe that further and needed insights into AD pathophysiology may also be gained by studying people with the FLG gene who do not have atopic predisposition and/or AD. Thus, a large population-based study is necessary to further validate these early interpretations and to gain detailed information about the role of FLG variants,” Dr. Manti and her coinvestigators concluded.
Read more in Manti S et al. Ann Allergy Asthma Immunol. 2017;119:446-51.
Filaggrin (FLG) polymorphism appears to be linked with Molluscum contagiosum virus skin infection in children with atopic dermatitis (AD), reported Sara Manti, MD, of the University of Messina (Italy), and her associates.
“To the best of our knowledge, this is the first study” to describe this association, they said.
In an Italian study of 100 children with AD and 97 healthy children who served as controls, both clinical and laboratory data showed that FLG gene mutations were linked to early AD onset, a more severe clinical course of disease, and a significantly higher risk of Molluscum contagiosum virus (MCV)–associated skin infection.
The data “suggest that FLG gene may serve as a potential biomarker to screen the atopic population, identifying patients at high risk of AD, to adopt preventive measures that can restore the barrier function of the skin and reduce patients’ susceptibility to recurrent skin infection,” they wrote. “Our findings also indicate that the identified SNPs [single-nucleotide polymorphisms] might have clinically relevant implications with respect to a major MCV [M. contagiosum virus] colonization of skin, also permitting the identification of a new AD phenotype in children. However, to date, because of the existence of controversial data, we believe that further and needed insights into AD pathophysiology may also be gained by studying people with the FLG gene who do not have atopic predisposition and/or AD. Thus, a large population-based study is necessary to further validate these early interpretations and to gain detailed information about the role of FLG variants,” Dr. Manti and her coinvestigators concluded.
Read more in Manti S et al. Ann Allergy Asthma Immunol. 2017;119:446-51.
FROM THE ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
FDA okays dosing software for hemophilia A
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
The Food and Drug Administration has granted 510(k) clearance to myPKFiT for ADVATE (Antihemophilic Factor, Recombinant), pharmokinetic dosing software used for tailoring prophylaxis regimens for hemophilia A patients.
The software can be used for hemophilia A patients aged 16 years or older who weigh at least 45 kilograms (about 99 pounds) and are treated with ADVATE.
The software is expected to be available in the United States by the end of the first quarter of 2018. A version of the software is already marketed in Europe.
Link between glucose control and CVD risk: It’s complicated
EXPERT ANALYSIS FROM WCIRDC 2017
LOS ANGELES – If you think the link between glucose control and cardiovascular disease is complicated, you’re not alone.
“Glucose is not the only risk factor for CVD, and it may not be the most important risk factor,” Peter Reaven, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Controlling blood pressure and lipids is also quite important. In current studies, patients with diabetes are aggressively treated for other risk factors with many vascular-acting medications, so it’s difficult to show the benefits of glucose lowering on its own. That is pertinent because it’s becoming clear that the benefits of glucose lowering may take a long time. How, and in whom, one controls glucose may influence the outcome.
Medications, hypoglycemia, glucose variation, and extent of disease all may influence vascular responses to glucose lowering.”
Dr. Reaven, an endocrinologist who directs the Diabetes Research Program at the University of Arizona and VA Health Care System, Phoenix, noted that, while a consistent body of evidence supports an association between higher levels of glucose and increased risk for CVD, it’s not as clear that tight control efforts decrease a patient’s risk for CVD at the microvascular and macrovascular level. “We also appreciate that complications from intensive glucose lowering – such as hypoglycemia, weight gain, time and cost, and increased mortality – are not minimal,” he said.
A meta-analysis of 27,049 patients with type 2 diabetes enrolled in four major trials found that those who were allocated to more-intensive, compared with less-intensive, glucose control had a reduced risk of major cardiovascular events by 9% (hazard ratio, 0.91), primarily because of a 15% reduced risk of myocardial infarction (Diabetologia 2009;52[11] 2288-98). “None of these studies actually achieved statistical significance, but they all showed a modest trend,” said Dr. Reaven, who was not involved in the meta-analysis. At the same time, interim data from the Veterans Affairs Diabetes Trial follow-up study (VADT-F) showed that, after about 10 years, the median HbA1c levels were similar between patients who had received either intensive or standard glucose for a median of 5.6 years in the initial VADT trial (N Engl J Med. 2009;360[2]:129-39). Other risk factors between the two groups were similar, including LDL and systolic and diastolic blood pressures.
In this extended follow-up of the VADT, a 17% reduction in CVD was observed among patients who were treated more intensively, compared with those on standard therapy, after about 12 years of treatment (P = .04; N Engl J Med. 2015;372:2197-206). “Why does it take so long?” he asked. “Why does it take 10-plus years of mean follow-up with an HbA1c separation of 1.5% to start to lead to cardiovascular events? The reality is, we don’t know the answer.”
It’s possible that many years of hyperglycemia created enough vascular injury and long-term consequences that are not easily turned around in short intervals, but Dr. Reaven noted that advanced glycation and oxidation products might also be contributing to long-term vascular legacy events. In an analysis of patients from the VADT-F, he and his associates found that specific advanced glycation end products and oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing type 2 diabetes mellitus (Diabetes Care 2017;40[4]:591-8). In particular, the combination of 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone and 2-aminoadipic acid was strongly associated with all measures of subclinical atherosclerosis.
