LOS ANGELES – On the male fertility front, obesity seems to hurt semen quality. So does weight-loss surgery reverse the trend? A new review of existing research suggests that there may be an effect, but the findings aren’t conclusive.

“We found something,” said Sikarin Upala, MD, a second-year endocrinology fellow at the University of Chicago, who pointed out that three of the four reports he and his colleagues reviewed suggested improvement in semen motility. “But we still need to study more about whether bariatric surgery will affect infertility,” he continued.

Dr. Upala, who led the systematic review and meta-analysis of research into bariatric surgery and semen quality, spoke in an interview after his presentation at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Researchers have linked obesity to infertility in men, but it’s not entirely clear how excess weight and sperm deficiencies are connected. As researchers explained in a 2018 report, “conflicting results have been observed in studies evaluating the correlation between [body mass index] and sperm parameters, such as sperm concentration and total sperm count.” However, they noted that it is “generally accepted” that men with obesity seem to be at higher risk of having a low sperm count or having azoospermia, which is the total lack of sperm in semen.

It’s also not clear whether weight loss directly improves male fertility. “We do know that androgen levels improve after weight-loss surgery, and that might be one factor among several that may contribute to improved male fertility,” Edward Lin, DO, MBA, FACS, professor of surgery and chief of gastrointestinal and general surgery at Emory University, Atlanta, said in an interview.

In their review, Dr. Upala and his colleagues analyzed four studies published between 2012 and 2018 that evaluated the effect of bariatric surgery on semen quality. All of the studies examined semen volume and sperm morphology and motility, and three examined sperm concentration.

A meta-analysis found that motility and volume improved after surgery; however, some of the studies (two for volume, one for motility) failed to show a statistically significant change.

There was no statistically significant difference in sperm morphology or concentration overall, although one study showed a statistically significant improvement in both categories.

Overall, “there might be a little bit of positive effect, but we couldn’t reach a good conclusion because there were too few studies,” Dr. Upala said.

Dr. Lin, director of the Emory Bariatrics Center, agreed that the review findings are limited. He said that although the findings hint at a positive effect on semen quality, “the jury is still out” when it comes to a link between bariatric surgery and male infertility.

“Multiple factors contribute to semen quality,” he added, pointing to vitamin deficiencies, micronutrient levels in the body, enzyme signaling pathways, and sperm chromatin integrity. “In fact, surgically or diet-induced weight loss may be associated with permissive malnutrition, which further exacerbates these deficiencies. Deficiencies in these areas can sometimes take months, if not years, to correct by taking vitamin D or copper or zinc, for example.”

Dr. Lin referred to a small study in which reporters observed semen abnormalities and subfertility after weight-loss surgery despite improvements in androgenic and quality of life levels.

Dr. Upala reported having no relevant disclosures.

LOS ANGELES – On the male fertility front, obesity seems to hurt semen quality. So does weight-loss surgery reverse the trend? A new review of existing research suggests that there may be an effect, but the findings aren’t conclusive.

“We found something,” said Sikarin Upala, MD, a second-year endocrinology fellow at the University of Chicago, who pointed out that three of the four reports he and his colleagues reviewed suggested improvement in semen motility. “But we still need to study more about whether bariatric surgery will affect infertility,” he continued.

Dr. Upala, who led the systematic review and meta-analysis of research into bariatric surgery and semen quality, spoke in an interview after his presentation at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Researchers have linked obesity to infertility in men, but it’s not entirely clear how excess weight and sperm deficiencies are connected. As researchers explained in a 2018 report, “conflicting results have been observed in studies evaluating the correlation between [body mass index] and sperm parameters, such as sperm concentration and total sperm count.” However, they noted that it is “generally accepted” that men with obesity seem to be at higher risk of having a low sperm count or having azoospermia, which is the total lack of sperm in semen.

It’s also not clear whether weight loss directly improves male fertility. “We do know that androgen levels improve after weight-loss surgery, and that might be one factor among several that may contribute to improved male fertility,” Edward Lin, DO, MBA, FACS, professor of surgery and chief of gastrointestinal and general surgery at Emory University, Atlanta, said in an interview.

In their review, Dr. Upala and his colleagues analyzed four studies published between 2012 and 2018 that evaluated the effect of bariatric surgery on semen quality. All of the studies examined semen volume and sperm morphology and motility, and three examined sperm concentration.

A meta-analysis found that motility and volume improved after surgery; however, some of the studies (two for volume, one for motility) failed to show a statistically significant change.

There was no statistically significant difference in sperm morphology or concentration overall, although one study showed a statistically significant improvement in both categories.

Overall, “there might be a little bit of positive effect, but we couldn’t reach a good conclusion because there were too few studies,” Dr. Upala said.

Dr. Lin, director of the Emory Bariatrics Center, agreed that the review findings are limited. He said that although the findings hint at a positive effect on semen quality, “the jury is still out” when it comes to a link between bariatric surgery and male infertility.

“Multiple factors contribute to semen quality,” he added, pointing to vitamin deficiencies, micronutrient levels in the body, enzyme signaling pathways, and sperm chromatin integrity. “In fact, surgically or diet-induced weight loss may be associated with permissive malnutrition, which further exacerbates these deficiencies. Deficiencies in these areas can sometimes take months, if not years, to correct by taking vitamin D or copper or zinc, for example.”

Dr. Lin referred to a small study in which reporters observed semen abnormalities and subfertility after weight-loss surgery despite improvements in androgenic and quality of life levels.

Dr. Upala reported having no relevant disclosures.

LOS ANGELES – On the male fertility front, obesity seems to hurt semen quality. So does weight-loss surgery reverse the trend? A new review of existing research suggests that there may be an effect, but the findings aren’t conclusive.

“We found something,” said Sikarin Upala, MD, a second-year endocrinology fellow at the University of Chicago, who pointed out that three of the four reports he and his colleagues reviewed suggested improvement in semen motility. “But we still need to study more about whether bariatric surgery will affect infertility,” he continued.

Dr. Upala, who led the systematic review and meta-analysis of research into bariatric surgery and semen quality, spoke in an interview after his presentation at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists.

Researchers have linked obesity to infertility in men, but it’s not entirely clear how excess weight and sperm deficiencies are connected. As researchers explained in a 2018 report, “conflicting results have been observed in studies evaluating the correlation between [body mass index] and sperm parameters, such as sperm concentration and total sperm count.” However, they noted that it is “generally accepted” that men with obesity seem to be at higher risk of having a low sperm count or having azoospermia, which is the total lack of sperm in semen.

It’s also not clear whether weight loss directly improves male fertility. “We do know that androgen levels improve after weight-loss surgery, and that might be one factor among several that may contribute to improved male fertility,” Edward Lin, DO, MBA, FACS, professor of surgery and chief of gastrointestinal and general surgery at Emory University, Atlanta, said in an interview.

In their review, Dr. Upala and his colleagues analyzed four studies published between 2012 and 2018 that evaluated the effect of bariatric surgery on semen quality. All of the studies examined semen volume and sperm morphology and motility, and three examined sperm concentration.

A meta-analysis found that motility and volume improved after surgery; however, some of the studies (two for volume, one for motility) failed to show a statistically significant change.

There was no statistically significant difference in sperm morphology or concentration overall, although one study showed a statistically significant improvement in both categories.

Overall, “there might be a little bit of positive effect, but we couldn’t reach a good conclusion because there were too few studies,” Dr. Upala said.

Dr. Lin, director of the Emory Bariatrics Center, agreed that the review findings are limited. He said that although the findings hint at a positive effect on semen quality, “the jury is still out” when it comes to a link between bariatric surgery and male infertility.

“Multiple factors contribute to semen quality,” he added, pointing to vitamin deficiencies, micronutrient levels in the body, enzyme signaling pathways, and sperm chromatin integrity. “In fact, surgically or diet-induced weight loss may be associated with permissive malnutrition, which further exacerbates these deficiencies. Deficiencies in these areas can sometimes take months, if not years, to correct by taking vitamin D or copper or zinc, for example.”

Dr. Lin referred to a small study in which reporters observed semen abnormalities and subfertility after weight-loss surgery despite improvements in androgenic and quality of life levels.

Dr. Upala reported having no relevant disclosures.

BIRMINGHAM, ENGLAND – Intradermal delivery of a tumor necrosis factor inhibitor (TNFi) could offer patients with discoid lupus erythematosus (DLE) a much-needed additional treatment option, according to results of a phase 2, “proof-of-concept” study.

Sara Freeman/MDedge News

Overall, 14 (56%) of the 25 patients in the study achieved a 20% or greater reduction in disease activity from baseline to week 12 via intradermal injection of etanercept (Enbrel), which was assessed via the modified limited Score of Activity and Damage in DLE (ML-SADDLE). About half (48%) and one-fifth (20%) also achieved greater reductions of 50% and 70%, respectively.

“Discoid lupus is a chronic form of cutaneous lupus. Usually it occurs in visible areas like the face and scalp, causing scarring, so it’s really disabling and affects patients’ quality of life,” observed the lead study investigator Md Yuzaiful Md Yusof, MBChB, PhD, NIHR Academic Clinical Lecturer at the University of Leeds, England.

“It’s also one of the most resistant manifestations of lupus,” he said during a poster presentation at the annual conference of the British Society for Rheumatology. “Usually, when people have discoid lupus, the dermatologist gives antimalarial treatment, but only 50% of people respond to these drugs. So, what happens to the rest of them?” Basically, it is trial and error, Dr. Md Yusof said; some patients may be given disease-modifying antirheumatic drugs and in some patients this may work well, but in others there may be toxicity that contraindicates treatment.

B-cell therapy with rituximab (Rituxan) has not been successful, he said. In a previous study of 35 patients with refractory discoid lupus, none of the patients responded to rituximab and half of them actually flared after taking the drug.

There is a pathologic case for using anti-TNF therapy in DLE, but the use of TNFis is not without concern. Such treatment can increase antinuclear antibody production and make lupus worse. “In order to overcome this, as the lesion is quite small, we don’t need to use a systemic approach,” Dr. Md Yusof explained in an interview. “If you give directly, it should just be confined to the lesion and not absorbed, that’s the whole idea of thinking outside the box.” He noted that if it worked, such treatment would be for inducing remission and not for maintenance.

The study, “Targeted therapy using intradermal injection of etanercept for remission induction in discoid lupus erythematosus” (TARGET-DLE) was designed to test the validity of using intradermal rather than subcutaneous TNFi therapy in patients with discoid lupus.

