BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[5]:286-287,295).

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[5]:286-287,295).

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[5]:286-287,295).

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

sworcester@mdedge.com

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

sworcester@mdedge.com

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

sworcester@mdedge.com

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

Case Reports

Patient 1
A 65-year-old woman presented to the dermatology clinic in July with a pruritic rash of 2 days’ duration that started on the back and spread diffusely. The patient gardened regularly. Physical examination showed inflammatory papules and pustules on the back (Figure 1), as well as the groin, breasts, and ears. There was a punctate black dot in the center of some papules, and dermoscopy revealed ticks (Figure 2). Removal and microscopic examination confirmed larval-stage lone star ticks (Figure 3). The patient was prescribed topical steroids for pruritus as well as oral doxycycline for prophylaxis against tick-borne illnesses.

Patient 2
A 54-year-old man presented to the same clinic in July with pruritic lesions on the back, legs, ankles, and scrotum of 3 days’ duration that first appeared 24 hours after performing yardwork. Physical examination revealed diffusely distributed papules, pustules, and vesicles on the back (Figure 4). Some papules featured a punctate black dot in the center (similar to patient 1), and dermoscopy again revealed ticks. Removal and microscopic examination confirmed larval-stage ticks. The patient was treated with topical steroids and oral antihistamines for pruritus as well as prophylactic oral doxycycline.

Comment

Ticks are well-known human parasites, representing the second most common vector of human infectious disease.¹ Ticks have 3 motile stages: larva (or “seed”), nymph, and adult. They can bite humans during all stages. Larval ticks, distinguished by having 6 legs rather than 8 legs in nymphs and adults, can attack in droves and cause an infestation that presents as diffuse, pruritic, erythematous papules and pustules.^2-4 The first report of larval tick infestation in humans may have been in 1728 by William Byrd who described finding ticks on the skin that were too small to see without a microscope.⁵

Identification
The ticks in both of our cases were lone star ticks (Amblyomma americanum). The larval stage of A americanum is a proven cause of cutaneous reaction.^6,7 A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the terms tick, seed tick, or tick bite in combination with rash, eruption, infestation, papule, pustule, or pruritic revealed 6 reported cases of larval tick infestation in the literature (including our case); 5 were caused by A americanum and 1 by Ixodes dammini (now known as Ixodes scapularis); all occurred in July or August.^3,7-10 This time frame is consistent with the general tick life cycle across species: Adults feed from April to June, then lay eggs that hatch into larval ticks within 4 to 6 weeks. After hatching, larval ticks climb grass and weeds awaiting a passing host.⁴

Diagnosis
Larval tick infestation remains a frequently misdiagnosed etiology of diffuse pruritic papules and pustules, especially in urban settings where physicians are less likely to be familiar with this type of manifestation.^3,9-11 Larval ticks are submillimeter in size and difficult to appreciate with the naked eye, contributing to misdiagnosis. A punctate black dot may sometimes be seen in papules; however, dermoscopy is critical for accurate diagnosis, as hemorrhagic crust is a frequent misdiagnosis.

Management
In addition to symptomatic therapy, both of our patients received doxycycline as antibiotic prophylaxis for tick-borne illnesses given that a high number of ticks had been attached for more than 2 days.^12,13 Antibiotic prophylaxis for tick-borne illness is controversial. The exception is Lyme disease transmitted by nymphal or adult I scapularis when specific conditions are met: the bite must have occurred in an endemic area, doxycycline cannot be contraindicated, estimated duration of attachment is at least 36 hours, and prophylaxis must be started within 72 hours of tick removal.¹³ There are no official recommendations for the A americanum species or for larval-stage ticks of any species. Larval-stage ticks acting as vectors for disease transmission is not well documented in recent literature, and there currently is limited evidence supporting prophylactic antibiotics for larval tick bites. The presence of spotted fever rickettsioses has been reported (with the exception of Rickettsia rickettsii and Ehrlichia chaffeensis) in larval A americanum ticks, suggesting a theoretical possibility that they could act as disease vectors.^3,8,11,14-17 At a minimum, both prompt tick removal and close patient follow-up is warranted.

Conclusion

Human infestation with larval ticks is a common occurrence but can present a diagnostic challenge to an unfamiliar physician. We encourage consideration of larval tick infestation as the etiology of multiple or diffuse pruritic papules with a history of outdoor exposure.

Case Reports

Patient 1
A 65-year-old woman presented to the dermatology clinic in July with a pruritic rash of 2 days’ duration that started on the back and spread diffusely. The patient gardened regularly. Physical examination showed inflammatory papules and pustules on the back (Figure 1), as well as the groin, breasts, and ears. There was a punctate black dot in the center of some papules, and dermoscopy revealed ticks (Figure 2). Removal and microscopic examination confirmed larval-stage lone star ticks (Figure 3). The patient was prescribed topical steroids for pruritus as well as oral doxycycline for prophylaxis against tick-borne illnesses.

Patient 2
A 54-year-old man presented to the same clinic in July with pruritic lesions on the back, legs, ankles, and scrotum of 3 days’ duration that first appeared 24 hours after performing yardwork. Physical examination revealed diffusely distributed papules, pustules, and vesicles on the back (Figure 4). Some papules featured a punctate black dot in the center (similar to patient 1), and dermoscopy again revealed ticks. Removal and microscopic examination confirmed larval-stage ticks. The patient was treated with topical steroids and oral antihistamines for pruritus as well as prophylactic oral doxycycline.

Comment

Ticks are well-known human parasites, representing the second most common vector of human infectious disease.¹ Ticks have 3 motile stages: larva (or “seed”), nymph, and adult. They can bite humans during all stages. Larval ticks, distinguished by having 6 legs rather than 8 legs in nymphs and adults, can attack in droves and cause an infestation that presents as diffuse, pruritic, erythematous papules and pustules.^2-4 The first report of larval tick infestation in humans may have been in 1728 by William Byrd who described finding ticks on the skin that were too small to see without a microscope.⁵

Identification
The ticks in both of our cases were lone star ticks (Amblyomma americanum). The larval stage of A americanum is a proven cause of cutaneous reaction.^6,7 A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the terms tick, seed tick, or tick bite in combination with rash, eruption, infestation, papule, pustule, or pruritic revealed 6 reported cases of larval tick infestation in the literature (including our case); 5 were caused by A americanum and 1 by Ixodes dammini (now known as Ixodes scapularis); all occurred in July or August.^3,7-10 This time frame is consistent with the general tick life cycle across species: Adults feed from April to June, then lay eggs that hatch into larval ticks within 4 to 6 weeks. After hatching, larval ticks climb grass and weeds awaiting a passing host.⁴

Diagnosis
Larval tick infestation remains a frequently misdiagnosed etiology of diffuse pruritic papules and pustules, especially in urban settings where physicians are less likely to be familiar with this type of manifestation.^3,9-11 Larval ticks are submillimeter in size and difficult to appreciate with the naked eye, contributing to misdiagnosis. A punctate black dot may sometimes be seen in papules; however, dermoscopy is critical for accurate diagnosis, as hemorrhagic crust is a frequent misdiagnosis.