In the initial VADT trial, severe hypoglycemia occurred nearly three times more commonly in the intensively treated group, compared with the standard therapy group. Severe hypoglycemia was defined as an episode of low blood glucose that was accompanied by confusion requiring assistance from another person or loss of consciousness. In related analyses, the hazard ratio for CV events, CV mortality, and overall mortality with severe hypoglycemia within the preceding 3 months was also increased. “So this is a consistent finding across multiple studies of the danger of severe hypoglycemia occurring during your efforts to improve glucose lowering,” Dr. Reaven said. “Interestingly, it appears that the risk for CVD events following severe hypoglycemia increases with higher baseline CV risk, based on the United Kingdom Prospective Diabetes Study 10-year CV risk score. So, how great your risk is begins to influence how well you do after severe hypoglycemia.”
In a separate stratified analysis of VADT data, the risk for CVD after severe hypoglycemia was more prominent in the standard treatment group, compared with the intensive treatment group. “There’s nearly a sevenfold increased risk for all-cause mortality following severe hypoglycemia in the preceding 3 months,” he said. “The same pattern is present for cardiovascular mortality and, somewhat, for cardiovascular events, although not statistically significant. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes was seen in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] population as well.”
A subset of patients in the VADT study showed that individuals in the standard therapy group who had a prior serious hypoglycemic episode actually had greater coronary calcium progression during the study, compared with the intensively treated group (P = .02; Diabetes Care 2016;39[3]:448-54). “One possibility is that serious hypoglycemia contributed to the development of atherosclerosis in this group,” Dr. Reaven said. “This held true when one examined high and lower glucose levels on average in the study. Those individuals that had A1c levels of 7.5% or above were the ones that appeared to show coronary calcium progression during the study following episodes of severe hypoglycemia, whereas it did not appear to be an issue among those with good glucose control. Another finding was that severe hypoglycemia is associated with increased glucose variability from office visit to office visit.”
He concluded his remarks by noting that being “glucose centric” is not the right approach to treating patients with diabetes. “Other risk factors may offer bigger and more rapid benefits,” he said. “The benefits of glucose lowering are likely most relevant in type 1 diabetes and in early type 2 diabetes, and the benefits of glucose lowering on vascular disease appear to take a long time. Avoid severe hypoglycemia, especially in older patients with type 2 diabetes. This last point may be particularly relevant for those in poor control.”
Dr. Reaven reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2017
LOS ANGELES – If you think the link between glucose control and cardiovascular disease is complicated, you’re not alone.
“Glucose is not the only risk factor for CVD, and it may not be the most important risk factor,” Peter Reaven, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Controlling blood pressure and lipids is also quite important. In current studies, patients with diabetes are aggressively treated for other risk factors with many vascular-acting medications, so it’s difficult to show the benefits of glucose lowering on its own. That is pertinent because it’s becoming clear that the benefits of glucose lowering may take a long time. How, and in whom, one controls glucose may influence the outcome.
Medications, hypoglycemia, glucose variation, and extent of disease all may influence vascular responses to glucose lowering.”
Dr. Reaven, an endocrinologist who directs the Diabetes Research Program at the University of Arizona and VA Health Care System, Phoenix, noted that, while a consistent body of evidence supports an association between higher levels of glucose and increased risk for CVD, it’s not as clear that tight control efforts decrease a patient’s risk for CVD at the microvascular and macrovascular level. “We also appreciate that complications from intensive glucose lowering – such as hypoglycemia, weight gain, time and cost, and increased mortality – are not minimal,” he said.
A meta-analysis of 27,049 patients with type 2 diabetes enrolled in four major trials found that those who were allocated to more-intensive, compared with less-intensive, glucose control had a reduced risk of major cardiovascular events by 9% (hazard ratio, 0.91), primarily because of a 15% reduced risk of myocardial infarction (Diabetologia 2009;52[11] 2288-98). “None of these studies actually achieved statistical significance, but they all showed a modest trend,” said Dr. Reaven, who was not involved in the meta-analysis. At the same time, interim data from the Veterans Affairs Diabetes Trial follow-up study (VADT-F) showed that, after about 10 years, the median HbA1c levels were similar between patients who had received either intensive or standard glucose for a median of 5.6 years in the initial VADT trial (N Engl J Med. 2009;360[2]:129-39). Other risk factors between the two groups were similar, including LDL and systolic and diastolic blood pressures.
In this extended follow-up of the VADT, a 17% reduction in CVD was observed among patients who were treated more intensively, compared with those on standard therapy, after about 12 years of treatment (P = .04; N Engl J Med. 2015;372:2197-206). “Why does it take so long?” he asked. “Why does it take 10-plus years of mean follow-up with an HbA1c separation of 1.5% to start to lead to cardiovascular events? The reality is, we don’t know the answer.”
It’s possible that many years of hyperglycemia created enough vascular injury and long-term consequences that are not easily turned around in short intervals, but Dr. Reaven noted that advanced glycation and oxidation products might also be contributing to long-term vascular legacy events. In an analysis of patients from the VADT-F, he and his associates found that specific advanced glycation end products and oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing type 2 diabetes mellitus (Diabetes Care 2017;40[4]:591-8). In particular, the combination of 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone and 2-aminoadipic acid was strongly associated with all measures of subclinical atherosclerosis.