Dr. Md Yusof noted that only 25 patients needed to be recruited into the single-arm, prospective trial as a “Simon’s two-stage minimized design” was used (Control Clin Trials. 1989;10[1]:1-10). This involved treating the first few patients to see if a response occurred and if it did, carrying on with treating the others, but if no response occurred in at least two patients, the trial would stop completely.

Adult patients were eligible for inclusion if they had one or more active DLE lesions and had not responded to antimalarial treatment. Stable doses of DMARDs and up to 10 mg of oral prednisolone daily was permitted if already being taken prior to entering the study.

Etanercept was injected intradermally around the most symptomatic lesion once a week for up to 12 weeks. The dosage was determined based on the radius of the selected discoid lesion. Over an 18-month period, all 25 patients were recruited, including 18 women. The median age of patients was 47 years, and six had systemic lupus erythematosus. The median number of prior DMARDs was 5 but ranged from 1 to 16, indicating a very resistant patient population.

The primary endpoint was at least 6 of the 25 patients having at least a 20% reduction in ML-SADDLE at week 12; 14 (56%) patients achieved this.

“We didn’t use CLASI [Cutaneous Lupus Area and Severity Index Activity Score] because that only includes erythema and atrophy,” Dr. Md Yusof explained. “In discoid lupus, induration is quite important as well, so that’s why we used ML-SADDLE. We called it ‘modified limited’ because the original SADDLE score is based on the whole organ score, but we only calculated the one lesion that we wanted to treat.”

In addition to meeting the primary endpoint, several secondary endpoints were met, including significant improvements in scores on visual analog scales as determined by pre- and posttreatment scoring by physicians (53.1 mm vs. 23.2 mm; P less than .001) and patients (56.9 mm vs. 29.7 mm; P = .001). Mean Dermatology Life Quality Index (DLQI) score significantly improved between pre- and post treatment, as did blood perfusion under the skin based on laser Doppler imaging and infrared thermography. However, no difference was seen with optical coherence tomography.

“There were only four grade 3/4 toxicities, and importantly, none of the SLE patients got worse, and none with DLE only converted into SLE,” Dr. Md Yusof reported. Of the four grade 3/4 adverse events, two were chest infections, one was heart failure, and one was a worsening of chilblains.

“It was a full-powered phase 2 trial, and because it was positive, now we can go to phase 3 trial,” he added.

Before conducting a phase 3 trial, however, Dr. Md Yusof wants to refine how the TNFi is delivered. Perhaps an intradermal patch with microneedles could be used. This would be left on the skin for a short amount of time to allow drug delivery and then removed. It could help ensure that all patients comply with treatment and perhaps even self-administer, he noted.

“The median compliance rate was 80%, which is not too bad, but I think when we come to run a phase 3 trial, I’m looking to improve the drug delivery,” he said. Changing the delivery method will need to be validated before a phase 3 trial can be started.

The study was not commercially funded. Dr. Md Yusof had no disclosures. Pfizer provided the study drug free of charge.

SOURCE: Md Yusof MY et al. Rheumatology. 2019;58(suppl 3): Abstract 244. doi: 10.1093/rheumatology/kez107.060.

BIRMINGHAM, ENGLAND – Intradermal delivery of a tumor necrosis factor inhibitor (TNFi) could offer patients with discoid lupus erythematosus (DLE) a much-needed additional treatment option, according to results of a phase 2, “proof-of-concept” study.

Sara Freeman/MDedge News

Overall, 14 (56%) of the 25 patients in the study achieved a 20% or greater reduction in disease activity from baseline to week 12 via intradermal injection of etanercept (Enbrel), which was assessed via the modified limited Score of Activity and Damage in DLE (ML-SADDLE). About half (48%) and one-fifth (20%) also achieved greater reductions of 50% and 70%, respectively.

“Discoid lupus is a chronic form of cutaneous lupus. Usually it occurs in visible areas like the face and scalp, causing scarring, so it’s really disabling and affects patients’ quality of life,” observed the lead study investigator Md Yuzaiful Md Yusof, MBChB, PhD, NIHR Academic Clinical Lecturer at the University of Leeds, England.

“It’s also one of the most resistant manifestations of lupus,” he said during a poster presentation at the annual conference of the British Society for Rheumatology. “Usually, when people have discoid lupus, the dermatologist gives antimalarial treatment, but only 50% of people respond to these drugs. So, what happens to the rest of them?” Basically, it is trial and error, Dr. Md Yusof said; some patients may be given disease-modifying antirheumatic drugs and in some patients this may work well, but in others there may be toxicity that contraindicates treatment.

B-cell therapy with rituximab (Rituxan) has not been successful, he said. In a previous study of 35 patients with refractory discoid lupus, none of the patients responded to rituximab and half of them actually flared after taking the drug.

There is a pathologic case for using anti-TNF therapy in DLE, but the use of TNFis is not without concern. Such treatment can increase antinuclear antibody production and make lupus worse. “In order to overcome this, as the lesion is quite small, we don’t need to use a systemic approach,” Dr. Md Yusof explained in an interview. “If you give directly, it should just be confined to the lesion and not absorbed, that’s the whole idea of thinking outside the box.” He noted that if it worked, such treatment would be for inducing remission and not for maintenance.

The study, “Targeted therapy using intradermal injection of etanercept for remission induction in discoid lupus erythematosus” (TARGET-DLE) was designed to test the validity of using intradermal rather than subcutaneous TNFi therapy in patients with discoid lupus.

Dr. Md Yusof noted that only 25 patients needed to be recruited into the single-arm, prospective trial as a “Simon’s two-stage minimized design” was used (Control Clin Trials. 1989;10[1]:1-10). This involved treating the first few patients to see if a response occurred and if it did, carrying on with treating the others, but if no response occurred in at least two patients, the trial would stop completely.

Adult patients were eligible for inclusion if they had one or more active DLE lesions and had not responded to antimalarial treatment. Stable doses of DMARDs and up to 10 mg of oral prednisolone daily was permitted if already being taken prior to entering the study.

Etanercept was injected intradermally around the most symptomatic lesion once a week for up to 12 weeks. The dosage was determined based on the radius of the selected discoid lesion. Over an 18-month period, all 25 patients were recruited, including 18 women. The median age of patients was 47 years, and six had systemic lupus erythematosus. The median number of prior DMARDs was 5 but ranged from 1 to 16, indicating a very resistant patient population.

The primary endpoint was at least 6 of the 25 patients having at least a 20% reduction in ML-SADDLE at week 12; 14 (56%) patients achieved this.

“We didn’t use CLASI [Cutaneous Lupus Area and Severity Index Activity Score] because that only includes erythema and atrophy,” Dr. Md Yusof explained. “In discoid lupus, induration is quite important as well, so that’s why we used ML-SADDLE. We called it ‘modified limited’ because the original SADDLE score is based on the whole organ score, but we only calculated the one lesion that we wanted to treat.”

In addition to meeting the primary endpoint, several secondary endpoints were met, including significant improvements in scores on visual analog scales as determined by pre- and posttreatment scoring by physicians (53.1 mm vs. 23.2 mm; P less than .001) and patients (56.9 mm vs. 29.7 mm; P = .001). Mean Dermatology Life Quality Index (DLQI) score significantly improved between pre- and post treatment, as did blood perfusion under the skin based on laser Doppler imaging and infrared thermography. However, no difference was seen with optical coherence tomography.

“There were only four grade 3/4 toxicities, and importantly, none of the SLE patients got worse, and none with DLE only converted into SLE,” Dr. Md Yusof reported. Of the four grade 3/4 adverse events, two were chest infections, one was heart failure, and one was a worsening of chilblains.

“It was a full-powered phase 2 trial, and because it was positive, now we can go to phase 3 trial,” he added.

Before conducting a phase 3 trial, however, Dr. Md Yusof wants to refine how the TNFi is delivered. Perhaps an intradermal patch with microneedles could be used. This would be left on the skin for a short amount of time to allow drug delivery and then removed. It could help ensure that all patients comply with treatment and perhaps even self-administer, he noted.

“The median compliance rate was 80%, which is not too bad, but I think when we come to run a phase 3 trial, I’m looking to improve the drug delivery,” he said. Changing the delivery method will need to be validated before a phase 3 trial can be started.

The study was not commercially funded. Dr. Md Yusof had no disclosures. Pfizer provided the study drug free of charge.

SOURCE: Md Yusof MY et al. Rheumatology. 2019;58(suppl 3): Abstract 244. doi: 10.1093/rheumatology/kez107.060.

BIRMINGHAM, ENGLAND – Intradermal delivery of a tumor necrosis factor inhibitor (TNFi) could offer patients with discoid lupus erythematosus (DLE) a much-needed additional treatment option, according to results of a phase 2, “proof-of-concept” study.

Sara Freeman/MDedge News

Overall, 14 (56%) of the 25 patients in the study achieved a 20% or greater reduction in disease activity from baseline to week 12 via intradermal injection of etanercept (Enbrel), which was assessed via the modified limited Score of Activity and Damage in DLE (ML-SADDLE). About half (48%) and one-fifth (20%) also achieved greater reductions of 50% and 70%, respectively.

“Discoid lupus is a chronic form of cutaneous lupus. Usually it occurs in visible areas like the face and scalp, causing scarring, so it’s really disabling and affects patients’ quality of life,” observed the lead study investigator Md Yuzaiful Md Yusof, MBChB, PhD, NIHR Academic Clinical Lecturer at the University of Leeds, England.

“It’s also one of the most resistant manifestations of lupus,” he said during a poster presentation at the annual conference of the British Society for Rheumatology. “Usually, when people have discoid lupus, the dermatologist gives antimalarial treatment, but only 50% of people respond to these drugs. So, what happens to the rest of them?” Basically, it is trial and error, Dr. Md Yusof said; some patients may be given disease-modifying antirheumatic drugs and in some patients this may work well, but in others there may be toxicity that contraindicates treatment.

B-cell therapy with rituximab (Rituxan) has not been successful, he said. In a previous study of 35 patients with refractory discoid lupus, none of the patients responded to rituximab and half of them actually flared after taking the drug.

There is a pathologic case for using anti-TNF therapy in DLE, but the use of TNFis is not without concern. Such treatment can increase antinuclear antibody production and make lupus worse. “In order to overcome this, as the lesion is quite small, we don’t need to use a systemic approach,” Dr. Md Yusof explained in an interview. “If you give directly, it should just be confined to the lesion and not absorbed, that’s the whole idea of thinking outside the box.” He noted that if it worked, such treatment would be for inducing remission and not for maintenance.

The study, “Targeted therapy using intradermal injection of etanercept for remission induction in discoid lupus erythematosus” (TARGET-DLE) was designed to test the validity of using intradermal rather than subcutaneous TNFi therapy in patients with discoid lupus.