Management
In addition to symptomatic therapy, both of our patients received doxycycline as antibiotic prophylaxis for tick-borne illnesses given that a high number of ticks had been attached for more than 2 days.^12,13 Antibiotic prophylaxis for tick-borne illness is controversial. The exception is Lyme disease transmitted by nymphal or adult I scapularis when specific conditions are met: the bite must have occurred in an endemic area, doxycycline cannot be contraindicated, estimated duration of attachment is at least 36 hours, and prophylaxis must be started within 72 hours of tick removal.¹³ There are no official recommendations for the A americanum species or for larval-stage ticks of any species. Larval-stage ticks acting as vectors for disease transmission is not well documented in recent literature, and there currently is limited evidence supporting prophylactic antibiotics for larval tick bites. The presence of spotted fever rickettsioses has been reported (with the exception of Rickettsia rickettsii and Ehrlichia chaffeensis) in larval A americanum ticks, suggesting a theoretical possibility that they could act as disease vectors.^3,8,11,14-17 At a minimum, both prompt tick removal and close patient follow-up is warranted.

Conclusion

Human infestation with larval ticks is a common occurrence but can present a diagnostic challenge to an unfamiliar physician. We encourage consideration of larval tick infestation as the etiology of multiple or diffuse pruritic papules with a history of outdoor exposure.

Case Reports

Patient 1
A 65-year-old woman presented to the dermatology clinic in July with a pruritic rash of 2 days’ duration that started on the back and spread diffusely. The patient gardened regularly. Physical examination showed inflammatory papules and pustules on the back (Figure 1), as well as the groin, breasts, and ears. There was a punctate black dot in the center of some papules, and dermoscopy revealed ticks (Figure 2). Removal and microscopic examination confirmed larval-stage lone star ticks (Figure 3). The patient was prescribed topical steroids for pruritus as well as oral doxycycline for prophylaxis against tick-borne illnesses.

Patient 2
A 54-year-old man presented to the same clinic in July with pruritic lesions on the back, legs, ankles, and scrotum of 3 days’ duration that first appeared 24 hours after performing yardwork. Physical examination revealed diffusely distributed papules, pustules, and vesicles on the back (Figure 4). Some papules featured a punctate black dot in the center (similar to patient 1), and dermoscopy again revealed ticks. Removal and microscopic examination confirmed larval-stage ticks. The patient was treated with topical steroids and oral antihistamines for pruritus as well as prophylactic oral doxycycline.

Comment

Ticks are well-known human parasites, representing the second most common vector of human infectious disease.¹ Ticks have 3 motile stages: larva (or “seed”), nymph, and adult. They can bite humans during all stages. Larval ticks, distinguished by having 6 legs rather than 8 legs in nymphs and adults, can attack in droves and cause an infestation that presents as diffuse, pruritic, erythematous papules and pustules.^2-4 The first report of larval tick infestation in humans may have been in 1728 by William Byrd who described finding ticks on the skin that were too small to see without a microscope.⁵

Identification
The ticks in both of our cases were lone star ticks (Amblyomma americanum). The larval stage of A americanum is a proven cause of cutaneous reaction.^6,7 A PubMed search of articles indexed for MEDLINE as well as a Google Scholar search using the terms tick, seed tick, or tick bite in combination with rash, eruption, infestation, papule, pustule, or pruritic revealed 6 reported cases of larval tick infestation in the literature (including our case); 5 were caused by A americanum and 1 by Ixodes dammini (now known as Ixodes scapularis); all occurred in July or August.^3,7-10 This time frame is consistent with the general tick life cycle across species: Adults feed from April to June, then lay eggs that hatch into larval ticks within 4 to 6 weeks. After hatching, larval ticks climb grass and weeds awaiting a passing host.⁴

Diagnosis
Larval tick infestation remains a frequently misdiagnosed etiology of diffuse pruritic papules and pustules, especially in urban settings where physicians are less likely to be familiar with this type of manifestation.^3,9-11 Larval ticks are submillimeter in size and difficult to appreciate with the naked eye, contributing to misdiagnosis. A punctate black dot may sometimes be seen in papules; however, dermoscopy is critical for accurate diagnosis, as hemorrhagic crust is a frequent misdiagnosis.

Management
In addition to symptomatic therapy, both of our patients received doxycycline as antibiotic prophylaxis for tick-borne illnesses given that a high number of ticks had been attached for more than 2 days.^12,13 Antibiotic prophylaxis for tick-borne illness is controversial. The exception is Lyme disease transmitted by nymphal or adult I scapularis when specific conditions are met: the bite must have occurred in an endemic area, doxycycline cannot be contraindicated, estimated duration of attachment is at least 36 hours, and prophylaxis must be started within 72 hours of tick removal.¹³ There are no official recommendations for the A americanum species or for larval-stage ticks of any species. Larval-stage ticks acting as vectors for disease transmission is not well documented in recent literature, and there currently is limited evidence supporting prophylactic antibiotics for larval tick bites. The presence of spotted fever rickettsioses has been reported (with the exception of Rickettsia rickettsii and Ehrlichia chaffeensis) in larval A americanum ticks, suggesting a theoretical possibility that they could act as disease vectors.^3,8,11,14-17 At a minimum, both prompt tick removal and close patient follow-up is warranted.

Conclusion

Human infestation with larval ticks is a common occurrence but can present a diagnostic challenge to an unfamiliar physician. We encourage consideration of larval tick infestation as the etiology of multiple or diffuse pruritic papules with a history of outdoor exposure.

Pregnant women taking oral corticosteroids for rheumatoid arthritis may be at increased risk of preterm birth, according to research published online Sept. 30 in Rheumatology.

Antonio_Diaz/Thinkstock

A study of 528 pregnant women with rheumatoid arthritis enrolled in the MotherToBaby Pregnancy Studies found that those taking a daily dose of 10 mg or more of prednisone equivalent – representing a mean cumulative dose of 2,208.6 mg over the first 139 days of pregnancy – had 4.77-fold higher odds of preterm birth, compared with those not taking oral corticosteroids. Women on medium doses – with a mean cumulative dose of 883 mg – had 81% higher odds of preterm birth, while those on low cumulative doses of 264.9 mg showed a nonsignificant 38% increase in preterm birth risk.

Women who did not use oral corticosteroids before day 140 of pregnancy had a 2.2% risk of early preterm birth. Among women with low use of oral corticosteroids, the risk was 3.4%, among those with medium use the risk was 3.3%, but among those with high use the risk was 26.7%.

After day 140 of gestation, there was a nonsignificant 64% increase in the risk for preterm birth with any use of oral corticosteroids, compared with no use. But among women taking 10 mg or more of prednisone equivalent per day, the risk was 2.45-fold higher, whereas those taking under 10 mg showed no significant increase in risk.

“Systemic corticosteroid use has been associated with serious infection in pregnant women and serious and nonserious infection in individuals with autoimmune diseases, independent of other immunosuppressive medications, especially for doses of 10 mg of prednisone equivalent per day and greater,” wrote Kristin Palmsten, ScD, a research investigator with HealthPartners Institute in Minneapolis, Minn., and coauthors.

Given that intrauterine infection is believed to contribute to preterm birth, some have suggested that the immunosuppressive effects of oral corticosteroids could be associated with an increased risk of preterm birth because of subclinical intra-amniotic infection, they wrote.

However, they noted that there was a lack of information on the effect of dose and timing of oral corticosteroids during pregnancy on the risk of preterm birth.

The authors acknowledged that dosage of oral corticosteroids during pregnancy was linked to disease activity, which was itself associated with preterm birth risk. They adjusted for self-assessed rheumatoid arthritis severity at enrollment, which was generally during the first trimester, and found that this did attenuate the association with preterm birth.