In the initial VADT trial, severe hypoglycemia occurred nearly three times more commonly in the intensively treated group, compared with the standard therapy group. Severe hypoglycemia was defined as an episode of low blood glucose that was accompanied by confusion requiring assistance from another person or loss of consciousness. In related analyses, the hazard ratio for CV events, CV mortality, and overall mortality with severe hypoglycemia within the preceding 3 months was also increased. “So this is a consistent finding across multiple studies of the danger of severe hypoglycemia occurring during your efforts to improve glucose lowering,” Dr. Reaven said. “Interestingly, it appears that the risk for CVD events following severe hypoglycemia increases with higher baseline CV risk, based on the United Kingdom Prospective Diabetes Study 10-year CV risk score. So, how great your risk is begins to influence how well you do after severe hypoglycemia.”
In a separate stratified analysis of VADT data, the risk for CVD after severe hypoglycemia was more prominent in the standard treatment group, compared with the intensive treatment group. “There’s nearly a sevenfold increased risk for all-cause mortality following severe hypoglycemia in the preceding 3 months,” he said. “The same pattern is present for cardiovascular mortality and, somewhat, for cardiovascular events, although not statistically significant. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes was seen in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] population as well.”
A subset of patients in the VADT study showed that individuals in the standard therapy group who had a prior serious hypoglycemic episode actually had greater coronary calcium progression during the study, compared with the intensively treated group (P = .02; Diabetes Care 2016;39[3]:448-54). “One possibility is that serious hypoglycemia contributed to the development of atherosclerosis in this group,” Dr. Reaven said. “This held true when one examined high and lower glucose levels on average in the study. Those individuals that had A1c levels of 7.5% or above were the ones that appeared to show coronary calcium progression during the study following episodes of severe hypoglycemia, whereas it did not appear to be an issue among those with good glucose control. Another finding was that severe hypoglycemia is associated with increased glucose variability from office visit to office visit.”
He concluded his remarks by noting that being “glucose centric” is not the right approach to treating patients with diabetes. “Other risk factors may offer bigger and more rapid benefits,” he said. “The benefits of glucose lowering are likely most relevant in type 1 diabetes and in early type 2 diabetes, and the benefits of glucose lowering on vascular disease appear to take a long time. Avoid severe hypoglycemia, especially in older patients with type 2 diabetes. This last point may be particularly relevant for those in poor control.”
Dr. Reaven reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2017
LOS ANGELES – If you think the link between glucose control and cardiovascular disease is complicated, you’re not alone.
“Glucose is not the only risk factor for CVD, and it may not be the most important risk factor,” Peter Reaven, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Controlling blood pressure and lipids is also quite important. In current studies, patients with diabetes are aggressively treated for other risk factors with many vascular-acting medications, so it’s difficult to show the benefits of glucose lowering on its own. That is pertinent because it’s becoming clear that the benefits of glucose lowering may take a long time. How, and in whom, one controls glucose may influence the outcome.
Medications, hypoglycemia, glucose variation, and extent of disease all may influence vascular responses to glucose lowering.”
Dr. Reaven, an endocrinologist who directs the Diabetes Research Program at the University of Arizona and VA Health Care System, Phoenix, noted that, while a consistent body of evidence supports an association between higher levels of glucose and increased risk for CVD, it’s not as clear that tight control efforts decrease a patient’s risk for CVD at the microvascular and macrovascular level. “We also appreciate that complications from intensive glucose lowering – such as hypoglycemia, weight gain, time and cost, and increased mortality – are not minimal,” he said.
A meta-analysis of 27,049 patients with type 2 diabetes enrolled in four major trials found that those who were allocated to more-intensive, compared with less-intensive, glucose control had a reduced risk of major cardiovascular events by 9% (hazard ratio, 0.91), primarily because of a 15% reduced risk of myocardial infarction (Diabetologia 2009;52[11] 2288-98). “None of these studies actually achieved statistical significance, but they all showed a modest trend,” said Dr. Reaven, who was not involved in the meta-analysis. At the same time, interim data from the Veterans Affairs Diabetes Trial follow-up study (VADT-F) showed that, after about 10 years, the median HbA1c levels were similar between patients who had received either intensive or standard glucose for a median of 5.6 years in the initial VADT trial (N Engl J Med. 2009;360[2]:129-39). Other risk factors between the two groups were similar, including LDL and systolic and diastolic blood pressures.
In this extended follow-up of the VADT, a 17% reduction in CVD was observed among patients who were treated more intensively, compared with those on standard therapy, after about 12 years of treatment (P = .04; N Engl J Med. 2015;372:2197-206). “Why does it take so long?” he asked. “Why does it take 10-plus years of mean follow-up with an HbA1c separation of 1.5% to start to lead to cardiovascular events? The reality is, we don’t know the answer.”
It’s possible that many years of hyperglycemia created enough vascular injury and long-term consequences that are not easily turned around in short intervals, but Dr. Reaven noted that advanced glycation and oxidation products might also be contributing to long-term vascular legacy events. In an analysis of patients from the VADT-F, he and his associates found that specific advanced glycation end products and oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing type 2 diabetes mellitus (Diabetes Care 2017;40[4]:591-8). In particular, the combination of 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone and 2-aminoadipic acid was strongly associated with all measures of subclinical atherosclerosis.