Dr. Md Yusof noted that only 25 patients needed to be recruited into the single-arm, prospective trial as a “Simon’s two-stage minimized design” was used (Control Clin Trials. 1989;10[1]:1-10). This involved treating the first few patients to see if a response occurred and if it did, carrying on with treating the others, but if no response occurred in at least two patients, the trial would stop completely.

Adult patients were eligible for inclusion if they had one or more active DLE lesions and had not responded to antimalarial treatment. Stable doses of DMARDs and up to 10 mg of oral prednisolone daily was permitted if already being taken prior to entering the study.

Etanercept was injected intradermally around the most symptomatic lesion once a week for up to 12 weeks. The dosage was determined based on the radius of the selected discoid lesion. Over an 18-month period, all 25 patients were recruited, including 18 women. The median age of patients was 47 years, and six had systemic lupus erythematosus. The median number of prior DMARDs was 5 but ranged from 1 to 16, indicating a very resistant patient population.

The primary endpoint was at least 6 of the 25 patients having at least a 20% reduction in ML-SADDLE at week 12; 14 (56%) patients achieved this.

“We didn’t use CLASI [Cutaneous Lupus Area and Severity Index Activity Score] because that only includes erythema and atrophy,” Dr. Md Yusof explained. “In discoid lupus, induration is quite important as well, so that’s why we used ML-SADDLE. We called it ‘modified limited’ because the original SADDLE score is based on the whole organ score, but we only calculated the one lesion that we wanted to treat.”

In addition to meeting the primary endpoint, several secondary endpoints were met, including significant improvements in scores on visual analog scales as determined by pre- and posttreatment scoring by physicians (53.1 mm vs. 23.2 mm; P less than .001) and patients (56.9 mm vs. 29.7 mm; P = .001). Mean Dermatology Life Quality Index (DLQI) score significantly improved between pre- and post treatment, as did blood perfusion under the skin based on laser Doppler imaging and infrared thermography. However, no difference was seen with optical coherence tomography.

“There were only four grade 3/4 toxicities, and importantly, none of the SLE patients got worse, and none with DLE only converted into SLE,” Dr. Md Yusof reported. Of the four grade 3/4 adverse events, two were chest infections, one was heart failure, and one was a worsening of chilblains.

“It was a full-powered phase 2 trial, and because it was positive, now we can go to phase 3 trial,” he added.

Before conducting a phase 3 trial, however, Dr. Md Yusof wants to refine how the TNFi is delivered. Perhaps an intradermal patch with microneedles could be used. This would be left on the skin for a short amount of time to allow drug delivery and then removed. It could help ensure that all patients comply with treatment and perhaps even self-administer, he noted.

“The median compliance rate was 80%, which is not too bad, but I think when we come to run a phase 3 trial, I’m looking to improve the drug delivery,” he said. Changing the delivery method will need to be validated before a phase 3 trial can be started.

The study was not commercially funded. Dr. Md Yusof had no disclosures. Pfizer provided the study drug free of charge.

SOURCE: Md Yusof MY et al. Rheumatology. 2019;58(suppl 3): Abstract 244. doi: 10.1093/rheumatology/kez107.060.

BIRMINGHAM, ENGLAND – An evidence-based approach coupled with expert consensus has been used to determine the best way to use MRI for the diagnosis of axial spondyloarthritis (axSpA).

Working under the auspices of the British Society for Spondyloarthritis (BRITSpA), a task force of nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA developed a set of seven recommendations that provide guidance on how to best to acquire and then interpret MRI images of the spine and sacroiliac joints.

The recommendations, which were published online (Rheumatology. 2019 May 2. doi: 10.1093/rheumatology/kez173), cover how to perform MRI when axSpA is suspected, such as by imaging both the sacroiliac joints and the spine, and provide guidance on the sequences and order of MRI planes to be used, and what features may increase the diagnostic confidence of axSpA.

The recommendations are as follows:

• When requesting an MRI for suspected axSpA, imaging of both the sacroiliac joints and the spine is recommended.

• T1-weighted and fat-suppressed, fluid-sensitive sequences are recommended for suspected axSpA.

• The minimum protocol when requesting an MRI for suspected axSpA should include sagittal images of the spine with extended lateral coverage and images of the sacroiliac joints that are in an oblique coronal plane to the joint.

• In the sacroiliac joints, the presence of bone marrow edema, fatty infiltration, or erosion is suggestive of the diagnosis of axSpA. The presence of more than one of these features increases the diagnostic confidence of axSpA.

• In the spine, the presence of multiple corner inflammatory lesions and/or multiple corner fatty lesions increases the diagnostic confidence of axSpA.

• In the sacroiliac joints and/or spine, the presence of characteristic new bone formation increases the diagnostic confidence of axSpA.

• The full range and combination of active and structural lesions of the sacroiliac joints and spine should be taken into account when deciding if the MRI scan is suggestive of axSpA or not.

The recommendations “are intended to standardize practice around the use of MRI,” said Alexis Jones, MBBS, MS (Rheumatology), a senior clinical research fellow at University College London Hospitals NHS Foundation Trust. She presented the recommendations on behalf of the expert task force at the annual conference of the British Society for Rheumatology.

“MRI has become an essential tool in axial spondyloarthritis. It facilitates earlier diagnoses and therefore has allowed for earlier initiation of treatment. It can be used to monitor the burden of inflammation and may predict response to therapy,” Dr. Jones said. Despite this, “there is significant inconsistency in the use of MRI” in clinical practice.

For instance, a survey performed in the United Kingdom (J Rheumatol. 2017;44[6]:780-5) highlighted the need for better collaboration between rheumatology and radiology departments to identify axSpA MRI lesions and develop appropriate protocols.

That survey showed that a quarter of radiologists were not aware of the term axSpA, and just 31% and 25%, respectively, were aware of Assessment of Spondyloarthritis international Society (ASAS) criteria for a positive MRI of the sacroiliac joints and spine. Furthermore, 18% of radiologists did not recognize bone marrow edema as a diagnostic feature of axSpA.

The heterogeneity in the performance of MRI in clinical practice could lead to a delay in diagnosis and potentially misdiagnosis, the task force’s lead author and consultant rheumatologist, Pedro Machado, MD, said in an interview.

“I think everyone has been focusing on demonstrating the value of MRI in the condition but then they forgot to look at the standardization aspect,” said Dr. Machado, who works at University College Hospital and the National Hospital for Neurology and Neurosurgery in London.

With that in mind, the BRITSpA-endorsed task force was set up and met to determine the scope of the recommendations. They looked at the evidence for the use of MRI in the diagnosis of axSpA and used two overarching principles to draft the recommendations: 1) the diagnosis of axSpA is based on clinical, laboratory, and imaging features; 2) Some patients with axSpA have isolated inflammation of the sacroiliac joints or spine.

“All of the recommendations were met with a high level of agreement, indicating a strong consensus” among rheumatologists and radiologists, Dr. Jones noted.

“These recommendations can be immediately applied to clinical practice,” said Dr. Machado, who noted that they should standardize practice and decrease heterogeneity around the use of MRI. “This will help ensure a more informed and consistent approach to the diagnosis of axSpA.”

One of the potential impacts of the recommendations, if followed, is that they may actually help to reduce health care costs, Dr. Machado suggested, because an optimized protocol would be used, making MRI more cost effective by not including sequences that do not add value in the condition.

The next task is to share the recommendations more widely and make sure they are applied in clinical practice.

A systematic literature review on which the recommendations were based was published simultaneously with the conference presentation (Rheumatology. 2019 May 2. doi: 10.1093/rheumatology/kez172).

The work was supported by BRITSpA. The authors had no relevant disclosures.

SOURCE: Bray TJP et al. Rheumatology 2019;58(suppl 3): Abstract 033. doi: 10.1093/rheumatology/kez105.032.

BIRMINGHAM, ENGLAND – An evidence-based approach coupled with expert consensus has been used to determine the best way to use MRI for the diagnosis of axial spondyloarthritis (axSpA).

Working under the auspices of the British Society for Spondyloarthritis (BRITSpA), a task force of nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA developed a set of seven recommendations that provide guidance on how to best to acquire and then interpret MRI images of the spine and sacroiliac joints.

The recommendations, which were published online (Rheumatology. 2019 May 2. doi: 10.1093/rheumatology/kez173), cover how to perform MRI when axSpA is suspected, such as by imaging both the sacroiliac joints and the spine, and provide guidance on the sequences and order of MRI planes to be used, and what features may increase the diagnostic confidence of axSpA.

The recommendations are as follows:

• When requesting an MRI for suspected axSpA, imaging of both the sacroiliac joints and the spine is recommended.

• T1-weighted and fat-suppressed, fluid-sensitive sequences are recommended for suspected axSpA.

• The minimum protocol when requesting an MRI for suspected axSpA should include sagittal images of the spine with extended lateral coverage and images of the sacroiliac joints that are in an oblique coronal plane to the joint.

• In the sacroiliac joints, the presence of bone marrow edema, fatty infiltration, or erosion is suggestive of the diagnosis of axSpA. The presence of more than one of these features increases the diagnostic confidence of axSpA.

• In the spine, the presence of multiple corner inflammatory lesions and/or multiple corner fatty lesions increases the diagnostic confidence of axSpA.

• In the sacroiliac joints and/or spine, the presence of characteristic new bone formation increases the diagnostic confidence of axSpA.

• The full range and combination of active and structural lesions of the sacroiliac joints and spine should be taken into account when deciding if the MRI scan is suggestive of axSpA or not.

The recommendations “are intended to standardize practice around the use of MRI,” said Alexis Jones, MBBS, MS (Rheumatology), a senior clinical research fellow at University College London Hospitals NHS Foundation Trust. She presented the recommendations on behalf of the expert task force at the annual conference of the British Society for Rheumatology.

“MRI has become an essential tool in axial spondyloarthritis. It facilitates earlier diagnoses and therefore has allowed for earlier initiation of treatment. It can be used to monitor the burden of inflammation and may predict response to therapy,” Dr. Jones said. Despite this, “there is significant inconsistency in the use of MRI” in clinical practice.

For instance, a survey performed in the United Kingdom (J Rheumatol. 2017;44[6]:780-5) highlighted the need for better collaboration between rheumatology and radiology departments to identify axSpA MRI lesions and develop appropriate protocols.

That survey showed that a quarter of radiologists were not aware of the term axSpA, and just 31% and 25%, respectively, were aware of Assessment of Spondyloarthritis international Society (ASAS) criteria for a positive MRI of the sacroiliac joints and spine. Furthermore, 18% of radiologists did not recognize bone marrow edema as a diagnostic feature of axSpA.