“Ideally, we would have measures of disease severity at the time of every medication start, stop, or dose change to account for time-varying confounding later in pregnancy,” they wrote.

The study did not find any effect of biologic or nonbiologic disease-modifying antirheumatic drugs, either before or after the first 140 days of gestation.

The authors also looked at pregnancy outcomes among women with inflammatory bowel disease and asthma who were taking corticosteroids for those conditions.

While noting that these estimates were “imprecise,” they did see the suggestion of an increase in preterm birth among women taking oral corticosteroids for asthma, especially when used in the first half of pregnancy. There was also a suggestion of increased preterm birth risk associated with high oral corticosteroid use for inflammatory bowel disease, but these estimates were unadjusted, they noted.

“Overall, IBD and asthma exploratory analyses align with the direction of the associations in the RA analysis despite limitations of precision and inability to adjust for IBD severity,” they wrote.

The conclusions to be drawn from the study are limited by its small size, the investigators noted, as well as a lack of information on the type of rheumatoid arthritis and longitudinal disease severity. They added that while the hypothesized mechanism of action linking oral corticosteroid use to preterm birth was subclinical intrauterine infection, they did not have access to placental pathology to confirm this.

The study was supported by the National Institutes of Health, and the MotherToBaby Pregnancy Studies are supported by research grants from a number of pharmaceutical companies. No other conflicts of interest were declared.

SOURCE: Palmsten K et al. Rheumatology 2019 Sep 30. doi: 10.1093/rheumatology/kez405.

Pregnant women taking oral corticosteroids for rheumatoid arthritis may be at increased risk of preterm birth, according to research published online Sept. 30 in Rheumatology.

Antonio_Diaz/Thinkstock

A study of 528 pregnant women with rheumatoid arthritis enrolled in the MotherToBaby Pregnancy Studies found that those taking a daily dose of 10 mg or more of prednisone equivalent – representing a mean cumulative dose of 2,208.6 mg over the first 139 days of pregnancy – had 4.77-fold higher odds of preterm birth, compared with those not taking oral corticosteroids. Women on medium doses – with a mean cumulative dose of 883 mg – had 81% higher odds of preterm birth, while those on low cumulative doses of 264.9 mg showed a nonsignificant 38% increase in preterm birth risk.

Women who did not use oral corticosteroids before day 140 of pregnancy had a 2.2% risk of early preterm birth. Among women with low use of oral corticosteroids, the risk was 3.4%, among those with medium use the risk was 3.3%, but among those with high use the risk was 26.7%.

After day 140 of gestation, there was a nonsignificant 64% increase in the risk for preterm birth with any use of oral corticosteroids, compared with no use. But among women taking 10 mg or more of prednisone equivalent per day, the risk was 2.45-fold higher, whereas those taking under 10 mg showed no significant increase in risk.

“Systemic corticosteroid use has been associated with serious infection in pregnant women and serious and nonserious infection in individuals with autoimmune diseases, independent of other immunosuppressive medications, especially for doses of 10 mg of prednisone equivalent per day and greater,” wrote Kristin Palmsten, ScD, a research investigator with HealthPartners Institute in Minneapolis, Minn., and coauthors.

Given that intrauterine infection is believed to contribute to preterm birth, some have suggested that the immunosuppressive effects of oral corticosteroids could be associated with an increased risk of preterm birth because of subclinical intra-amniotic infection, they wrote.

However, they noted that there was a lack of information on the effect of dose and timing of oral corticosteroids during pregnancy on the risk of preterm birth.

The authors acknowledged that dosage of oral corticosteroids during pregnancy was linked to disease activity, which was itself associated with preterm birth risk. They adjusted for self-assessed rheumatoid arthritis severity at enrollment, which was generally during the first trimester, and found that this did attenuate the association with preterm birth.

“Ideally, we would have measures of disease severity at the time of every medication start, stop, or dose change to account for time-varying confounding later in pregnancy,” they wrote.

The study did not find any effect of biologic or nonbiologic disease-modifying antirheumatic drugs, either before or after the first 140 days of gestation.

The authors also looked at pregnancy outcomes among women with inflammatory bowel disease and asthma who were taking corticosteroids for those conditions.

While noting that these estimates were “imprecise,” they did see the suggestion of an increase in preterm birth among women taking oral corticosteroids for asthma, especially when used in the first half of pregnancy. There was also a suggestion of increased preterm birth risk associated with high oral corticosteroid use for inflammatory bowel disease, but these estimates were unadjusted, they noted.

“Overall, IBD and asthma exploratory analyses align with the direction of the associations in the RA analysis despite limitations of precision and inability to adjust for IBD severity,” they wrote.

The conclusions to be drawn from the study are limited by its small size, the investigators noted, as well as a lack of information on the type of rheumatoid arthritis and longitudinal disease severity. They added that while the hypothesized mechanism of action linking oral corticosteroid use to preterm birth was subclinical intrauterine infection, they did not have access to placental pathology to confirm this.

The study was supported by the National Institutes of Health, and the MotherToBaby Pregnancy Studies are supported by research grants from a number of pharmaceutical companies. No other conflicts of interest were declared.

SOURCE: Palmsten K et al. Rheumatology 2019 Sep 30. doi: 10.1093/rheumatology/kez405.

Pregnant women taking oral corticosteroids for rheumatoid arthritis may be at increased risk of preterm birth, according to research published online Sept. 30 in Rheumatology.

Antonio_Diaz/Thinkstock

A study of 528 pregnant women with rheumatoid arthritis enrolled in the MotherToBaby Pregnancy Studies found that those taking a daily dose of 10 mg or more of prednisone equivalent – representing a mean cumulative dose of 2,208.6 mg over the first 139 days of pregnancy – had 4.77-fold higher odds of preterm birth, compared with those not taking oral corticosteroids. Women on medium doses – with a mean cumulative dose of 883 mg – had 81% higher odds of preterm birth, while those on low cumulative doses of 264.9 mg showed a nonsignificant 38% increase in preterm birth risk.

Women who did not use oral corticosteroids before day 140 of pregnancy had a 2.2% risk of early preterm birth. Among women with low use of oral corticosteroids, the risk was 3.4%, among those with medium use the risk was 3.3%, but among those with high use the risk was 26.7%.

After day 140 of gestation, there was a nonsignificant 64% increase in the risk for preterm birth with any use of oral corticosteroids, compared with no use. But among women taking 10 mg or more of prednisone equivalent per day, the risk was 2.45-fold higher, whereas those taking under 10 mg showed no significant increase in risk.

“Systemic corticosteroid use has been associated with serious infection in pregnant women and serious and nonserious infection in individuals with autoimmune diseases, independent of other immunosuppressive medications, especially for doses of 10 mg of prednisone equivalent per day and greater,” wrote Kristin Palmsten, ScD, a research investigator with HealthPartners Institute in Minneapolis, Minn., and coauthors.

Given that intrauterine infection is believed to contribute to preterm birth, some have suggested that the immunosuppressive effects of oral corticosteroids could be associated with an increased risk of preterm birth because of subclinical intra-amniotic infection, they wrote.

However, they noted that there was a lack of information on the effect of dose and timing of oral corticosteroids during pregnancy on the risk of preterm birth.

The authors acknowledged that dosage of oral corticosteroids during pregnancy was linked to disease activity, which was itself associated with preterm birth risk. They adjusted for self-assessed rheumatoid arthritis severity at enrollment, which was generally during the first trimester, and found that this did attenuate the association with preterm birth.