In the initial VADT trial, severe hypoglycemia occurred nearly three times more commonly in the intensively treated group, compared with the standard therapy group. Severe hypoglycemia was defined as an episode of low blood glucose that was accompanied by confusion requiring assistance from another person or loss of consciousness. In related analyses, the hazard ratio for CV events, CV mortality, and overall mortality with severe hypoglycemia within the preceding 3 months was also increased. “So this is a consistent finding across multiple studies of the danger of severe hypoglycemia occurring during your efforts to improve glucose lowering,” Dr. Reaven said. “Interestingly, it appears that the risk for CVD events following severe hypoglycemia increases with higher baseline CV risk, based on the United Kingdom Prospective Diabetes Study 10-year CV risk score. So, how great your risk is begins to influence how well you do after severe hypoglycemia.”
In a separate stratified analysis of VADT data, the risk for CVD after severe hypoglycemia was more prominent in the standard treatment group, compared with the intensive treatment group. “There’s nearly a sevenfold increased risk for all-cause mortality following severe hypoglycemia in the preceding 3 months,” he said. “The same pattern is present for cardiovascular mortality and, somewhat, for cardiovascular events, although not statistically significant. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes was seen in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] population as well.”
A subset of patients in the VADT study showed that individuals in the standard therapy group who had a prior serious hypoglycemic episode actually had greater coronary calcium progression during the study, compared with the intensively treated group (P = .02; Diabetes Care 2016;39[3]:448-54). “One possibility is that serious hypoglycemia contributed to the development of atherosclerosis in this group,” Dr. Reaven said. “This held true when one examined high and lower glucose levels on average in the study. Those individuals that had A1c levels of 7.5% or above were the ones that appeared to show coronary calcium progression during the study following episodes of severe hypoglycemia, whereas it did not appear to be an issue among those with good glucose control. Another finding was that severe hypoglycemia is associated with increased glucose variability from office visit to office visit.”
He concluded his remarks by noting that being “glucose centric” is not the right approach to treating patients with diabetes. “Other risk factors may offer bigger and more rapid benefits,” he said. “The benefits of glucose lowering are likely most relevant in type 1 diabetes and in early type 2 diabetes, and the benefits of glucose lowering on vascular disease appear to take a long time. Avoid severe hypoglycemia, especially in older patients with type 2 diabetes. This last point may be particularly relevant for those in poor control.”
Dr. Reaven reported having no relevant financial disclosures.
Intraoperative Use of External Fixator Attachments for Reduction of Lower Extremity Fractures and Dislocations
Take-Home Points
- External fixator attachments are fast and easy to assemble with existing external fixator equipment.
- They allow for multi-directional force application and use of extrinsic power grip.
- They limit radiation exposure and provides unobstructred line of sight to zone of injury.
- The attachments can then be removed once reduction is achieved.
External fixation has a long history both for initial open or closed management of fractures and for definitive management.1 After the introduction of internal fixation constructs using nails or plates, external fixation largely transitioned from a means of definitive management to a temporizing measure taken before definitive internal fixation.
The Delta Frame external fixator (DePuy Synthes), which is used for significantly swollen ankle and pilon fractures, features anteromedially placed tibial shaft pins and a transcalcaneal pin. For distal tibia fractures that are not amenable to urgent internal fixation because of the degree of swelling or soft-tissue injury, it provides ligamentotaxis and traction for reduction of fracture fragments and stabilization.2
Numerous other external fixator configurations, such as knee-spanning or tibia-spanning external fixators, can be used for similar purposes. These stabilization methods are all minimally invasive and thus cause little trauma to the zone of injury3 and give soft-tissue injuries time to heal before definitive internal fixation.
Several different external fixator configurations can be used for a variety of fracture patterns and locations, but we propose using the external fixator as a starting point and adding proximal and distal attachments. These attachments have the potential to create more reduction force, and they provide more control of proximal and distal fracture fragments, continue to be minimally invasive, offer extrinsic grip power, are easily assembled and disassembled for intraoperative fracture reduction, and reduce the surgeon’s radiation exposure.
Materials and Methods
Our institution employs an external fixator system that is often used for high-energy lower extremity pathology. This system facilitates assembly of a Sweet T–Cherry II configuration. For periarticular ankle injuries, a Delta Frame external fixator is applied as described in the AO (Arbeitsgemeinschaft für Osteosynthesefragen) surgical reference. Two diaphyseal Schanz pins are inserted into the tibia anterior to posterior based on the pin-placement guide and confirmed with fluoroscopy. These pins must be positioned close enough to the fracture site to provide stability, but not so close as to enter the zone of injury. A Denham pin is placed in the calcaneus medial to lateral. Care is taken to avoid the posterior tibial neurovascular bundle. Then, with use of pin-carbon fiber rod connectors, rods are attached so the Schanz pins connect with the Denham pin. In Sweet T–Cherry II assembly, a different rod configuration is used; rods are attached to the proximal-most Schanz pin and the Denham pin. In Sweet T assembly, a rod-rod connector is used to attach 2 carbon fiber rods to each other. 
Next, in Cherry II assembly, 2 carbon fiber rods are attached to and locked to the Denham pin, one medial and the other lateral in an orientation orthogonal to the Denham pin extending distally. The Cherry II apparatus is completed with a third rod and is placed parallel to the Denham pin and orthogonal to the first 2 rods. 
For knee-spanning external fixators, 2 Sweet T assemblies can be attached to the 2 Schanz pins. Furthermore, if 2 transverse pins are used for tibial external fixation, 2 Cherry II attachments can be used for multidirectional traction. An added benefit is extrinsic grip power, vs the intrinsic grip power provided with use of only the Schanz and Denham pins.