The heterogeneity in the performance of MRI in clinical practice could lead to a delay in diagnosis and potentially misdiagnosis, the task force’s lead author and consultant rheumatologist, Pedro Machado, MD, said in an interview.

“I think everyone has been focusing on demonstrating the value of MRI in the condition but then they forgot to look at the standardization aspect,” said Dr. Machado, who works at University College Hospital and the National Hospital for Neurology and Neurosurgery in London.

With that in mind, the BRITSpA-endorsed task force was set up and met to determine the scope of the recommendations. They looked at the evidence for the use of MRI in the diagnosis of axSpA and used two overarching principles to draft the recommendations: 1) the diagnosis of axSpA is based on clinical, laboratory, and imaging features; 2) Some patients with axSpA have isolated inflammation of the sacroiliac joints or spine.

“All of the recommendations were met with a high level of agreement, indicating a strong consensus” among rheumatologists and radiologists, Dr. Jones noted.

“These recommendations can be immediately applied to clinical practice,” said Dr. Machado, who noted that they should standardize practice and decrease heterogeneity around the use of MRI. “This will help ensure a more informed and consistent approach to the diagnosis of axSpA.”

One of the potential impacts of the recommendations, if followed, is that they may actually help to reduce health care costs, Dr. Machado suggested, because an optimized protocol would be used, making MRI more cost effective by not including sequences that do not add value in the condition.

The next task is to share the recommendations more widely and make sure they are applied in clinical practice.

A systematic literature review on which the recommendations were based was published simultaneously with the conference presentation (Rheumatology. 2019 May 2. doi: 10.1093/rheumatology/kez172).

The work was supported by BRITSpA. The authors had no relevant disclosures.

SOURCE: Bray TJP et al. Rheumatology 2019;58(suppl 3): Abstract 033. doi: 10.1093/rheumatology/kez105.032.

BIRMINGHAM, ENGLAND – An evidence-based approach coupled with expert consensus has been used to determine the best way to use MRI for the diagnosis of axial spondyloarthritis (axSpA).

Working under the auspices of the British Society for Spondyloarthritis (BRITSpA), a task force of nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA developed a set of seven recommendations that provide guidance on how to best to acquire and then interpret MRI images of the spine and sacroiliac joints.

The recommendations, which were published online (Rheumatology. 2019 May 2. doi: 10.1093/rheumatology/kez173), cover how to perform MRI when axSpA is suspected, such as by imaging both the sacroiliac joints and the spine, and provide guidance on the sequences and order of MRI planes to be used, and what features may increase the diagnostic confidence of axSpA.

The recommendations are as follows:

• When requesting an MRI for suspected axSpA, imaging of both the sacroiliac joints and the spine is recommended.

• T1-weighted and fat-suppressed, fluid-sensitive sequences are recommended for suspected axSpA.

• The minimum protocol when requesting an MRI for suspected axSpA should include sagittal images of the spine with extended lateral coverage and images of the sacroiliac joints that are in an oblique coronal plane to the joint.

• In the sacroiliac joints, the presence of bone marrow edema, fatty infiltration, or erosion is suggestive of the diagnosis of axSpA. The presence of more than one of these features increases the diagnostic confidence of axSpA.

• In the spine, the presence of multiple corner inflammatory lesions and/or multiple corner fatty lesions increases the diagnostic confidence of axSpA.

• In the sacroiliac joints and/or spine, the presence of characteristic new bone formation increases the diagnostic confidence of axSpA.

• The full range and combination of active and structural lesions of the sacroiliac joints and spine should be taken into account when deciding if the MRI scan is suggestive of axSpA or not.

The recommendations “are intended to standardize practice around the use of MRI,” said Alexis Jones, MBBS, MS (Rheumatology), a senior clinical research fellow at University College London Hospitals NHS Foundation Trust. She presented the recommendations on behalf of the expert task force at the annual conference of the British Society for Rheumatology.

“MRI has become an essential tool in axial spondyloarthritis. It facilitates earlier diagnoses and therefore has allowed for earlier initiation of treatment. It can be used to monitor the burden of inflammation and may predict response to therapy,” Dr. Jones said. Despite this, “there is significant inconsistency in the use of MRI” in clinical practice.

For instance, a survey performed in the United Kingdom (J Rheumatol. 2017;44[6]:780-5) highlighted the need for better collaboration between rheumatology and radiology departments to identify axSpA MRI lesions and develop appropriate protocols.

That survey showed that a quarter of radiologists were not aware of the term axSpA, and just 31% and 25%, respectively, were aware of Assessment of Spondyloarthritis international Society (ASAS) criteria for a positive MRI of the sacroiliac joints and spine. Furthermore, 18% of radiologists did not recognize bone marrow edema as a diagnostic feature of axSpA.

The heterogeneity in the performance of MRI in clinical practice could lead to a delay in diagnosis and potentially misdiagnosis, the task force’s lead author and consultant rheumatologist, Pedro Machado, MD, said in an interview.

“I think everyone has been focusing on demonstrating the value of MRI in the condition but then they forgot to look at the standardization aspect,” said Dr. Machado, who works at University College Hospital and the National Hospital for Neurology and Neurosurgery in London.

With that in mind, the BRITSpA-endorsed task force was set up and met to determine the scope of the recommendations. They looked at the evidence for the use of MRI in the diagnosis of axSpA and used two overarching principles to draft the recommendations: 1) the diagnosis of axSpA is based on clinical, laboratory, and imaging features; 2) Some patients with axSpA have isolated inflammation of the sacroiliac joints or spine.

“All of the recommendations were met with a high level of agreement, indicating a strong consensus” among rheumatologists and radiologists, Dr. Jones noted.

“These recommendations can be immediately applied to clinical practice,” said Dr. Machado, who noted that they should standardize practice and decrease heterogeneity around the use of MRI. “This will help ensure a more informed and consistent approach to the diagnosis of axSpA.”

One of the potential impacts of the recommendations, if followed, is that they may actually help to reduce health care costs, Dr. Machado suggested, because an optimized protocol would be used, making MRI more cost effective by not including sequences that do not add value in the condition.

The next task is to share the recommendations more widely and make sure they are applied in clinical practice.

A systematic literature review on which the recommendations were based was published simultaneously with the conference presentation (Rheumatology. 2019 May 2. doi: 10.1093/rheumatology/kez172).

The work was supported by BRITSpA. The authors had no relevant disclosures.

SOURCE: Bray TJP et al. Rheumatology 2019;58(suppl 3): Abstract 033. doi: 10.1093/rheumatology/kez105.032.

We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.

What is the concept behind the topographical model of multiple sclerosis (MS)?

DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.

We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.

The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.

As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.

This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.

 In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms.  What the topographical model displays is that  patients with MS lose reserve as time passes.

We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.

In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?

DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.

The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.

One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.

To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore,  those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.

This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.

How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?

DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.

Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.

Is there any other recent research that supports these concepts?

DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.

A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.

In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.

We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.

What is the concept behind the topographical model of multiple sclerosis (MS)?

DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.

We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.

The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.

As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.

This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.

 In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms.  What the topographical model displays is that  patients with MS lose reserve as time passes.

We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.

In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?

DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.

The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.

One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.

To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore,  those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.

This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.

How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?

DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.

Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.

Is there any other recent research that supports these concepts?

DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.

A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.

In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.

We interviewed Dr. Stephen Krieger to discuss his research in the implementation of the topographical model of Multiple Sclerosis.

What is the concept behind the topographical model of multiple sclerosis (MS)?

DR. KRIEGER: MS is an incredibly heterogeneous, and in many ways, unpredictable disease. Some people with MS will have a relapsing course, others will take a progressive course of disease, and many will have a disease course that spans both a relapsing phase and a progressive phase.

We have traditionally divided MS into phenotypes like relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), or primary-progressive MS (PPMS), and these phenotypes have been foundational in our field and used to define clinical trial cohorts and outcomes. They also have been used for the approval of our medicines. In practice, however, it sometimes can be difficult to know precisely what kind of MS, what phenotypes of MS, that an individual patient has.

The topographical model, which was proposed four years ago, tries to unify our concepts of MS in a way that spans across those phenotypes and animates the disease course in a more dynamic way to bridge from one phenotype to another.

As an individual patient, for example, develops clinically isolated syndrome (CIS) or first attack, and then RRMS, and then later SPMS, that gets depicted in a dynamic visualization through the topographical model. The model also makes use of the idea that where an MS lesion is in the central nervous system (CNS) defines the clinical symptoms that it causes.

This is something that we have long known, and the art of localization in neurology has existed for at least a couple hundred years. But we have not used that in the way we have depicted MS clinical course in recent decades. The topographical model tries to bring this idea of mapping an individual patient’s disease topography back into the clinical picture.

 In the topographical model, the lesions are shown as different topographical peaks, via the hills and valleys of areas of MS damage across different regions of the CNS [image]. They are compensated for by reserve, by the ability that the nervous system has to compensate and to keep a disease process from crossing the clinical threshold and causing symptoms.  What the topographical model displays is that  patients with MS lose reserve as time passes.

We know that there is brain atrophy, brain stem atrophy, spinal cord atrophy, and retinal nerve fiber layer thinning in this disease. The topographical model takes the concept that MS causes a loss of tissue across the CNS and applies it to where the lesions are in the CNS. The coming together of those two things brings about the clinical picture unmasking the deficit from those lesions over time. The short version is a depiction of disease course in MS. The way it looks has been likened to a leaking swimming pool, where there is a shallow end and a deep end, and as reserve drains over time more and more of that subclinical disease becomes unmasked.

In the Laitman article (2018), you applied the model to real patients. What were the main findings from that study?

DR. KRIEGER: Until now, the topographical model has been conceptual with a visual depiction, and I think it has been important as an educational tool and an aid to help shape our thinking about MS in a unified way.

The Laitman et al research, is the first time we have applied the concepts of the model to individual patients to confirm whether we could map individual patients’ MS histories in the topographical model and see if we could depict their clinical course this way. We found that we could.

One of the most important points that the topographical model makes is the idea that as progression occurs and reserve is lost, there is an unmasking of underlying disease. Meaning, all of the signs and symptoms that a patient has had during their relapse when they were accumulating lesions should be re-revealed or recapitulated when reserve is lost and progression occurs.

To confirm this, we mapped ten patients in the topographical model. We characterized their signs and symptoms of relapses during the relapsing phase and we found that the vast majority of these symptoms had redeclared themselves at the time that these patients developed SPMS. Furthermore,  those symptoms were continuing to worsen in their pattern; that is in the pattern of their disease topography as the years have continued to pass since they developed SPMS.