“Ideally, we would have measures of disease severity at the time of every medication start, stop, or dose change to account for time-varying confounding later in pregnancy,” they wrote.

The study did not find any effect of biologic or nonbiologic disease-modifying antirheumatic drugs, either before or after the first 140 days of gestation.

The authors also looked at pregnancy outcomes among women with inflammatory bowel disease and asthma who were taking corticosteroids for those conditions.

While noting that these estimates were “imprecise,” they did see the suggestion of an increase in preterm birth among women taking oral corticosteroids for asthma, especially when used in the first half of pregnancy. There was also a suggestion of increased preterm birth risk associated with high oral corticosteroid use for inflammatory bowel disease, but these estimates were unadjusted, they noted.

“Overall, IBD and asthma exploratory analyses align with the direction of the associations in the RA analysis despite limitations of precision and inability to adjust for IBD severity,” they wrote.

The conclusions to be drawn from the study are limited by its small size, the investigators noted, as well as a lack of information on the type of rheumatoid arthritis and longitudinal disease severity. They added that while the hypothesized mechanism of action linking oral corticosteroid use to preterm birth was subclinical intrauterine infection, they did not have access to placental pathology to confirm this.

The study was supported by the National Institutes of Health, and the MotherToBaby Pregnancy Studies are supported by research grants from a number of pharmaceutical companies. No other conflicts of interest were declared.

SOURCE: Palmsten K et al. Rheumatology 2019 Sep 30. doi: 10.1093/rheumatology/kez405.

STOCKHOLM – Baseline levels of neurofilament light (NfL) in cerebrospinal fluid (CSF) correlated well with imaging findings in patients with multiple sclerosis (MS) over the course of 10 years, according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).

Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.

Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.

Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.

NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.

To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.

Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.

Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.

Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).

Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.

Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.

“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.

Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
 

koakes@mdedgecom

SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.

STOCKHOLM – Baseline levels of neurofilament light (NfL) in cerebrospinal fluid (CSF) correlated well with imaging findings in patients with multiple sclerosis (MS) over the course of 10 years, according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).

Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.

Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.

Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.

NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.

To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.

Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.

Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.

Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).

Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.

Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.

“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.

Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
 

koakes@mdedgecom

SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.

STOCKHOLM – Baseline levels of neurofilament light (NfL) in cerebrospinal fluid (CSF) correlated well with imaging findings in patients with multiple sclerosis (MS) over the course of 10 years, according to a recent study. The correlation between CSF NfL at baseline and the percent of total brain volume change was statistically significant and persisted over time, said Alok Bhan, MD, in an interview at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

“We found a significant correlation between loss of total brain volume with baseline CSF NfL at the 5- and 10-year follow-up,” reported Dr. Bhan. At the 5-year mark, the correlation coefficient (r) was –0.430 (P = .003); at 10 years, the correlation coefficient was –0.395 (P = .042).

Higher CSF levels of the neuropeptide “thereby predicted steeper loss of brain volume over a 10-year disease course, and baseline CSF NfL could thus be a prognostic factor for later MRI-confirmed progression,” reported Dr. Bhan, of the department of neurology at Stavanger (Norway) University Hospital, and his coinvestigators.

Magnetic resonance imaging, the current standard in tracking MS lesions, has limitations, noted the investigators. “MRI pathology is only revealed after the injury has manifested itself, and as it is commonly being conducted no more frequent[ly] than annually, lesions may have developed up to a year” before they are evident on MRI scans, they said.

Concerns about long-term effects of the gadolinium deposition that results from frequent scans are rising as well, said Dr. Bhan. For these reasons, he said, MRI is an imperfect biomarker for MS progression.

NfL is a polypeptide in neurons that has been proposed as prognostic in MS, but “longitudinal data regarding its prognostic value” are still scarce, said Dr. Bhan.

To help fill that knowledge gap, the study aimed to assess how NfL obtained from CSF at the time of MS diagnosis correlated with MRI-determined loss of brain volume over a period of 10 years.

Participants’ brain atrophy was assessed using MRI performed at baseline and at 5 and 10 years using the same protocol on a 1.5 Tesla scanner. The protocol included dual spin echo T2-weighted imaging, 3-D T1-weighted imaging, and dual spin echo T1-weighted imaging. In addition to obtaining both global and regional changes in brain volume, the investigators also calculated regional volumes for subcortical deep gray matter.

Cerebrospinal fluid obtained from the lumbar puncture performed at the time of baseline assessment was the source for the single NfL value, obtained by use of a commercially available enzyme-linked immunosorbent assay.

Looking at volume loss in specific brain regions, significant correlations were seen between volume loss in the deep gray matter at both 5 and 10 years (r = –0.430 and –0.395; P = .006 and .042, respectively). At 10 years, pallidal nuclei and hippocampal volume losses also correlated significantly with baseline CSF NfL (r = –0.445 and –0.472; P = .020 and .013, respectively).

Attrition was substantial in the cohort, with the initial 44 patients dropping to 39 at 5 years and 27 by 10 years. Of those 44 initial enrollees, 30 were female, and the mean age was about 42 years at baseline. Duration of MS was a median 60 months at the time of enrollment, and the mean Extended Disability Status Scale (EDSS) score was 3.5 at baseline. Most patients (n = 35) had relapsing-remitting MS.

Just 16% of enrollees were on disease-modifying therapy at baseline, but this figure climbed to 52% by the end of the study period, said Dr. Bhan, a trend that in part reflected changes in practice patterns over the study period.

“Our study is yet another report that supports the use of CSF NfL in the routine work-up of newly diagnosed MS,” noted Dr. Bhan and his coauthors. Having a baseline CSF NfL level “would give patients an indication of future disease burden 10 years in advance,” thereby adding to the prognostic toolkit, they said.

Dr. Bhan reported receiving research funding from Novartis Norway, and two other coauthors reported several financial relationships with pharmaceutical companies.
 

koakes@mdedgecom

SOURCE: Bhan A et al. ECTRIMS 2019, Abstract P592.

MINNEAPOLIS -- Medical professionals within the US Department of Veterans Affairs (VA) can’t prescribe cannabis or certify patients to be able to get it. VA pharmacists can’t dispense it. Still, “we’re asked about it plenty,” a hospice and palliative care specialist told colleagues, at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

That brings up a big question, said Michael Stellini, MD, MS, FACP, FAAHPM, of Wayne State University, Karmanos Cancer Center, and the John D. Dingell VA Medical Center, in Detroit Michigan: “Should sick people be smoking pot?”

Even the question itself isn’t a simple one to answer since smoking isn’t the only way to consume cannabis for medical purposes. And figuring out the best advice is difficult. As Dr. Stellini said, there’s plenty of uncertainty about crucial cannabis topics like safety and benefits.

Dr. Stellini offered a number of facts and tips about cannabis in medicine.

Understand ‘qualifying conditions’ in your state

In states with legal medical marijuana, he said, physicians do not prescribe marijuana. However, they may certify that patients are eligible to get the drug for medical purposes if they meet certain qualifications.

A typical list of qualifying conditions includes diseases such as cancer, glaucoma, HIV/AIDS and Crohn’s disease. Qualifying conditions also tend to include treatments for severe diseases that produce wasting syndrome, severe and chronic pain, severe nausea, seizures and severe and persistent muscle spasm.