Results
The fully assembled apparatus provides a firm, well-fixed configuration for applying traction in multiple directions. Axial traction can be applied, as can anterior or posterior translation forces, which may be helpful in fracture reduction and joint dislocation. For difficult-to-reduce fractures or dislocations, the surgeon can apply multidirectional traction distally while the assistant applies countertraction proximally. Fracture reduction is confirmed with fluoroscopy, and the external fixator is locked in position to maintain reduction. After reduction is confirmed, Sweet T and Cherry II are easily removed. The end result is a reduced fracture or dislocation that has the typical appearance of the temporizing external fixator.
Discussion
The Sweet T–Cherry II configuration is assembled quickly and can aid the orthopedic surgeon and assistant in managing trauma cases involving difficult-to-reduce fractures. The principle is the same as in any other traction-countertraction model, though the materials required for assembly are already available to the surgeon, and additional equipment is not required. Furthermore, the large size of the attachments has the potential to offer more points of manipulation by the surgeon and assistant, when compared with Schanz and Denham pins alone. The configuration allows full extrinsic grip power as well (Figure 4), whereas only intrinsic hand power is allowed with traction applied through Schanz and Denham pins alone. 
These attachments also have the potential to reduce surgeon and assistant radiation exposure. By positioning Sweet T and Cherry II proximally and distally, with the fluoroscopy machine over the zone of injury, the operators of the attachments increase their distance from the source of radiation. This strategic positioning decreases radiation exposure and reduces direct and scatter energy from the fluoroscopy machine and the patient.4 In addition, with the operators of the attachments farther from the zone of injury, the surgeon has a clear and direct view of the procedure, which may otherwise be obstructed with use of tensioning devices or conventional external fixator configurations. Sweet T and Cherry II attachments theoretically could be used for any configuration that uses proximal and distal fixation points. There is also the added benefit that these attachments are not restricted to applying traction axially but can also translate fracture fragments anteriorly, posteriorly, medially, or laterally, which has the potential to aid in reducing fractures and dislocations with varying degrees of translation, not only shortening. Although these attachments have mechanical counterparts, such as femoral distractors and other tensioning devices, the counterparts may take longer to assemble, apply, and activate. Sweet T and Cherry II attachments are included in the external fixator equipment and may generate more force and control while achieving reduction and stabilization similar to those achieved with other traction or tensioning devices. In addition, other tensioning devices may be cumbersome and unwieldy relative to Sweet T and Cherry II. For these attachments, research is needed on forces generated, time of assembly, and ease of use.
Conclusion
The Sweet T and Cherry II external fixator attachments have the potential to aid in managing difficult-to-reduce complex fractures and dislocations. These attachments are quickly assembled and may generate more force than does reduction with Schanz and Denham pins alone. The shape of these attachments may also provide a more comfortable and easier-to-manipulate base for application of traction in multiple directions. An added benefit is extrinsic grip power. Use of these attachments also has the potential to reduce operator radiation exposure and may provide an unobstructed view of the operative field, as the attachment operators are farther from the zone of injury. In addition, the materials used to assemble these attachments are included in almost all external fixation sets. More research comparing standard external fixator configurations with external fixator configurations using Sweet T and Cherry II attachments is needed.
1. Tejwani N, Polonet D, Wolinsky PR. External fixation of tibial fractures. J Am Acad Orthop Surg. 2015;23(2):126-130.
2. Patterson MJ, Cole JD. Two-staged delayed open reduction and internal fixation of severe pilon fractures. J Orthop Trauma. 1999;13(2):85-91.
3. Bible JE, Mir HR. External fixation: principles and applications. J Am Acad Orthop Surg. 2015;23(11):683-690.
4. Giordano BD, Ryder S, Baumhauer JF, DiGiovanni BF. Exposure to direct and scatter radiation with use of mini-c-arm fluoroscopy. J Bone Joint Surg Am. 2007;89(5):948-952.
Take-Home Points
- External fixator attachments are fast and easy to assemble with existing external fixator equipment.
- They allow for multi-directional force application and use of extrinsic power grip.
- They limit radiation exposure and provides unobstructred line of sight to zone of injury.
- The attachments can then be removed once reduction is achieved.
External fixation has a long history both for initial open or closed management of fractures and for definitive management.1 After the introduction of internal fixation constructs using nails or plates, external fixation largely transitioned from a means of definitive management to a temporizing measure taken before definitive internal fixation.
The Delta Frame external fixator (DePuy Synthes), which is used for significantly swollen ankle and pilon fractures, features anteromedially placed tibial shaft pins and a transcalcaneal pin. For distal tibia fractures that are not amenable to urgent internal fixation because of the degree of swelling or soft-tissue injury, it provides ligamentotaxis and traction for reduction of fracture fragments and stabilization.2
Numerous other external fixator configurations, such as knee-spanning or tibia-spanning external fixators, can be used for similar purposes. These stabilization methods are all minimally invasive and thus cause little trauma to the zone of injury3 and give soft-tissue injuries time to heal before definitive internal fixation.
Several different external fixator configurations can be used for a variety of fracture patterns and locations, but we propose using the external fixator as a starting point and adding proximal and distal attachments. These attachments have the potential to create more reduction force, and they provide more control of proximal and distal fracture fragments, continue to be minimally invasive, offer extrinsic grip power, are easily assembled and disassembled for intraoperative fracture reduction, and reduce the surgeon’s radiation exposure.