This was the first empirical study in real patients to show that the principles of the topographical model held true. This recapitulation hypothesis of symptoms in progressive disease was borne out, and that can help to lay the groundwork for future empirical studies to see how this model can be used as a predictive tool.

How does this new theory of MS disease progression better inform treatment decisions than the disease course theories that currently exist?

DR. KRIEGER: We have had the clinical phenotypes for 20 years and it has been very helpful to us in the development of treatments that we have shown are effective for RRMS and in more recent years for PPMS. What we don’t really have is a way of personalizing and predicting the individual person’s disease trajectory.

Although we have prognostic factors that we know are important, such as age and MRI disease burden, there is still great uncertainty of the clinical course in the individual patient. If the topographical model can be further empirically validated using real world data, that could help us to predict what is going to happen to an individual patient. That can help us to make better treatment decisions for them because it could inform our treatment decisions in a more personalized way.

Is there any other recent research that supports these concepts?

DR. KRIEGER: We talk a lot about the need for biomarkers in MS to help us predict disease course and the topographical model makes the case that lesion location is a crucial biomarker. That is, the patient that has lesions in the spinal cord and the brain stem is more likely to have progressive signs and symptoms referable to those lesions.

A separate piece of work recently done by Keegan and colleagues that was published in Multiple Sclerosis Journal, looked at their own cohort of patients that had at least one critically located lesion, typically in the high cervical spinal cord or the lower brain stem, as being the crucial driver of the development of motor dysfunction and progressive disability.

In an editorial I wrote with my colleague, Fred Lublin, called “Location, location, location,” we point out that this is in some ways the best data in support of the concept of the topographical model that I have seen. It outlines a framework or a methodology where the importance of lesion location in defining the clinical picture and the risk of progression for an individual patient can be studied.

The majority of postapproval clinical trials conducted by pharmaceutical companies explored novel or expanded uses as opposed to monitoring original indications, according to results from a cross-sectional study.

“The U.S. Food and Drug Administration can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics,” wrote Joshua J. Skydel of Tufts University, Boston, and colleagues in JAMA Network Open.

“From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications,” the researchers reported.

Of those approved, 37 novel agents were identified that lacked requirements for postmarket monitoring. Data was obtained from the Drugs@FDA database and consisted of industry-sponsored postapproval clinical studies conducted in the United States.

Postapproval study information included 600 trials registered on ClinicalTrials.gov that were primarily aimed at producing additional efficacy and safety data in approved or unapproved uses. The majority of these trials were for novel therapeutics being evaluated in oncology- and hematology-related indications.

After analysis, the researchers found that most of these trials examined agents for novel or expanded indications (60.5%) or widened populations of the initially indicated condition (20.3%).

In addition, several of these studies were nonrandomized (59.8%), had small sample sizes (median, 44 participants), and did not include comparators (63.5%).

“Among 600 trials, only 12.0% exclusively evaluated the originally approved indication,” the authors wrote.

The researchers acknowledged that a key limitation of the study was the inclusion of only postapproval clinical studies affiliated with pharmaceutical companies.

“The FDA may need to impose additional postmarketing requirements to generate further evidence for the original indications,” they concluded.

The study was funded by the Tufts University School of Medicine and the Laura and John Arnold Foundation. The authors reported financial affiliations with Johnson & Johnson, Medtronic, the Blue Cross Blue Shield Association, the National Institutes of Health, the Laura and John Arnold Foundation, and the Food and Drug Administration.

SOURCE: Skydel JJ et al. JAMA Netw Open. 2019 May 9. doi: 10.1001/jamanetworkopen.2019.3410.

The majority of postapproval clinical trials conducted by pharmaceutical companies explored novel or expanded uses as opposed to monitoring original indications, according to results from a cross-sectional study.

“The U.S. Food and Drug Administration can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics,” wrote Joshua J. Skydel of Tufts University, Boston, and colleagues in JAMA Network Open.

“From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications,” the researchers reported.

Of those approved, 37 novel agents were identified that lacked requirements for postmarket monitoring. Data was obtained from the Drugs@FDA database and consisted of industry-sponsored postapproval clinical studies conducted in the United States.

Postapproval study information included 600 trials registered on ClinicalTrials.gov that were primarily aimed at producing additional efficacy and safety data in approved or unapproved uses. The majority of these trials were for novel therapeutics being evaluated in oncology- and hematology-related indications.

After analysis, the researchers found that most of these trials examined agents for novel or expanded indications (60.5%) or widened populations of the initially indicated condition (20.3%).

In addition, several of these studies were nonrandomized (59.8%), had small sample sizes (median, 44 participants), and did not include comparators (63.5%).

“Among 600 trials, only 12.0% exclusively evaluated the originally approved indication,” the authors wrote.

The researchers acknowledged that a key limitation of the study was the inclusion of only postapproval clinical studies affiliated with pharmaceutical companies.

“The FDA may need to impose additional postmarketing requirements to generate further evidence for the original indications,” they concluded.

The study was funded by the Tufts University School of Medicine and the Laura and John Arnold Foundation. The authors reported financial affiliations with Johnson & Johnson, Medtronic, the Blue Cross Blue Shield Association, the National Institutes of Health, the Laura and John Arnold Foundation, and the Food and Drug Administration.

SOURCE: Skydel JJ et al. JAMA Netw Open. 2019 May 9. doi: 10.1001/jamanetworkopen.2019.3410.

The majority of postapproval clinical trials conducted by pharmaceutical companies explored novel or expanded uses as opposed to monitoring original indications, according to results from a cross-sectional study.

“The U.S. Food and Drug Administration can use postmarketing requirements to mandate pharmaceutical companies to conduct clinical trials after the approval of novel therapeutics,” wrote Joshua J. Skydel of Tufts University, Boston, and colleagues in JAMA Network Open.

“From 2009 through 2012, the FDA approved 110 novel therapeutics for 120 indications,” the researchers reported.

Of those approved, 37 novel agents were identified that lacked requirements for postmarket monitoring. Data was obtained from the Drugs@FDA database and consisted of industry-sponsored postapproval clinical studies conducted in the United States.

Postapproval study information included 600 trials registered on ClinicalTrials.gov that were primarily aimed at producing additional efficacy and safety data in approved or unapproved uses. The majority of these trials were for novel therapeutics being evaluated in oncology- and hematology-related indications.

After analysis, the researchers found that most of these trials examined agents for novel or expanded indications (60.5%) or widened populations of the initially indicated condition (20.3%).

In addition, several of these studies were nonrandomized (59.8%), had small sample sizes (median, 44 participants), and did not include comparators (63.5%).

“Among 600 trials, only 12.0% exclusively evaluated the originally approved indication,” the authors wrote.

The researchers acknowledged that a key limitation of the study was the inclusion of only postapproval clinical studies affiliated with pharmaceutical companies.

“The FDA may need to impose additional postmarketing requirements to generate further evidence for the original indications,” they concluded.

The study was funded by the Tufts University School of Medicine and the Laura and John Arnold Foundation. The authors reported financial affiliations with Johnson & Johnson, Medtronic, the Blue Cross Blue Shield Association, the National Institutes of Health, the Laura and John Arnold Foundation, and the Food and Drug Administration.

SOURCE: Skydel JJ et al. JAMA Netw Open. 2019 May 9. doi: 10.1001/jamanetworkopen.2019.3410.

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

What does your patient need to know at the first visit?  

A patient may be scheduled for a total-body skin examination (TBSE) through several routes: primary care referral, continued cancer screening for an at-risk patient or patient transfer, or patient-directed scheduling for general screening regardless of risk factors. At the patient's first visit, it is imperative that the course of the appointment is smooth and predictable for patient comfort and for a thorough and effective examination. The nurse initially solicits salient medical history, particularly personal and family history of skin cancer, current medications, and any acute concerns. The nurse then prepares the patient for the logistics of the TBSE, namely to undress, don a gown that ties and opens in the back, and be seated on the examination table. When I enter the room, the conversation commences with me seated across from the patient, reviewing specifics about his/her history and risk factors. Then the TBSE is executed from head to toe.  

Do you broadly recommend TBSE? 

Firstly, TBSE is a safe clinical tool, supported by data outlining a lack of notable patient morbidity during the examination, including psychosocial factors, and it is generally well-received by patients (Risica et al). In 2016, the US Preventative Services Task Force (USPSTF) outlined its recommendations regarding screening for skin cancer, concluding that there is insufficient evidence to broadly recommend TBSE. Unfortunately, USPSTF findings amassed data from all types of screenings, including those by nondermatologists, and did not extract specialty-specific benefits and risks to patients. The recommendation also did not outline the influence of TBSE on morbidity and mortality for at-risk groups. The guidelines target primary care practice trends; therefore, specialty societies such as the American Academy of Dermatology issued statements following the USPSTF recommendation outlining these salient clarifications, namely that TBSE detects melanoma and keratinocyte carcinomas earlier than in patients who are not screened. Randomized controlled trials to prove this observation are lacking, particularly because of the ethics of withholding screening from a prospective study group. However, in 2017, Johnson et al outlined the best available survival data in concert with the USPSTF statement to arrive at the most beneficial screening recommendations for patients, specifically targeting risk groups--those with a history of skin cancer, immunosuppression, indoor tanning and/or many blistering sunburns, and several other genetic parameters--for at least annual TBSE. 

The technique and reproducibility of TBSE also are not standardized, though they seem to have been endearingly apprenticed but variably implemented through generations of dermatology residents going forward into practice. As it is, depending on patient body surface area, mobility, willingness to disrobe, and adornments (eg, tattoos, hair appliances), multiple factors can restrict full view of a patient's skin. Recently, Helm et al proposed standardizing the TBSE sequence to minimize omitted areas of the body, which may become an imperative tool for streamlined resident teaching and optimal screening encounters.  

How do you keep patients compliant with TBSE? 

During and following TBSE, I typically outline any lesions of concern and plan for further testing, screening, and behavioral prevention strategies. Frequency of TBSE and importance of compliance are discussed during the visit and reinforced at checkout where the appointment templates are established a year in advance for those with skin cancer. Further, for those with melanoma, their appointment slots are given priority status so that any cancellations or delays are rescheduled preferentially. Particularly during the discussion about TBSE frequency, I emphasize the comparison and importance of this visit akin to other recommended screenings, such as mammograms and colonoscopies, and that we, as dermatologists, are part of their cancer surveillance team. 

What do you do if patients refuse your recommendations? 

