Patrice Wendling

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

[email protected]

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

[email protected]

The world health community has lost ground in its fight to reduce end-stage renal disease in patients with lupus nephritis, a systematic review and meta-analysis concluded.

The risk of end-stage renal disease (ESRD) at 5 years of lupus nephritis decreased substantially from the 1970s, when it was 16%, to the mid-1990s, when it plateaued at 11%.

ESRD risks at 10 years and 15 years declined more sharply in the 1970s and 1980s but also plateaued in the mid-1990s at 17% and 22%, respectively.

This plateau was followed by a notable increase in risk in the late 2000s, particularly in the 10-year and 15-year estimates, Dr. Maria Tektonidou of the University of Athens and her coauthors reported (Arthritis Rheumatol. 2016 Jan 27. doi: 10.1002/art.39594).

“Despite extensive use of immunosuppressive medications through the 2000s, we did not find continued improvement in ESRD risks, but instead a slight increase in risks in the late 2000s,” they wrote.

The increase did not appear to be related to greater representation in recent studies of ethnic minorities, who may be more likely to develop ESRD. In the main analysis involving 148 of the 187 studies, “trends suggest this increase may have been temporary, but further follow-up will be needed to determine if this is sustained,” the investigators added.

Notably, patients with class-IV lupus nephritis had the greatest risk of ESRD during the 2000s, with a 15-year risk of 44%.

The 15-year risk of ESRD also was higher by 10 percentage points in developing countries than in developed countries during the 2000s.

The trends are worrisome because ESRD is a costly complication of lupus nephritis, which affects more than half of all patients with systemic lupus erythematosus (SLE). Patients with lupus nephritis have a 26-fold increased risk of death and estimated annual health care costs between $43,000 and $107,000 per patient, the authors noted.

The systematic review and Bayesian meta-analysis included 187 studies reporting on 18,309 adults with lupus nephritis from 1971 to 2015. The main analysis of ESRD risk included 102 studies from developed countries and 46 studies from developing countries.

Across all studies, 86% of patients were women, 32% had elevated serum creatinine levels at study entry, and proteinuria averaged 3.6 g daily. The average age was 31.2 years and mean duration of lupus nephritis was 2.7 years.

The proportion of patients treated with glucocorticoids alone in the studies declined from 54% in 1966 to 9% in 2010, while use of immunosuppressive therapies increased.

The decrease in ESRD risks early on coincided with increased use of immunosuppressives, particularly cyclophosphamide, and better control of hypertension and proteinuria. As for why those gains have stalled, Dr. Tektonidou and her colleagues said it’s possible that the limits of effectiveness of current treatments have been reached and better outcomes will require new therapies. “It is also possible that the plateau primarily reflects lack of progress in the way currently available and effective treatments are deployed,” they added. “This includes health system factors that result in delays in treatment initiation, and patient and health system factors that result in treatment interruptions and reduced adherence.”

In an accompanying editorial, Dr. Candace Feldman and Dr. Karen Costenbader, both of Brigham and Women’s Hospital in Boston, wrote, “While we have made advances over the past 50 years in our understanding of immunosuppressive medications, there have been few meaningful improvements in other domains that contribute to ESRD and to the persistent and disproportionate burden among vulnerable populations” (Ann Rheum Dis. 2016 Jan 27. doi: 10.1002/art.39593).

Despite the clear importance of medication adherence to SLE care, a recent systematic review of adherence interventions in rheumatic diseases (Ann Rheum Dis. 2015 Feb 9. doi: 10.1136/annrheumdis-2014-206593) found few SLE-specific interventions overall and none that significantly improved adherence outcomes, Dr. Feldman and Dr. Costenbader pointed out.

Dr. Tektonidou and her associates acknowledged that the new systematic review and meta-analysis were limited by the inability to estimate risks beyond 15 years and because the findings were similar only when observational studies were considered. Factors associated with ESRD, such as renal flares and uncontrolled hypertension, were not examined, and few studies were judged to be of high-quality.

Still, the results can be used to counsel patients on risks of ESRD and also will provide benchmarks to judge the effectiveness of future treatments, the authors concluded.