In Michigan, where Dr. Stellini practices, a panel in 2018 approved a long list of added qualifying conditions such as chronic pain, obsessive compulsive disorder and arthritis. But the panel rejected other conditions such as anxiety, asthma, panic attacks and schizophrenia.

Vaporizers are an alternative to joints, but...

Vaporizers are commonly used as an alternative to smoking marijuana joints, Dr. Stellini said, and they don’t significantly release tars or much if any carbon monoxide. While research is limited, he said, use of vaporizers hasn’t been linked to more lung cancer or chronic obstructive pulmonary disease.

“Vaping” is another option, but it’s been linked to dozens of deaths and hundreds of cases of illness in recent weeks. Many patients have reported using products that contain THC, a component of marijuana.

Other delivery methods exist

Marijuana can be ingested in liquid and solid food. “But edibles can have a slow onset of action compared to vaporizing or smoking,” Dr. Stellini said. “You might over-indulge. When users get to their steady state, they might have some adverse effects [AEs].”

Marijuana still has risks

Cannabis use has a long list of well-known AEs linked to the THC component. The most common are drowsiness, fatigue, dizziness, dry mouth, anxiety, cognitive effects, cough, and nausea, Dr. Stellini said. More serious AEs such as psychosis have been reported.

And, of course, users of cannabis with THC get high if they use enough.

A 2017 National Academies of Sciences, Engineering and Medicine report linked cannabis use to a higher risk of motor vehicle accidents. Still, Dr. Stellini said, “it’s relatively safe with respect to mortality, especially compared to opioids.”¹

Risk of use in cancer may be low

Research suggest that patients with cancer use cannabis as much as other people and perhaps even more, Dr. Stellini said. But are they facing any extra risks? In general, he said, it doesn’t appear that way.

Cannabis seems to be safe when used with chemotherapy, he said, and drug-drug interactions in cancer appear to be rare. Some studies have suggested that cannabinoids—a component of marijuana—may be an effective treatment for chemotherapy-induced peripheral neuropathy.

However, he said, 1 study has raised a red flag about a possible interaction with cancer immunotherapy. Researchers found evidence that patients who used cannabis had lower tumor response rates to nivolomab for advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. However, survival wasn’t affected.²

Meanwhile, he said, there’s no strong evidence that cannabis is a useful treatment for cancer, he said, although it’s worth investigating.

Cannabidiol is the hot new product

Cannabidiol, also known as CBD, has become hugely popular, Dr. Stellini said. It is derived from hemp and doesn’t cause a “buzz” like cannabis.

Due to lack of regulation, he said, buyers should beware. And, he said, CBD has multiple EAs. Standard doses can cause drowsiness, fatigue, dizziness, dry mouth, hypotension and lightheadedness.

Dr. Stellini reports no relevant disclosures.

MINNEAPOLIS -- Medical professionals within the US Department of Veterans Affairs (VA) can’t prescribe cannabis or certify patients to be able to get it. VA pharmacists can’t dispense it. Still, “we’re asked about it plenty,” a hospice and palliative care specialist told colleagues, at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

That brings up a big question, said Michael Stellini, MD, MS, FACP, FAAHPM, of Wayne State University, Karmanos Cancer Center, and the John D. Dingell VA Medical Center, in Detroit Michigan: “Should sick people be smoking pot?”

Even the question itself isn’t a simple one to answer since smoking isn’t the only way to consume cannabis for medical purposes. And figuring out the best advice is difficult. As Dr. Stellini said, there’s plenty of uncertainty about crucial cannabis topics like safety and benefits.

Dr. Stellini offered a number of facts and tips about cannabis in medicine.

Understand ‘qualifying conditions’ in your state

In states with legal medical marijuana, he said, physicians do not prescribe marijuana. However, they may certify that patients are eligible to get the drug for medical purposes if they meet certain qualifications.

A typical list of qualifying conditions includes diseases such as cancer, glaucoma, HIV/AIDS and Crohn’s disease. Qualifying conditions also tend to include treatments for severe diseases that produce wasting syndrome, severe and chronic pain, severe nausea, seizures and severe and persistent muscle spasm.

In Michigan, where Dr. Stellini practices, a panel in 2018 approved a long list of added qualifying conditions such as chronic pain, obsessive compulsive disorder and arthritis. But the panel rejected other conditions such as anxiety, asthma, panic attacks and schizophrenia.

Vaporizers are an alternative to joints, but...

Vaporizers are commonly used as an alternative to smoking marijuana joints, Dr. Stellini said, and they don’t significantly release tars or much if any carbon monoxide. While research is limited, he said, use of vaporizers hasn’t been linked to more lung cancer or chronic obstructive pulmonary disease.

“Vaping” is another option, but it’s been linked to dozens of deaths and hundreds of cases of illness in recent weeks. Many patients have reported using products that contain THC, a component of marijuana.

Other delivery methods exist

Marijuana can be ingested in liquid and solid food. “But edibles can have a slow onset of action compared to vaporizing or smoking,” Dr. Stellini said. “You might over-indulge. When users get to their steady state, they might have some adverse effects [AEs].”

Marijuana still has risks

Cannabis use has a long list of well-known AEs linked to the THC component. The most common are drowsiness, fatigue, dizziness, dry mouth, anxiety, cognitive effects, cough, and nausea, Dr. Stellini said. More serious AEs such as psychosis have been reported.

And, of course, users of cannabis with THC get high if they use enough.

A 2017 National Academies of Sciences, Engineering and Medicine report linked cannabis use to a higher risk of motor vehicle accidents. Still, Dr. Stellini said, “it’s relatively safe with respect to mortality, especially compared to opioids.”¹

Risk of use in cancer may be low

Research suggest that patients with cancer use cannabis as much as other people and perhaps even more, Dr. Stellini said. But are they facing any extra risks? In general, he said, it doesn’t appear that way.

Cannabis seems to be safe when used with chemotherapy, he said, and drug-drug interactions in cancer appear to be rare. Some studies have suggested that cannabinoids—a component of marijuana—may be an effective treatment for chemotherapy-induced peripheral neuropathy.

However, he said, 1 study has raised a red flag about a possible interaction with cancer immunotherapy. Researchers found evidence that patients who used cannabis had lower tumor response rates to nivolomab for advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. However, survival wasn’t affected.²

Meanwhile, he said, there’s no strong evidence that cannabis is a useful treatment for cancer, he said, although it’s worth investigating.

Cannabidiol is the hot new product

Cannabidiol, also known as CBD, has become hugely popular, Dr. Stellini said. It is derived from hemp and doesn’t cause a “buzz” like cannabis.

Due to lack of regulation, he said, buyers should beware. And, he said, CBD has multiple EAs. Standard doses can cause drowsiness, fatigue, dizziness, dry mouth, hypotension and lightheadedness.

Dr. Stellini reports no relevant disclosures.

MINNEAPOLIS -- Medical professionals within the US Department of Veterans Affairs (VA) can’t prescribe cannabis or certify patients to be able to get it. VA pharmacists can’t dispense it. Still, “we’re asked about it plenty,” a hospice and palliative care specialist told colleagues, at the annual meeting of the Association of VA Hematology/Oncology (AVAHO).

That brings up a big question, said Michael Stellini, MD, MS, FACP, FAAHPM, of Wayne State University, Karmanos Cancer Center, and the John D. Dingell VA Medical Center, in Detroit Michigan: “Should sick people be smoking pot?”