Some patients refuse a gown or removal of certain clothing items (eg, undergarments, socks, wigs). Some patients defer a yearly TBSE upon checkout and schedule an appointment only when a lesion of concern arises. My advice is not to shame patients and to take advantage of as much as the patient is able and comfortable to show us and be present for, welcoming that we have the opportunity to take care of them and screen for cancer in any capacity. In underserved or limited budget practice regions, lesion-directed examination vs TBSE may be the only screening method utilized and may even attract more patients to a screening facility (Hoorens et al). 

In the opposite corner are those patients who deem the recommended TBSE interval as too infrequent, which poses a delicate dilemma. In my opinion, these situations present another cohort of risks. Namely, the patient may become (or continue to be) overly fixated on the small details of every skin lesion, and in my experience, they tend to develop the habit of expecting at least 1 biopsy at each visit, typically of a lesion of their choosing. Depending on the validity of this expectation vs my clinical examination, it can lead to a difficult discussion with the patient about oversampling lesions and the potential for many scars, copious reexcisions for ambiguous lesion pathology, and a trend away from prudent clinical care. In addition, multiple visits incur more patient co-pays and time away from school, work, or home. To ease the patient's mind, I advise to call our office for a more acute visit if there is a lesion of concern; I additionally recommend taking a smartphone photograph of a concerning lesion and monitoring it for changes or sending the photograph to our patient portal messaging system so we can evaluate its acuity. 

What take-home advice do you give to patients? 

As the visit ends, I further explain that home self-examination or examination by a partner between visits is intuitively a valuable screening adjunct for skin cancer. In 2018, the USPSTF recommended behavioral skin cancer prevention counseling and self-examination only for younger-age cohorts with fair skin (6 months to 24 years), but its utility in specialty practice must be qualified. The American Academy of Dermatology Association subsequently issued a statement to support safe sun-protective practices and diligent self-screening for changing lesions, as earlier detection and management of skin cancer can lead to decreased morbidity and mortality from these neoplasms.  

Resources for Patients

American Academy of Dermatology's SPOT Skin Cancer

Centers for Disease Control and Prevention: What Screening Tests Are There?
 

NEW ORLEANS – Results of the largest-ever analysis of TAVR in patients with bicuspid aortic stenosis indicate that key 30-day and 1-year outcomes are similar to those of propensity-matched TAVR patients with tricuspid disease, Raj R. Makkar, MD, said at the annual meeting of the American College of Cardiology.

“Select bicuspid anatomy is amenable to TAVR with current-generation, balloon-expandable TAVR technology with acceptable clinical outcomes. These data provide an argument for TAVR to be a reasonable alternative for bicuspid AS [aortic stenosis] patients who are at intermediate or high risk for surgical aortic valve replacement, which are the patients that are enrolled in this registry, and provide a sound basis to conduct a randomized clinical trial in young patients with bicuspid AS who are at low risk for surgery,” declared Dr. Makkar, director of interventional cardiology and the cardiac catheterization laboratory at Cedars-Sinai Medical Center in Los Angeles.

The landmark randomized trials of TAVR versus SAVR (surgical aortic valve replacement) that established TAVR as the preferred treatment for patients with severe aortic stenosis who are at high, intermediate, or low surgical risk systematically excluded patients with bicuspid AS, even though bicuspid anatomy is common, particularly in younger patients with AS.

Despite the absence of supportive randomized trial data, TAVR is being done for bicuspid AS. To learn how patients with bicuspid disease have fared, Dr. Makkar and coinvestigators analyzed the real-world Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry of all patients who underwent TAVR with the balloon-expandable Sapien 3 stent in the United States during 2015-2018. They compared outcomes in 2,691 patients with high or intermediate surgical risk who underwent TAVR for bicuspid AS to an equal number of patients who had TAVR for tricuspid disease, with the two groups being propensity-matched across 25 variables.

Key outcomes were reassuringly similar in the two groups. For example, 30-day and 1-year all-cause mortality rates were 2.6% and 10.8% in patients with bicuspid valves and similar, at 2.5% and 12.1%, in those with tricuspid AS. Paravalvular leak rates at 30 days and 1 year were similar in the two groups. The Kansas City Cardiomyopathy Questionnaire scores, reflecting quality of life, improved dramatically – by nearly 30 points – from pre-TAVR baseline in both groups. The proportion of patients who were New York Heart Association functional class III or IV improved from nearly 85% at baseline to about 8% at 30 days and 1 year, again with no significant difference between the bicuspid and tricuspid AS groups. And there were other benefits, too.

“Despite the concerns regarding optimal expansion of these valves in a bicuspid anatomy, what we observed here was a significant and similar reduction in mean gradients and increase in valve area, both in the bicuspid and tricuspid AS patients. So there was no impact of bicuspid anatomy as seen here in terms of valve hemodynamics,” according to the cardiologist.

Conversion from TAVR to open surgery was required in 0.9% of bicuspid and 0.4% of tricuspid AS patients. Rates of aortic dissection and need for aortic valve reintervention were similarly low in both groups.

The 30-day stroke rate was significantly higher in the bicuspid patients – 2.4% versus 1.6% – but by 1 year there was no significant between-group difference, with stroke rates of 3.4% in the bicuspid and 3.1% in the tricuspid TAVR patients.

“I’d like to point out that more than 75% of strokes occurred in the first 3 days. These are periprocedural strokes, and there was no difference in the time distribution of strokes between the bicuspid and tricuspid groups,” Dr. Makkar said.

These stroke data make a compelling case for the routine use of cerebral protection devices in patients undergoing TAVR, something which now occurs in less than 10% of cases nationally, he continued.

“I would argue that, based on these data, it would be wise for us to use cerebral protection devices, especially when we are doing TAVR in patients with bicuspid AS, because their valves tend to be more heavily calcified than is often the case in tricuspid AS,” Dr. Makkar said.

Discussant Mayra Guerrero, MD, of the Mayo Clinic in Rochester, Minn., took issue with Dr. Makkar’s comment regarding the need for a randomized trial of TAVR in bicuspid AS patients with low surgical risk.

“Do we really need a randomized trial when we see in real-world experience with more than 2,600 patients that the outcomes are fairly similar?” she asked.

Affirmative, Dr. Makkar responded, in light of the fact that the STS/ACC TVT Registry doesn’t include low–surgical risk, typically relatively young bicuspid AS TAVR patients.

“I would say that these data are reassuring and encouraging, but we must not get carried away. I think that would be the important message that I must give,” Dr. Makkar replied. “I think for patients who are high risk and who are intermediate risk, with STS scores of what they were here – 5 and more – I think it’s reasonable to consider them for TAVR based upon CT anatomy. For young patients, as I concluded, I think we must do a randomized clinical trial to definitely establish the safety and efficacy in these patients.”

Dr. Makkar reported receiving research grants from and serving as a consultant to Edwards Lifesciences, which supported the study, as well as Abbott, Medtronic, and Boston Scientific.

[email protected]

SOURCE: Makkar RR. ACC 19, 404-15. Late-breaking clinical trials


 

NEW ORLEANS – Results of the largest-ever analysis of TAVR in patients with bicuspid aortic stenosis indicate that key 30-day and 1-year outcomes are similar to those of propensity-matched TAVR patients with tricuspid disease, Raj R. Makkar, MD, said at the annual meeting of the American College of Cardiology.

“Select bicuspid anatomy is amenable to TAVR with current-generation, balloon-expandable TAVR technology with acceptable clinical outcomes. These data provide an argument for TAVR to be a reasonable alternative for bicuspid AS [aortic stenosis] patients who are at intermediate or high risk for surgical aortic valve replacement, which are the patients that are enrolled in this registry, and provide a sound basis to conduct a randomized clinical trial in young patients with bicuspid AS who are at low risk for surgery,” declared Dr. Makkar, director of interventional cardiology and the cardiac catheterization laboratory at Cedars-Sinai Medical Center in Los Angeles.

The landmark randomized trials of TAVR versus SAVR (surgical aortic valve replacement) that established TAVR as the preferred treatment for patients with severe aortic stenosis who are at high, intermediate, or low surgical risk systematically excluded patients with bicuspid AS, even though bicuspid anatomy is common, particularly in younger patients with AS.

Despite the absence of supportive randomized trial data, TAVR is being done for bicuspid AS. To learn how patients with bicuspid disease have fared, Dr. Makkar and coinvestigators analyzed the real-world Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry of all patients who underwent TAVR with the balloon-expandable Sapien 3 stent in the United States during 2015-2018. They compared outcomes in 2,691 patients with high or intermediate surgical risk who underwent TAVR for bicuspid AS to an equal number of patients who had TAVR for tricuspid disease, with the two groups being propensity-matched across 25 variables.

Key outcomes were reassuringly similar in the two groups. For example, 30-day and 1-year all-cause mortality rates were 2.6% and 10.8% in patients with bicuspid valves and similar, at 2.5% and 12.1%, in those with tricuspid AS. Paravalvular leak rates at 30 days and 1 year were similar in the two groups. The Kansas City Cardiomyopathy Questionnaire scores, reflecting quality of life, improved dramatically – by nearly 30 points – from pre-TAVR baseline in both groups. The proportion of patients who were New York Heart Association functional class III or IV improved from nearly 85% at baseline to about 8% at 30 days and 1 year, again with no significant difference between the bicuspid and tricuspid AS groups. And there were other benefits, too.

“Despite the concerns regarding optimal expansion of these valves in a bicuspid anatomy, what we observed here was a significant and similar reduction in mean gradients and increase in valve area, both in the bicuspid and tricuspid AS patients. So there was no impact of bicuspid anatomy as seen here in terms of valve hemodynamics,” according to the cardiologist.

Conversion from TAVR to open surgery was required in 0.9% of bicuspid and 0.4% of tricuspid AS patients. Rates of aortic dissection and need for aortic valve reintervention were similarly low in both groups.

The 30-day stroke rate was significantly higher in the bicuspid patients – 2.4% versus 1.6% – but by 1 year there was no significant between-group difference, with stroke rates of 3.4% in the bicuspid and 3.1% in the tricuspid TAVR patients.

“I’d like to point out that more than 75% of strokes occurred in the first 3 days. These are periprocedural strokes, and there was no difference in the time distribution of strokes between the bicuspid and tricuspid groups,” Dr. Makkar said.

These stroke data make a compelling case for the routine use of cerebral protection devices in patients undergoing TAVR, something which now occurs in less than 10% of cases nationally, he continued.

“I would argue that, based on these data, it would be wise for us to use cerebral protection devices, especially when we are doing TAVR in patients with bicuspid AS, because their valves tend to be more heavily calcified than is often the case in tricuspid AS,” Dr. Makkar said.