Materials and Methods
Our institution employs an external fixator system that is often used for high-energy lower extremity pathology. This system facilitates assembly of a Sweet T–Cherry II configuration. For periarticular ankle injuries, a Delta Frame external fixator is applied as described in the AO (Arbeitsgemeinschaft für Osteosynthesefragen) surgical reference. Two diaphyseal Schanz pins are inserted into the tibia anterior to posterior based on the pin-placement guide and confirmed with fluoroscopy. These pins must be positioned close enough to the fracture site to provide stability, but not so close as to enter the zone of injury. A Denham pin is placed in the calcaneus medial to lateral. Care is taken to avoid the posterior tibial neurovascular bundle. Then, with use of pin-carbon fiber rod connectors, rods are attached so the Schanz pins connect with the Denham pin. In Sweet T–Cherry II assembly, a different rod configuration is used; rods are attached to the proximal-most Schanz pin and the Denham pin. In Sweet T assembly, a rod-rod connector is used to attach 2 carbon fiber rods to each other.
Next, in Cherry II assembly, 2 carbon fiber rods are attached to and locked to the Denham pin, one medial and the other lateral in an orientation orthogonal to the Denham pin extending distally. The Cherry II apparatus is completed with a third rod and is placed parallel to the Denham pin and orthogonal to the first 2 rods.
For knee-spanning external fixators, 2 Sweet T assemblies can be attached to the 2 Schanz pins. Furthermore, if 2 transverse pins are used for tibial external fixation, 2 Cherry II attachments can be used for multidirectional traction. An added benefit is extrinsic grip power, vs the intrinsic grip power provided with use of only the Schanz and Denham pins.
Results
The fully assembled apparatus provides a firm, well-fixed configuration for applying traction in multiple directions. Axial traction can be applied, as can anterior or posterior translation forces, which may be helpful in fracture reduction and joint dislocation. For difficult-to-reduce fractures or dislocations, the surgeon can apply multidirectional traction distally while the assistant applies countertraction proximally. Fracture reduction is confirmed with fluoroscopy, and the external fixator is locked in position to maintain reduction. After reduction is confirmed, Sweet T and Cherry II are easily removed. The end result is a reduced fracture or dislocation that has the typical appearance of the temporizing external fixator.
Discussion
The Sweet T–Cherry II configuration is assembled quickly and can aid the orthopedic surgeon and assistant in managing trauma cases involving difficult-to-reduce fractures. The principle is the same as in any other traction-countertraction model, though the materials required for assembly are already available to the surgeon, and additional equipment is not required. Furthermore, the large size of the attachments has the potential to offer more points of manipulation by the surgeon and assistant, when compared with Schanz and Denham pins alone. The configuration allows full extrinsic grip power as well (Figure 4), whereas only intrinsic hand power is allowed with traction applied through Schanz and Denham pins alone.
These attachments also have the potential to reduce surgeon and assistant radiation exposure. By positioning Sweet T and Cherry II proximally and distally, with the fluoroscopy machine over the zone of injury, the operators of the attachments increase their distance from the source of radiation. This strategic positioning decreases radiation exposure and reduces direct and scatter energy from the fluoroscopy machine and the patient.4 In addition, with the operators of the attachments farther from the zone of injury, the surgeon has a clear and direct view of the procedure, which may otherwise be obstructed with use of tensioning devices or conventional external fixator configurations. Sweet T and Cherry II attachments theoretically could be used for any configuration that uses proximal and distal fixation points. There is also the added benefit that these attachments are not restricted to applying traction axially but can also translate fracture fragments anteriorly, posteriorly, medially, or laterally, which has the potential to aid in reducing fractures and dislocations with varying degrees of translation, not only shortening. Although these attachments have mechanical counterparts, such as femoral distractors and other tensioning devices, the counterparts may take longer to assemble, apply, and activate. Sweet T and Cherry II attachments are included in the external fixator equipment and may generate more force and control while achieving reduction and stabilization similar to those achieved with other traction or tensioning devices. In addition, other tensioning devices may be cumbersome and unwieldy relative to Sweet T and Cherry II. For these attachments, research is needed on forces generated, time of assembly, and ease of use.
Conclusion
The Sweet T and Cherry II external fixator attachments have the potential to aid in managing difficult-to-reduce complex fractures and dislocations. These attachments are quickly assembled and may generate more force than does reduction with Schanz and Denham pins alone. The shape of these attachments may also provide a more comfortable and easier-to-manipulate base for application of traction in multiple directions. An added benefit is extrinsic grip power. Use of these attachments also has the potential to reduce operator radiation exposure and may provide an unobstructed view of the operative field, as the attachment operators are farther from the zone of injury. In addition, the materials used to assemble these attachments are included in almost all external fixation sets. More research comparing standard external fixator configurations with external fixator configurations using Sweet T and Cherry II attachments is needed.
Take-Home Points
- External fixator attachments are fast and easy to assemble with existing external fixator equipment.
- They allow for multi-directional force application and use of extrinsic power grip.
- They limit radiation exposure and provides unobstructred line of sight to zone of injury.
- The attachments can then be removed once reduction is achieved.
External fixation has a long history both for initial open or closed management of fractures and for definitive management.1 After the introduction of internal fixation constructs using nails or plates, external fixation largely transitioned from a means of definitive management to a temporizing measure taken before definitive internal fixation.