Even the question itself isn’t a simple one to answer since smoking isn’t the only way to consume cannabis for medical purposes. And figuring out the best advice is difficult. As Dr. Stellini said, there’s plenty of uncertainty about crucial cannabis topics like safety and benefits.

Dr. Stellini offered a number of facts and tips about cannabis in medicine.

Understand ‘qualifying conditions’ in your state

In states with legal medical marijuana, he said, physicians do not prescribe marijuana. However, they may certify that patients are eligible to get the drug for medical purposes if they meet certain qualifications.

A typical list of qualifying conditions includes diseases such as cancer, glaucoma, HIV/AIDS and Crohn’s disease. Qualifying conditions also tend to include treatments for severe diseases that produce wasting syndrome, severe and chronic pain, severe nausea, seizures and severe and persistent muscle spasm.

In Michigan, where Dr. Stellini practices, a panel in 2018 approved a long list of added qualifying conditions such as chronic pain, obsessive compulsive disorder and arthritis. But the panel rejected other conditions such as anxiety, asthma, panic attacks and schizophrenia.

Vaporizers are an alternative to joints, but...

Vaporizers are commonly used as an alternative to smoking marijuana joints, Dr. Stellini said, and they don’t significantly release tars or much if any carbon monoxide. While research is limited, he said, use of vaporizers hasn’t been linked to more lung cancer or chronic obstructive pulmonary disease.

“Vaping” is another option, but it’s been linked to dozens of deaths and hundreds of cases of illness in recent weeks. Many patients have reported using products that contain THC, a component of marijuana.

Other delivery methods exist

Marijuana can be ingested in liquid and solid food. “But edibles can have a slow onset of action compared to vaporizing or smoking,” Dr. Stellini said. “You might over-indulge. When users get to their steady state, they might have some adverse effects [AEs].”

Marijuana still has risks

Cannabis use has a long list of well-known AEs linked to the THC component. The most common are drowsiness, fatigue, dizziness, dry mouth, anxiety, cognitive effects, cough, and nausea, Dr. Stellini said. More serious AEs such as psychosis have been reported.

And, of course, users of cannabis with THC get high if they use enough.

A 2017 National Academies of Sciences, Engineering and Medicine report linked cannabis use to a higher risk of motor vehicle accidents. Still, Dr. Stellini said, “it’s relatively safe with respect to mortality, especially compared to opioids.”¹

Risk of use in cancer may be low

Research suggest that patients with cancer use cannabis as much as other people and perhaps even more, Dr. Stellini said. But are they facing any extra risks? In general, he said, it doesn’t appear that way.

Cannabis seems to be safe when used with chemotherapy, he said, and drug-drug interactions in cancer appear to be rare. Some studies have suggested that cannabinoids—a component of marijuana—may be an effective treatment for chemotherapy-induced peripheral neuropathy.

However, he said, 1 study has raised a red flag about a possible interaction with cancer immunotherapy. Researchers found evidence that patients who used cannabis had lower tumor response rates to nivolomab for advanced melanoma, non-small cell lung cancer, and renal clear cell carcinoma. However, survival wasn’t affected.²

Meanwhile, he said, there’s no strong evidence that cannabis is a useful treatment for cancer, he said, although it’s worth investigating.

Cannabidiol is the hot new product

Cannabidiol, also known as CBD, has become hugely popular, Dr. Stellini said. It is derived from hemp and doesn’t cause a “buzz” like cannabis.

Due to lack of regulation, he said, buyers should beware. And, he said, CBD has multiple EAs. Standard doses can cause drowsiness, fatigue, dizziness, dry mouth, hypotension and lightheadedness.

Dr. Stellini reports no relevant disclosures.

Up-to-date vaccination rates rose significantly in a neonatal ICU after implementation of five interventions targeting root causes of low immunization, according to a study in Pediatrics.

MarianVejcik/Getty Images

Investigators led by Raymond C. Stetson, MD, of the Mayo Clinic in Rochester, Minn., identified three root causes of underimmunization in a NICU at Mayo Clinic: providers’ lack of knowledge about recommended immunization schedules; immunizations not being ordered when they were due; and parental hesitancy toward vaccination. They addressed these causes with the following five phases of intervention: an intranet resource educating providers about vaccine schedules and dosing intervals; a spreadsheet-based checklist to track and flag immunization status; an intranet resource aimed at discussion with vaccine-hesitant parents; education about safety in providing immunization and review of material from the first three interventions; and education about documentation, including parental consent.

Over the project period, 1,242 infants were discharged or transferred from the NICU. The study included a 6-month “improve phase,” during which interventions were implemented, and a “control phase,” during which the ongoing effects after implementation were observed. At baseline, the rate of fully immunized infants in the NICU was only 56% by time of discharge or transfer, but during the combined improve and control phases, it was 93% with a P value of less than .001.

One of the limitations of the study is that the first three interventions were introduced simultaneously, which makes it hard to determine how much effect each might have had.

“Infants treated in NICUs represent a vulnerable population with the potential for high morbidity and mortality from vaccine-preventable infections,” the investigators wrote. “Our [quality improvement] effort, and others, demonstrate that this population is at risk for underimmunization and that immunization rates can be improved with a small number of interventions. Additionally, we were able to significantly decrease the number of days that immunizations were delayed compared to the routine infant vaccination schedule.”

There was no external funding for the study. One of the coauthors is on safety committees of vaccine studies for Merck. The other authors have no relevant financial disclosures.

cpalmer@mdedge.com

SOURCE: Stetson R et al. Pediatr. 2019. doi: 10.1542/peds.2019-0337.

Up-to-date vaccination rates rose significantly in a neonatal ICU after implementation of five interventions targeting root causes of low immunization, according to a study in Pediatrics.

MarianVejcik/Getty Images

Investigators led by Raymond C. Stetson, MD, of the Mayo Clinic in Rochester, Minn., identified three root causes of underimmunization in a NICU at Mayo Clinic: providers’ lack of knowledge about recommended immunization schedules; immunizations not being ordered when they were due; and parental hesitancy toward vaccination. They addressed these causes with the following five phases of intervention: an intranet resource educating providers about vaccine schedules and dosing intervals; a spreadsheet-based checklist to track and flag immunization status; an intranet resource aimed at discussion with vaccine-hesitant parents; education about safety in providing immunization and review of material from the first three interventions; and education about documentation, including parental consent.

Over the project period, 1,242 infants were discharged or transferred from the NICU. The study included a 6-month “improve phase,” during which interventions were implemented, and a “control phase,” during which the ongoing effects after implementation were observed. At baseline, the rate of fully immunized infants in the NICU was only 56% by time of discharge or transfer, but during the combined improve and control phases, it was 93% with a P value of less than .001.

One of the limitations of the study is that the first three interventions were introduced simultaneously, which makes it hard to determine how much effect each might have had.

“Infants treated in NICUs represent a vulnerable population with the potential for high morbidity and mortality from vaccine-preventable infections,” the investigators wrote. “Our [quality improvement] effort, and others, demonstrate that this population is at risk for underimmunization and that immunization rates can be improved with a small number of interventions. Additionally, we were able to significantly decrease the number of days that immunizations were delayed compared to the routine infant vaccination schedule.”

There was no external funding for the study. One of the coauthors is on safety committees of vaccine studies for Merck. The other authors have no relevant financial disclosures.

cpalmer@mdedge.com

SOURCE: Stetson R et al. Pediatr. 2019. doi: 10.1542/peds.2019-0337.