Discussant Mayra Guerrero, MD, of the Mayo Clinic in Rochester, Minn., took issue with Dr. Makkar’s comment regarding the need for a randomized trial of TAVR in bicuspid AS patients with low surgical risk.

“Do we really need a randomized trial when we see in real-world experience with more than 2,600 patients that the outcomes are fairly similar?” she asked.

Affirmative, Dr. Makkar responded, in light of the fact that the STS/ACC TVT Registry doesn’t include low–surgical risk, typically relatively young bicuspid AS TAVR patients.

“I would say that these data are reassuring and encouraging, but we must not get carried away. I think that would be the important message that I must give,” Dr. Makkar replied. “I think for patients who are high risk and who are intermediate risk, with STS scores of what they were here – 5 and more – I think it’s reasonable to consider them for TAVR based upon CT anatomy. For young patients, as I concluded, I think we must do a randomized clinical trial to definitely establish the safety and efficacy in these patients.”

Dr. Makkar reported receiving research grants from and serving as a consultant to Edwards Lifesciences, which supported the study, as well as Abbott, Medtronic, and Boston Scientific.

[email protected]

SOURCE: Makkar RR. ACC 19, 404-15. Late-breaking clinical trials


 

NEW ORLEANS – Results of the largest-ever analysis of TAVR in patients with bicuspid aortic stenosis indicate that key 30-day and 1-year outcomes are similar to those of propensity-matched TAVR patients with tricuspid disease, Raj R. Makkar, MD, said at the annual meeting of the American College of Cardiology.

“Select bicuspid anatomy is amenable to TAVR with current-generation, balloon-expandable TAVR technology with acceptable clinical outcomes. These data provide an argument for TAVR to be a reasonable alternative for bicuspid AS [aortic stenosis] patients who are at intermediate or high risk for surgical aortic valve replacement, which are the patients that are enrolled in this registry, and provide a sound basis to conduct a randomized clinical trial in young patients with bicuspid AS who are at low risk for surgery,” declared Dr. Makkar, director of interventional cardiology and the cardiac catheterization laboratory at Cedars-Sinai Medical Center in Los Angeles.

The landmark randomized trials of TAVR versus SAVR (surgical aortic valve replacement) that established TAVR as the preferred treatment for patients with severe aortic stenosis who are at high, intermediate, or low surgical risk systematically excluded patients with bicuspid AS, even though bicuspid anatomy is common, particularly in younger patients with AS.

Despite the absence of supportive randomized trial data, TAVR is being done for bicuspid AS. To learn how patients with bicuspid disease have fared, Dr. Makkar and coinvestigators analyzed the real-world Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry of all patients who underwent TAVR with the balloon-expandable Sapien 3 stent in the United States during 2015-2018. They compared outcomes in 2,691 patients with high or intermediate surgical risk who underwent TAVR for bicuspid AS to an equal number of patients who had TAVR for tricuspid disease, with the two groups being propensity-matched across 25 variables.

Key outcomes were reassuringly similar in the two groups. For example, 30-day and 1-year all-cause mortality rates were 2.6% and 10.8% in patients with bicuspid valves and similar, at 2.5% and 12.1%, in those with tricuspid AS. Paravalvular leak rates at 30 days and 1 year were similar in the two groups. The Kansas City Cardiomyopathy Questionnaire scores, reflecting quality of life, improved dramatically – by nearly 30 points – from pre-TAVR baseline in both groups. The proportion of patients who were New York Heart Association functional class III or IV improved from nearly 85% at baseline to about 8% at 30 days and 1 year, again with no significant difference between the bicuspid and tricuspid AS groups. And there were other benefits, too.

“Despite the concerns regarding optimal expansion of these valves in a bicuspid anatomy, what we observed here was a significant and similar reduction in mean gradients and increase in valve area, both in the bicuspid and tricuspid AS patients. So there was no impact of bicuspid anatomy as seen here in terms of valve hemodynamics,” according to the cardiologist.

Conversion from TAVR to open surgery was required in 0.9% of bicuspid and 0.4% of tricuspid AS patients. Rates of aortic dissection and need for aortic valve reintervention were similarly low in both groups.

The 30-day stroke rate was significantly higher in the bicuspid patients – 2.4% versus 1.6% – but by 1 year there was no significant between-group difference, with stroke rates of 3.4% in the bicuspid and 3.1% in the tricuspid TAVR patients.

“I’d like to point out that more than 75% of strokes occurred in the first 3 days. These are periprocedural strokes, and there was no difference in the time distribution of strokes between the bicuspid and tricuspid groups,” Dr. Makkar said.

These stroke data make a compelling case for the routine use of cerebral protection devices in patients undergoing TAVR, something which now occurs in less than 10% of cases nationally, he continued.

“I would argue that, based on these data, it would be wise for us to use cerebral protection devices, especially when we are doing TAVR in patients with bicuspid AS, because their valves tend to be more heavily calcified than is often the case in tricuspid AS,” Dr. Makkar said.

Discussant Mayra Guerrero, MD, of the Mayo Clinic in Rochester, Minn., took issue with Dr. Makkar’s comment regarding the need for a randomized trial of TAVR in bicuspid AS patients with low surgical risk.

“Do we really need a randomized trial when we see in real-world experience with more than 2,600 patients that the outcomes are fairly similar?” she asked.

Affirmative, Dr. Makkar responded, in light of the fact that the STS/ACC TVT Registry doesn’t include low–surgical risk, typically relatively young bicuspid AS TAVR patients.

“I would say that these data are reassuring and encouraging, but we must not get carried away. I think that would be the important message that I must give,” Dr. Makkar replied. “I think for patients who are high risk and who are intermediate risk, with STS scores of what they were here – 5 and more – I think it’s reasonable to consider them for TAVR based upon CT anatomy. For young patients, as I concluded, I think we must do a randomized clinical trial to definitely establish the safety and efficacy in these patients.”

Dr. Makkar reported receiving research grants from and serving as a consultant to Edwards Lifesciences, which supported the study, as well as Abbott, Medtronic, and Boston Scientific.

[email protected]

SOURCE: Makkar RR. ACC 19, 404-15. Late-breaking clinical trials


 

PHILADELPHIA – About 17% of patients discharged from a hospital after treatment for generalized convulsive status epilepticus are readmitted within 30 days, according to research presented at the annual meeting of the American Academy of Neurology. It is possible to identify patients at high risk of readmission, which could allow neurologists to reduce their clinical and economic burden, said the investigators.

Status epilepticus is a major neurologic emergency. Patients often have significant disability and may represent a burden on their families and on the health care system. To identify independent predictors of 30-day hospital readmission among patients discharged after generalized convulsive status epilepticus, Mohamad Rahwan, MD, a neurologist at the Medical University of South Carolina, Charleston, and colleagues examined data from the 2014 Nationwide Readmission Database.

The investigators included adults with a primary discharge diagnosis of generalized convulsive status epilepticus, identified by the ICD-9-CM code 345.3, in their study. Patients who died during hospitalization, had missing information on the length of stay, or were discharged in December 2014 were excluded from analysis. Dr. Rahwan and colleagues calculated the overall 30-day readmission rate for the sample and compared prespecified groups by their 30-day readmission status. They performed multiple logistic regression analysis to identify independent predictors of 30-day readmission, adjusting for potential confounders.

In all, 14,562 adults were discharged with a diagnosis of generalized convulsive status epilepticus. Of this population, 2,520 patients (17.3%) were readmitted within 30 days. Multivariate logistic regression analysis indicated that patients discharged against medical advice (odds ratio, 1.45), those discharged to short-term hospital (OR, 1.39), those with comorbid conditions (OR for Charlson Comorbidity Index of 1, 1.12; OR for Charlson Comorbidity Index of 2 or greater, 1.32), and those with a length of stay exceeding 6 days (OR, 1.42) had a greater risk of 30-day readmission. The researchers observed an inverse association for patients aged 45 years or older and for those in high-income households. “Greater attention to high-risk subgroups may identify opportunities to ameliorate the clinical and economic burden of early readmissions after generalized convulsive status epilepticus,” said the researchers.

The researchers had no disclosures.

[email protected]

SOURCE: Rahwan M et al. AAN 2019, Abstract S36.006.

PHILADELPHIA – About 17% of patients discharged from a hospital after treatment for generalized convulsive status epilepticus are readmitted within 30 days, according to research presented at the annual meeting of the American Academy of Neurology. It is possible to identify patients at high risk of readmission, which could allow neurologists to reduce their clinical and economic burden, said the investigators.

Status epilepticus is a major neurologic emergency. Patients often have significant disability and may represent a burden on their families and on the health care system. To identify independent predictors of 30-day hospital readmission among patients discharged after generalized convulsive status epilepticus, Mohamad Rahwan, MD, a neurologist at the Medical University of South Carolina, Charleston, and colleagues examined data from the 2014 Nationwide Readmission Database.

The investigators included adults with a primary discharge diagnosis of generalized convulsive status epilepticus, identified by the ICD-9-CM code 345.3, in their study. Patients who died during hospitalization, had missing information on the length of stay, or were discharged in December 2014 were excluded from analysis. Dr. Rahwan and colleagues calculated the overall 30-day readmission rate for the sample and compared prespecified groups by their 30-day readmission status. They performed multiple logistic regression analysis to identify independent predictors of 30-day readmission, adjusting for potential confounders.

In all, 14,562 adults were discharged with a diagnosis of generalized convulsive status epilepticus. Of this population, 2,520 patients (17.3%) were readmitted within 30 days. Multivariate logistic regression analysis indicated that patients discharged against medical advice (odds ratio, 1.45), those discharged to short-term hospital (OR, 1.39), those with comorbid conditions (OR for Charlson Comorbidity Index of 1, 1.12; OR for Charlson Comorbidity Index of 2 or greater, 1.32), and those with a length of stay exceeding 6 days (OR, 1.42) had a greater risk of 30-day readmission. The researchers observed an inverse association for patients aged 45 years or older and for those in high-income households. “Greater attention to high-risk subgroups may identify opportunities to ameliorate the clinical and economic burden of early readmissions after generalized convulsive status epilepticus,” said the researchers.

The researchers had no disclosures.

[email protected]

SOURCE: Rahwan M et al. AAN 2019, Abstract S36.006.

PHILADELPHIA – About 17% of patients discharged from a hospital after treatment for generalized convulsive status epilepticus are readmitted within 30 days, according to research presented at the annual meeting of the American Academy of Neurology. It is possible to identify patients at high risk of readmission, which could allow neurologists to reduce their clinical and economic burden, said the investigators.