The Delta Frame external fixator (DePuy Synthes), which is used for significantly swollen ankle and pilon fractures, features anteromedially placed tibial shaft pins and a transcalcaneal pin. For distal tibia fractures that are not amenable to urgent internal fixation because of the degree of swelling or soft-tissue injury, it provides ligamentotaxis and traction for reduction of fracture fragments and stabilization.2
Numerous other external fixator configurations, such as knee-spanning or tibia-spanning external fixators, can be used for similar purposes. These stabilization methods are all minimally invasive and thus cause little trauma to the zone of injury3 and give soft-tissue injuries time to heal before definitive internal fixation.
Several different external fixator configurations can be used for a variety of fracture patterns and locations, but we propose using the external fixator as a starting point and adding proximal and distal attachments. These attachments have the potential to create more reduction force, and they provide more control of proximal and distal fracture fragments, continue to be minimally invasive, offer extrinsic grip power, are easily assembled and disassembled for intraoperative fracture reduction, and reduce the surgeon’s radiation exposure.
Materials and Methods
Our institution employs an external fixator system that is often used for high-energy lower extremity pathology. This system facilitates assembly of a Sweet T–Cherry II configuration. For periarticular ankle injuries, a Delta Frame external fixator is applied as described in the AO (Arbeitsgemeinschaft für Osteosynthesefragen) surgical reference. Two diaphyseal Schanz pins are inserted into the tibia anterior to posterior based on the pin-placement guide and confirmed with fluoroscopy. These pins must be positioned close enough to the fracture site to provide stability, but not so close as to enter the zone of injury. A Denham pin is placed in the calcaneus medial to lateral. Care is taken to avoid the posterior tibial neurovascular bundle. Then, with use of pin-carbon fiber rod connectors, rods are attached so the Schanz pins connect with the Denham pin. In Sweet T–Cherry II assembly, a different rod configuration is used; rods are attached to the proximal-most Schanz pin and the Denham pin. In Sweet T assembly, a rod-rod connector is used to attach 2 carbon fiber rods to each other.
Next, in Cherry II assembly, 2 carbon fiber rods are attached to and locked to the Denham pin, one medial and the other lateral in an orientation orthogonal to the Denham pin extending distally. The Cherry II apparatus is completed with a third rod and is placed parallel to the Denham pin and orthogonal to the first 2 rods.
For knee-spanning external fixators, 2 Sweet T assemblies can be attached to the 2 Schanz pins. Furthermore, if 2 transverse pins are used for tibial external fixation, 2 Cherry II attachments can be used for multidirectional traction. An added benefit is extrinsic grip power, vs the intrinsic grip power provided with use of only the Schanz and Denham pins.
Results
The fully assembled apparatus provides a firm, well-fixed configuration for applying traction in multiple directions. Axial traction can be applied, as can anterior or posterior translation forces, which may be helpful in fracture reduction and joint dislocation. For difficult-to-reduce fractures or dislocations, the surgeon can apply multidirectional traction distally while the assistant applies countertraction proximally. Fracture reduction is confirmed with fluoroscopy, and the external fixator is locked in position to maintain reduction. After reduction is confirmed, Sweet T and Cherry II are easily removed. The end result is a reduced fracture or dislocation that has the typical appearance of the temporizing external fixator.
Discussion
The Sweet T–Cherry II configuration is assembled quickly and can aid the orthopedic surgeon and assistant in managing trauma cases involving difficult-to-reduce fractures. The principle is the same as in any other traction-countertraction model, though the materials required for assembly are already available to the surgeon, and additional equipment is not required. Furthermore, the large size of the attachments has the potential to offer more points of manipulation by the surgeon and assistant, when compared with Schanz and Denham pins alone. The configuration allows full extrinsic grip power as well (Figure 4), whereas only intrinsic hand power is allowed with traction applied through Schanz and Denham pins alone.
These attachments also have the potential to reduce surgeon and assistant radiation exposure. By positioning Sweet T and Cherry II proximally and distally, with the fluoroscopy machine over the zone of injury, the operators of the attachments increase their distance from the source of radiation. This strategic positioning decreases radiation exposure and reduces direct and scatter energy from the fluoroscopy machine and the patient.4 In addition, with the operators of the attachments farther from the zone of injury, the surgeon has a clear and direct view of the procedure, which may otherwise be obstructed with use of tensioning devices or conventional external fixator configurations. Sweet T and Cherry II attachments theoretically could be used for any configuration that uses proximal and distal fixation points. There is also the added benefit that these attachments are not restricted to applying traction axially but can also translate fracture fragments anteriorly, posteriorly, medially, or laterally, which has the potential to aid in reducing fractures and dislocations with varying degrees of translation, not only shortening. Although these attachments have mechanical counterparts, such as femoral distractors and other tensioning devices, the counterparts may take longer to assemble, apply, and activate. Sweet T and Cherry II attachments are included in the external fixator equipment and may generate more force and control while achieving reduction and stabilization similar to those achieved with other traction or tensioning devices. In addition, other tensioning devices may be cumbersome and unwieldy relative to Sweet T and Cherry II. For these attachments, research is needed on forces generated, time of assembly, and ease of use.
Conclusion
The Sweet T and Cherry II external fixator attachments have the potential to aid in managing difficult-to-reduce complex fractures and dislocations. These attachments are quickly assembled and may generate more force than does reduction with Schanz and Denham pins alone. The shape of these attachments may also provide a more comfortable and easier-to-manipulate base for application of traction in multiple directions. An added benefit is extrinsic grip power. Use of these attachments also has the potential to reduce operator radiation exposure and may provide an unobstructed view of the operative field, as the attachment operators are farther from the zone of injury. In addition, the materials used to assemble these attachments are included in almost all external fixation sets. More research comparing standard external fixator configurations with external fixator configurations using Sweet T and Cherry II attachments is needed.