Up-to-date vaccination rates rose significantly in a neonatal ICU after implementation of five interventions targeting root causes of low immunization, according to a study in Pediatrics.

MarianVejcik/Getty Images

Investigators led by Raymond C. Stetson, MD, of the Mayo Clinic in Rochester, Minn., identified three root causes of underimmunization in a NICU at Mayo Clinic: providers’ lack of knowledge about recommended immunization schedules; immunizations not being ordered when they were due; and parental hesitancy toward vaccination. They addressed these causes with the following five phases of intervention: an intranet resource educating providers about vaccine schedules and dosing intervals; a spreadsheet-based checklist to track and flag immunization status; an intranet resource aimed at discussion with vaccine-hesitant parents; education about safety in providing immunization and review of material from the first three interventions; and education about documentation, including parental consent.

Over the project period, 1,242 infants were discharged or transferred from the NICU. The study included a 6-month “improve phase,” during which interventions were implemented, and a “control phase,” during which the ongoing effects after implementation were observed. At baseline, the rate of fully immunized infants in the NICU was only 56% by time of discharge or transfer, but during the combined improve and control phases, it was 93% with a P value of less than .001.

One of the limitations of the study is that the first three interventions were introduced simultaneously, which makes it hard to determine how much effect each might have had.

“Infants treated in NICUs represent a vulnerable population with the potential for high morbidity and mortality from vaccine-preventable infections,” the investigators wrote. “Our [quality improvement] effort, and others, demonstrate that this population is at risk for underimmunization and that immunization rates can be improved with a small number of interventions. Additionally, we were able to significantly decrease the number of days that immunizations were delayed compared to the routine infant vaccination schedule.”

There was no external funding for the study. One of the coauthors is on safety committees of vaccine studies for Merck. The other authors have no relevant financial disclosures.

cpalmer@mdedge.com

SOURCE: Stetson R et al. Pediatr. 2019. doi: 10.1542/peds.2019-0337.

A judge has sided with a medical malpractice insurer in a legal challenge that accused the company of misallocating blame among physicians after a liability settlement.

In a Sept. 27 decision, Judge Debra Squires-Lee of the Commonwealth of Massachusetts Superior Court ruled that Medical Professional Mutual Insurance Company (ProMutual) acted reasonably when it settled a medical liability claim for $500,000 against several health providers and allocated responsibility for 30% of the settlement ($150,000) to internist Nataly Minkina, MD. ProMutual was well within its rights and obligations when it settled the underlying claim and did not act in bad faith when assigning responsibility in the case, Judge Squires-Lee wrote in her 49-page ruling.

“At its heart, this case is about a multiple defendant malpractice lawsuit with finger pointing by Dr. Minkina against her codefendants and others, and a disagreement about ProMutual’s ultimate determination about how to allocate a global settlement with the plaintiffs amongst ProMutual’s insureds,” Judge Squires-Lee wrote in the decision. “Dr. Minkina strongly believes that she did not fail [the patient], that she acted reasonably, and that her treatment of [the patient] satisfied the standard of care. She also questions why ProMutual failed to allocate liability in the [patient’s] suit to other physicians. However ... the question for this court is whether ProMutual committed unfair or deceptive acts or practices in its settlement and allocation of its settlement. I conclude that ProMutual did not.”

The case stems from a patient’s lawsuit against Dr. Minkina and several others at Blue Hills Medical Associates in Braintree, Mass. The patient alleged that the health care professionals were responsible for a missed breast cancer diagnosis. Dr. Minkina saw the patient just once in 2002 while covering for another doctor. During the visit, she confirmed some nodularity in the 55-year-old women’s breast and referred her for a mammogram and an ultrasound. A radiologist twice reported no abnormalities, which Dr. Minkina said she relayed to the patient. Dr. Minkina left the practice shortly after.

The patient visited the practice several more times and was referred for another mammogram in 2006, the results of which revealed some signs of malignancy, according to court documents. However, a nurse at the practice misread, misunderstood, or overlooked the signs and recorded that “the benign breast condition had no changes,” according to court transcripts. Later that year, the patient visited the practice complaining of headaches and a droopy eye at which time her primary care physician diagnosed sinusitis and prescribed antibiotics. In 2007, the patient underwent magnetic resonance imaging of the brain and the breast, which revealed widespread metastatic carcinoma. She and her family sued Dr. Minkina and several others in June 2007. The patient died in 2008.

ProMutual settled the case against the defendants for $500,000 in 2008, allocating 30% of the liability to Dr. Minkina, 10% of the nurse practitioner, 60% to the medical practice, and no liability to the other doctors named. ProMutual contended Dr. Minkina bore more responsibility than the other health care professionals named for the delayed diagnosis because of causation factors and standard of care violations, namely that Dr. Minkina should have pursued a biopsy for the patient.

Dr. Minkina sued the insurer in 2012, claiming chiefly that the insurer allocated an unjustifiably high percentage of liability to her because she was no longer insured and because the company had an economic incentive to allocate a disproportionate percentage of responsibility and damages.

A lower court initially dismissed Dr. Minkina’s suit, but the Commonwealth of Massachusetts Appeals Court in 2015 overturned that decision, ruling the case could move forward. In 2018, the superior court agreed Dr. Minkina had a valid bad faith claim, stating that she had provided information about ProMutual’s conduct from which “a reasonable juror could infer the defendant’s bad faith in connection with its settling the underlying malpractice suit, including the allocation of liability.

But Judge Squires-Lee ruled that trial evidence showed that ProMutual did not act for its own benefit or favor other insureds over Dr. Minkina. The judge wrote that the insurer satisfied its contractual and legal obligations when defending the underlying legal claim.

Dr. Minkina said she was disappointed with the ruling, but that she is considering her legal avenues.

“[The] judge’s decision in my case against ProMutual is obviously disappointing, but it is not the first time [the] trial court decided against me in this case,” Dr. Minkina said in an interview. “It is a battle between David and Goliath, [a] single physician against [a] $3.6 billion insurance company with unlimited resources. The decision has just been announced and it is voluminous. I am still reading it and evaluating my options with my attorneys, but it is not the end of the road yet.”

ProMutual declined to comment about the decision.

agallegos@mdedge.com

A judge has sided with a medical malpractice insurer in a legal challenge that accused the company of misallocating blame among physicians after a liability settlement.

In a Sept. 27 decision, Judge Debra Squires-Lee of the Commonwealth of Massachusetts Superior Court ruled that Medical Professional Mutual Insurance Company (ProMutual) acted reasonably when it settled a medical liability claim for $500,000 against several health providers and allocated responsibility for 30% of the settlement ($150,000) to internist Nataly Minkina, MD. ProMutual was well within its rights and obligations when it settled the underlying claim and did not act in bad faith when assigning responsibility in the case, Judge Squires-Lee wrote in her 49-page ruling.

“At its heart, this case is about a multiple defendant malpractice lawsuit with finger pointing by Dr. Minkina against her codefendants and others, and a disagreement about ProMutual’s ultimate determination about how to allocate a global settlement with the plaintiffs amongst ProMutual’s insureds,” Judge Squires-Lee wrote in the decision. “Dr. Minkina strongly believes that she did not fail [the patient], that she acted reasonably, and that her treatment of [the patient] satisfied the standard of care. She also questions why ProMutual failed to allocate liability in the [patient’s] suit to other physicians. However ... the question for this court is whether ProMutual committed unfair or deceptive acts or practices in its settlement and allocation of its settlement. I conclude that ProMutual did not.”