Status epilepticus is a major neurologic emergency. Patients often have significant disability and may represent a burden on their families and on the health care system. To identify independent predictors of 30-day hospital readmission among patients discharged after generalized convulsive status epilepticus, Mohamad Rahwan, MD, a neurologist at the Medical University of South Carolina, Charleston, and colleagues examined data from the 2014 Nationwide Readmission Database.

The investigators included adults with a primary discharge diagnosis of generalized convulsive status epilepticus, identified by the ICD-9-CM code 345.3, in their study. Patients who died during hospitalization, had missing information on the length of stay, or were discharged in December 2014 were excluded from analysis. Dr. Rahwan and colleagues calculated the overall 30-day readmission rate for the sample and compared prespecified groups by their 30-day readmission status. They performed multiple logistic regression analysis to identify independent predictors of 30-day readmission, adjusting for potential confounders.

In all, 14,562 adults were discharged with a diagnosis of generalized convulsive status epilepticus. Of this population, 2,520 patients (17.3%) were readmitted within 30 days. Multivariate logistic regression analysis indicated that patients discharged against medical advice (odds ratio, 1.45), those discharged to short-term hospital (OR, 1.39), those with comorbid conditions (OR for Charlson Comorbidity Index of 1, 1.12; OR for Charlson Comorbidity Index of 2 or greater, 1.32), and those with a length of stay exceeding 6 days (OR, 1.42) had a greater risk of 30-day readmission. The researchers observed an inverse association for patients aged 45 years or older and for those in high-income households. “Greater attention to high-risk subgroups may identify opportunities to ameliorate the clinical and economic burden of early readmissions after generalized convulsive status epilepticus,” said the researchers.

The researchers had no disclosures.

[email protected]

SOURCE: Rahwan M et al. AAN 2019, Abstract S36.006.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one summarizes a presentation at the European Lung Cancer Congress on the value of durvalumab as adjuvant treatment in patients with locally-advanced non–small cell lung cancer and the other confirms the safety and efficacy of subcutaneously-administered trastuzumab as neoadjuvant treatment in HER2/-positive breast cancer patients.

PACIFIC trial

In the PACIFIC trial, 713 patients with unresectable, stage III non–small cell lung cancer (NSCLC) who received concurrent chemoradiation were randomized to receive adjuvant durvalumab or an identical placebo, for a year after radiation ended. The results were dramatic in favor of durvalumab (N Engl J Med. 2018;379:2342-50).

Durvalumab showed 24-month overall survival of 66.3% versus 55.6% with placebo (hazard ratio, 0.68, P = .0025) and progression-free survival of 17.2 months versus 5. 6 months (HR, 0.51). As expected, there were more grade 3-4 toxicities and treatment discontinuations with durvalumab than with placebo, but the toxicity seemed modest, given the substantial improvements in tumor-related outcomes.

At the recent European Lung Cancer Congress, Marina Garassino, MD, reported on Patient-Reported Outcomes (PRO) in PACIFIC. PROs were analyzed by PD-L1 level. A total of 63% of patients had PD-L1 tumor expression data for analysis. Overall, there were no major differences in PROs by PD-L1. Global quality of life did not differ by PD-L1 expression cohort.



These data support adjuvant durvalumab for stage III, chemoradiation-treated NSCLC patients, not only from efficacy and toxicity viewpoints, but also from the standpoint of the patient experience, independent of PD-L1 tumor expression.
 

What this means in practice

From every relevant perspective, regardless of histology and molecular features associated with their particular tumor, it is worthwhile for us to recommend – and for our patients to receive – durvalumab adjuvant therapy for up to 1 year after radiation ends, with close follow-up and adherence to the criteria for treatment modification or discontinuation as performed in the PACIFIC trial. These new data remove any lingering concerns about the value of this life-prolonging treatment.

Subcutaneous vs. IV trastuzumab

In this international phase 3 trial in early breast cancer patients, neoadjuvant chemotherapy was paired with either standard IV trastuzumab or subcutaneous trastuzumab at intervals of every 3 weeks. After the cytotoxic chemotherapy concluded, patients completed a 12-month course of trastuzumab with either the IV or subcutaneous administration, as previously randomized. The 6-year event-free survival and overall survival were 65% and 84%, respectively, for both the IV and subcutaneous treatment administration.

The authors concluded that these results are relevant to patients with low-risk HER2-positive breast cancer patients, for whom T-DM1 is not needed (JAMA Oncol. 2019 Apr 18. doi: 10.1001/jamaoncol.2019.0339).

What this means in practice

These long-term data from the HannaH trial show persuasively that patients should be offered the more convenient, hopefully cheaper, subcutaneous route of administration. Since relapses beyond year 6 are unlikely, these data are unlikely to change with further follow-up. At our hospital, we recently made the decision to add subcutaneous trastuzumab to our formulary.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one summarizes a presentation at the European Lung Cancer Congress on the value of durvalumab as adjuvant treatment in patients with locally-advanced non–small cell lung cancer and the other confirms the safety and efficacy of subcutaneously-administered trastuzumab as neoadjuvant treatment in HER2/-positive breast cancer patients.

PACIFIC trial

In the PACIFIC trial, 713 patients with unresectable, stage III non–small cell lung cancer (NSCLC) who received concurrent chemoradiation were randomized to receive adjuvant durvalumab or an identical placebo, for a year after radiation ended. The results were dramatic in favor of durvalumab (N Engl J Med. 2018;379:2342-50).

Durvalumab showed 24-month overall survival of 66.3% versus 55.6% with placebo (hazard ratio, 0.68, P = .0025) and progression-free survival of 17.2 months versus 5. 6 months (HR, 0.51). As expected, there were more grade 3-4 toxicities and treatment discontinuations with durvalumab than with placebo, but the toxicity seemed modest, given the substantial improvements in tumor-related outcomes.

At the recent European Lung Cancer Congress, Marina Garassino, MD, reported on Patient-Reported Outcomes (PRO) in PACIFIC. PROs were analyzed by PD-L1 level. A total of 63% of patients had PD-L1 tumor expression data for analysis. Overall, there were no major differences in PROs by PD-L1. Global quality of life did not differ by PD-L1 expression cohort.



These data support adjuvant durvalumab for stage III, chemoradiation-treated NSCLC patients, not only from efficacy and toxicity viewpoints, but also from the standpoint of the patient experience, independent of PD-L1 tumor expression.
 

What this means in practice

From every relevant perspective, regardless of histology and molecular features associated with their particular tumor, it is worthwhile for us to recommend – and for our patients to receive – durvalumab adjuvant therapy for up to 1 year after radiation ends, with close follow-up and adherence to the criteria for treatment modification or discontinuation as performed in the PACIFIC trial. These new data remove any lingering concerns about the value of this life-prolonging treatment.

Subcutaneous vs. IV trastuzumab

In this international phase 3 trial in early breast cancer patients, neoadjuvant chemotherapy was paired with either standard IV trastuzumab or subcutaneous trastuzumab at intervals of every 3 weeks. After the cytotoxic chemotherapy concluded, patients completed a 12-month course of trastuzumab with either the IV or subcutaneous administration, as previously randomized. The 6-year event-free survival and overall survival were 65% and 84%, respectively, for both the IV and subcutaneous treatment administration.

The authors concluded that these results are relevant to patients with low-risk HER2-positive breast cancer patients, for whom T-DM1 is not needed (JAMA Oncol. 2019 Apr 18. doi: 10.1001/jamaoncol.2019.0339).

What this means in practice

These long-term data from the HannaH trial show persuasively that patients should be offered the more convenient, hopefully cheaper, subcutaneous route of administration. Since relapses beyond year 6 are unlikely, these data are unlikely to change with further follow-up. At our hospital, we recently made the decision to add subcutaneous trastuzumab to our formulary.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one summarizes a presentation at the European Lung Cancer Congress on the value of durvalumab as adjuvant treatment in patients with locally-advanced non–small cell lung cancer and the other confirms the safety and efficacy of subcutaneously-administered trastuzumab as neoadjuvant treatment in HER2/-positive breast cancer patients.

PACIFIC trial

In the PACIFIC trial, 713 patients with unresectable, stage III non–small cell lung cancer (NSCLC) who received concurrent chemoradiation were randomized to receive adjuvant durvalumab or an identical placebo, for a year after radiation ended. The results were dramatic in favor of durvalumab (N Engl J Med. 2018;379:2342-50).

Durvalumab showed 24-month overall survival of 66.3% versus 55.6% with placebo (hazard ratio, 0.68, P = .0025) and progression-free survival of 17.2 months versus 5. 6 months (HR, 0.51). As expected, there were more grade 3-4 toxicities and treatment discontinuations with durvalumab than with placebo, but the toxicity seemed modest, given the substantial improvements in tumor-related outcomes.

At the recent European Lung Cancer Congress, Marina Garassino, MD, reported on Patient-Reported Outcomes (PRO) in PACIFIC. PROs were analyzed by PD-L1 level. A total of 63% of patients had PD-L1 tumor expression data for analysis. Overall, there were no major differences in PROs by PD-L1. Global quality of life did not differ by PD-L1 expression cohort.



These data support adjuvant durvalumab for stage III, chemoradiation-treated NSCLC patients, not only from efficacy and toxicity viewpoints, but also from the standpoint of the patient experience, independent of PD-L1 tumor expression.
 

What this means in practice

From every relevant perspective, regardless of histology and molecular features associated with their particular tumor, it is worthwhile for us to recommend – and for our patients to receive – durvalumab adjuvant therapy for up to 1 year after radiation ends, with close follow-up and adherence to the criteria for treatment modification or discontinuation as performed in the PACIFIC trial. These new data remove any lingering concerns about the value of this life-prolonging treatment.

Subcutaneous vs. IV trastuzumab

In this international phase 3 trial in early breast cancer patients, neoadjuvant chemotherapy was paired with either standard IV trastuzumab or subcutaneous trastuzumab at intervals of every 3 weeks. After the cytotoxic chemotherapy concluded, patients completed a 12-month course of trastuzumab with either the IV or subcutaneous administration, as previously randomized. The 6-year event-free survival and overall survival were 65% and 84%, respectively, for both the IV and subcutaneous treatment administration.

The authors concluded that these results are relevant to patients with low-risk HER2-positive breast cancer patients, for whom T-DM1 is not needed (JAMA Oncol. 2019 Apr 18. doi: 10.1001/jamaoncol.2019.0339).

What this means in practice

These long-term data from the HannaH trial show persuasively that patients should be offered the more convenient, hopefully cheaper, subcutaneous route of administration. Since relapses beyond year 6 are unlikely, these data are unlikely to change with further follow-up. At our hospital, we recently made the decision to add subcutaneous trastuzumab to our formulary.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.