1. Tejwani N, Polonet D, Wolinsky PR. External fixation of tibial fractures. J Am Acad Orthop Surg. 2015;23(2):126-130.
2. Patterson MJ, Cole JD. Two-staged delayed open reduction and internal fixation of severe pilon fractures. J Orthop Trauma. 1999;13(2):85-91.
3. Bible JE, Mir HR. External fixation: principles and applications. J Am Acad Orthop Surg. 2015;23(11):683-690.
4. Giordano BD, Ryder S, Baumhauer JF, DiGiovanni BF. Exposure to direct and scatter radiation with use of mini-c-arm fluoroscopy. J Bone Joint Surg Am. 2007;89(5):948-952.
1. Tejwani N, Polonet D, Wolinsky PR. External fixation of tibial fractures. J Am Acad Orthop Surg. 2015;23(2):126-130.
2. Patterson MJ, Cole JD. Two-staged delayed open reduction and internal fixation of severe pilon fractures. J Orthop Trauma. 1999;13(2):85-91.
3. Bible JE, Mir HR. External fixation: principles and applications. J Am Acad Orthop Surg. 2015;23(11):683-690.
4. Giordano BD, Ryder S, Baumhauer JF, DiGiovanni BF. Exposure to direct and scatter radiation with use of mini-c-arm fluoroscopy. J Bone Joint Surg Am. 2007;89(5):948-952.
FDA approves cabozantinib for the frontline treatment of advanced RCC
The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).
The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.
The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.
Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.
Cabozantinib is marketed as Cabometyx by Exelixis.
The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).
The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.
The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.
Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.
Cabozantinib is marketed as Cabometyx by Exelixis.
The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).
The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.
The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.
Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.
Cabozantinib is marketed as Cabometyx by Exelixis.
Path CR signals good outcomes in treated high-risk breast cancers
REPORTING FROM SABCS 2017
SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.
Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.
He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.
I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.
As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10, and 0.14, P less than .001 for each).
However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.
The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”
I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.
SOURCE: Yee, D et al. SABCS Abstract GS3-08.
REPORTING FROM SABCS 2017
SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.
Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.
He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.
I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.
As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10, and 0.14, P less than .001 for each).
However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.
The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”
I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.
SOURCE: Yee, D et al. SABCS Abstract GS3-08.
REPORTING FROM SABCS 2017
SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.
Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.
He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.
I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.
As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10, and 0.14, P less than .001 for each).
However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.
The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”
I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.
SOURCE: Yee, D et al. SABCS Abstract GS3-08.
Stereotactic Laser Ablation May Improve Cognitive Outcomes
MRI-guided stereotactic laser ablation (MRI-SLA) seems to offer advantages over more traditional open resection in patients requiring epileptic surgery, according to a recent review of the evidence.
- MRI-SLA has been found to improve several types of cognitive outcomes when compared to open surgery.
- Daniel Drane, MD, from Emory University points out that stereotactic laser ablation reduces collateral neurological damage.
- Stereotatic laser amygdalohippocampotomy may result in better neurological functioning in areas that include category related naming, verbal fluency, and object/familiar person recognition, when compared to traditional resection.
- The evidence suggests that using a neurosurgical technique like MRI-SLE offers advantages in patients undergoing epilepsy surgery by limiting the size of the surgical lesion zone.
Drane DL. MRI-Guided stereotactic laser ablation for epilepsy surgery: Promising preliminary results for cognitive outcome. [Published online ahead of print Sept 23, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.016
MRI-guided stereotactic laser ablation (MRI-SLA) seems to offer advantages over more traditional open resection in patients requiring epileptic surgery, according to a recent review of the evidence.
- MRI-SLA has been found to improve several types of cognitive outcomes when compared to open surgery.
- Daniel Drane, MD, from Emory University points out that stereotactic laser ablation reduces collateral neurological damage.
- Stereotatic laser amygdalohippocampotomy may result in better neurological functioning in areas that include category related naming, verbal fluency, and object/familiar person recognition, when compared to traditional resection.
- The evidence suggests that using a neurosurgical technique like MRI-SLE offers advantages in patients undergoing epilepsy surgery by limiting the size of the surgical lesion zone.
Drane DL. MRI-Guided stereotactic laser ablation for epilepsy surgery: Promising preliminary results for cognitive outcome. [Published online ahead of print Sept 23, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.016
MRI-guided stereotactic laser ablation (MRI-SLA) seems to offer advantages over more traditional open resection in patients requiring epileptic surgery, according to a recent review of the evidence.
- MRI-SLA has been found to improve several types of cognitive outcomes when compared to open surgery.
- Daniel Drane, MD, from Emory University points out that stereotactic laser ablation reduces collateral neurological damage.
- Stereotatic laser amygdalohippocampotomy may result in better neurological functioning in areas that include category related naming, verbal fluency, and object/familiar person recognition, when compared to traditional resection.
- The evidence suggests that using a neurosurgical technique like MRI-SLE offers advantages in patients undergoing epilepsy surgery by limiting the size of the surgical lesion zone.
Drane DL. MRI-Guided stereotactic laser ablation for epilepsy surgery: Promising preliminary results for cognitive outcome. [Published online ahead of print Sept 23, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.016