The case stems from a patient’s lawsuit against Dr. Minkina and several others at Blue Hills Medical Associates in Braintree, Mass. The patient alleged that the health care professionals were responsible for a missed breast cancer diagnosis. Dr. Minkina saw the patient just once in 2002 while covering for another doctor. During the visit, she confirmed some nodularity in the 55-year-old women’s breast and referred her for a mammogram and an ultrasound. A radiologist twice reported no abnormalities, which Dr. Minkina said she relayed to the patient. Dr. Minkina left the practice shortly after.

The patient visited the practice several more times and was referred for another mammogram in 2006, the results of which revealed some signs of malignancy, according to court documents. However, a nurse at the practice misread, misunderstood, or overlooked the signs and recorded that “the benign breast condition had no changes,” according to court transcripts. Later that year, the patient visited the practice complaining of headaches and a droopy eye at which time her primary care physician diagnosed sinusitis and prescribed antibiotics. In 2007, the patient underwent magnetic resonance imaging of the brain and the breast, which revealed widespread metastatic carcinoma. She and her family sued Dr. Minkina and several others in June 2007. The patient died in 2008.

ProMutual settled the case against the defendants for $500,000 in 2008, allocating 30% of the liability to Dr. Minkina, 10% of the nurse practitioner, 60% to the medical practice, and no liability to the other doctors named. ProMutual contended Dr. Minkina bore more responsibility than the other health care professionals named for the delayed diagnosis because of causation factors and standard of care violations, namely that Dr. Minkina should have pursued a biopsy for the patient.

Dr. Minkina sued the insurer in 2012, claiming chiefly that the insurer allocated an unjustifiably high percentage of liability to her because she was no longer insured and because the company had an economic incentive to allocate a disproportionate percentage of responsibility and damages.

A lower court initially dismissed Dr. Minkina’s suit, but the Commonwealth of Massachusetts Appeals Court in 2015 overturned that decision, ruling the case could move forward. In 2018, the superior court agreed Dr. Minkina had a valid bad faith claim, stating that she had provided information about ProMutual’s conduct from which “a reasonable juror could infer the defendant’s bad faith in connection with its settling the underlying malpractice suit, including the allocation of liability.

But Judge Squires-Lee ruled that trial evidence showed that ProMutual did not act for its own benefit or favor other insureds over Dr. Minkina. The judge wrote that the insurer satisfied its contractual and legal obligations when defending the underlying legal claim.

Dr. Minkina said she was disappointed with the ruling, but that she is considering her legal avenues.

“[The] judge’s decision in my case against ProMutual is obviously disappointing, but it is not the first time [the] trial court decided against me in this case,” Dr. Minkina said in an interview. “It is a battle between David and Goliath, [a] single physician against [a] $3.6 billion insurance company with unlimited resources. The decision has just been announced and it is voluminous. I am still reading it and evaluating my options with my attorneys, but it is not the end of the road yet.”

ProMutual declined to comment about the decision.

agallegos@mdedge.com

A judge has sided with a medical malpractice insurer in a legal challenge that accused the company of misallocating blame among physicians after a liability settlement.

In a Sept. 27 decision, Judge Debra Squires-Lee of the Commonwealth of Massachusetts Superior Court ruled that Medical Professional Mutual Insurance Company (ProMutual) acted reasonably when it settled a medical liability claim for $500,000 against several health providers and allocated responsibility for 30% of the settlement ($150,000) to internist Nataly Minkina, MD. ProMutual was well within its rights and obligations when it settled the underlying claim and did not act in bad faith when assigning responsibility in the case, Judge Squires-Lee wrote in her 49-page ruling.

“At its heart, this case is about a multiple defendant malpractice lawsuit with finger pointing by Dr. Minkina against her codefendants and others, and a disagreement about ProMutual’s ultimate determination about how to allocate a global settlement with the plaintiffs amongst ProMutual’s insureds,” Judge Squires-Lee wrote in the decision. “Dr. Minkina strongly believes that she did not fail [the patient], that she acted reasonably, and that her treatment of [the patient] satisfied the standard of care. She also questions why ProMutual failed to allocate liability in the [patient’s] suit to other physicians. However ... the question for this court is whether ProMutual committed unfair or deceptive acts or practices in its settlement and allocation of its settlement. I conclude that ProMutual did not.”

The case stems from a patient’s lawsuit against Dr. Minkina and several others at Blue Hills Medical Associates in Braintree, Mass. The patient alleged that the health care professionals were responsible for a missed breast cancer diagnosis. Dr. Minkina saw the patient just once in 2002 while covering for another doctor. During the visit, she confirmed some nodularity in the 55-year-old women’s breast and referred her for a mammogram and an ultrasound. A radiologist twice reported no abnormalities, which Dr. Minkina said she relayed to the patient. Dr. Minkina left the practice shortly after.

The patient visited the practice several more times and was referred for another mammogram in 2006, the results of which revealed some signs of malignancy, according to court documents. However, a nurse at the practice misread, misunderstood, or overlooked the signs and recorded that “the benign breast condition had no changes,” according to court transcripts. Later that year, the patient visited the practice complaining of headaches and a droopy eye at which time her primary care physician diagnosed sinusitis and prescribed antibiotics. In 2007, the patient underwent magnetic resonance imaging of the brain and the breast, which revealed widespread metastatic carcinoma. She and her family sued Dr. Minkina and several others in June 2007. The patient died in 2008.

ProMutual settled the case against the defendants for $500,000 in 2008, allocating 30% of the liability to Dr. Minkina, 10% of the nurse practitioner, 60% to the medical practice, and no liability to the other doctors named. ProMutual contended Dr. Minkina bore more responsibility than the other health care professionals named for the delayed diagnosis because of causation factors and standard of care violations, namely that Dr. Minkina should have pursued a biopsy for the patient.

Dr. Minkina sued the insurer in 2012, claiming chiefly that the insurer allocated an unjustifiably high percentage of liability to her because she was no longer insured and because the company had an economic incentive to allocate a disproportionate percentage of responsibility and damages.

A lower court initially dismissed Dr. Minkina’s suit, but the Commonwealth of Massachusetts Appeals Court in 2015 overturned that decision, ruling the case could move forward. In 2018, the superior court agreed Dr. Minkina had a valid bad faith claim, stating that she had provided information about ProMutual’s conduct from which “a reasonable juror could infer the defendant’s bad faith in connection with its settling the underlying malpractice suit, including the allocation of liability.

But Judge Squires-Lee ruled that trial evidence showed that ProMutual did not act for its own benefit or favor other insureds over Dr. Minkina. The judge wrote that the insurer satisfied its contractual and legal obligations when defending the underlying legal claim.

Dr. Minkina said she was disappointed with the ruling, but that she is considering her legal avenues.

“[The] judge’s decision in my case against ProMutual is obviously disappointing, but it is not the first time [the] trial court decided against me in this case,” Dr. Minkina said in an interview. “It is a battle between David and Goliath, [a] single physician against [a] $3.6 billion insurance company with unlimited resources. The decision has just been announced and it is voluminous. I am still reading it and evaluating my options with my attorneys, but it is not the end of the road yet.”

ProMutual declined to comment about the decision.

agallegos@mdedge.com