Dr. Feldman and Dr. Costenbader disagreed with this conclusion, citing various study limitations and the many nuanced factors that play into a patient’s risk of developing ESRD.

“This study should rather be used to provide a broad overview of our understanding of changes in SLE ESRD over time, rather than data to counsel an individual patient on his/her risks,” they wrote.

The study was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors reported having no conflicts of interest.

[email protected]

A wearable pulsed electromagnetic fields device reduced pain intensity and improved physical functioning in patients with painful knee osteoarthritis (OA) in a double-blind, randomized trial.

The commercially available device (ActiPatch, Bioelectronics Corp.) did not improve patients’ mental health, but significantly reduced patients’ intake of NSAIDs and analgesics, compared with placebo.

“Although NSAIDs remain the gold standard for the treatment of pain in OA, there is increasing need to find conservative and alternative approaches, in order to avoid the toxicity associated with the chronic use of the analgesics, mostly in the elderly population,” wrote Dr. Gian Luca Bagnato of the University of Messina (Italy) and his colleagues (Rheumatology [Oxford]. 2015 Dec 24. doi: 10.1093/rheumatology/kev426).

courtesy BioElectronics Corporation

Pulsed electromagnetic fields (PEMF) therapy has been shown to reduce chondrocyte apoptosis and MMP-13 expression of knee cartilage and favorably affect cartilage homeostasis in animal models, but data regarding osteoarthritis (OA) pain and function in humans are mixed.

A recent systematic review found no effect in all 14 trials analyzed, but when only high-quality randomized clinical trials were included, PEMF provided significantly better pain relief at 4 and 8 weeks and better function at 8 weeks than did placebo (Rheumatology [Oxford]. 2013;52[5]:815-24).

Not only has the quality of trials varied, so has the PEMF pulse frequency and duration used in trials, “further limiting the possibility of comparing efficacy and safety,” Dr. Bagnato and associates observed.

The current study evenly randomized 60 patients with radiologic evidence of knee OA and persistent pain to wear the PEMF or a placebo device for a minimum of 12 hours, mainly at night, with the device kept in place with a wrap. The active device emits a form of non-ionizing electromagnetic radiation at a frequency of 27.12 MHz, a pulse rate of 1,000 Hz, and a burst width of 100 microsec.

Persistent pain was defined as a minimal mean score of 40 mm for global pain on the VAS (visual analog scale) and daily pain during the month prior to enrollment despite maximal tolerated doses of conventional medical therapy, including acetaminophen and/or an NSAID. The patients’ mean age was 67.7 years and mean OA duration 12 years.

The primary efficacy endpoint was reduction in pain intensity at 1 month on the VAS and WOMAC (Western Ontario and McMaster Universities Arthritis Index). The mean WOMAC total score at baseline was 132.9.

At 1 month, VAS pain scores were reduced 25.5% with the PEMF device and 3.6% with the placebo device. The standardized treatment effect size induced by PEMF therapy was –0.73 (95% confidence interval, –1.24 to –0.19), the investigators reported.

WOMAC pain subscale and total scores fell 23.4% and 18.4% with the PEMF device versus a 2.3% reduction for both scores with the placebo device. The standardized effect size was –0.61 for WOMAC pain (95% CI, –1.12 to –0.09) and –0.34 for WOMAC total score (95% CI, –0.85 to 0.17).

At 1 month, the mean Short Form-36 physical health score was significantly better in the PEMF group than in the placebo group (55.8 vs. 53.1; P = .024), while SF-36 mental health scores were nearly identical (43.8 vs. 43.6; P = .6).

Patients were allowed per protocol to take prescribed analgesic therapy as needed, but eight patients from the PEMF group stopped these medications, while one patient from the placebo group stopped medication and three started a new therapy for chronic pain. No adverse events were reported during the study.

“Given that our data are limited to a low number of participants and the long-term efficacy of the wearable device is unknown, the generalizability of the results needs to be confirmed in a larger clinical trial with a longer duration of treatment,” Dr. Bagnato and his coauthors concluded. “However, the use of a wearable PEMF therapy in knee OA can be considered as an alternative safe and effective therapy in knee OA, providing the possibility for home-based management of pain, compared with previous studies.”

[email protected]

A wearable pulsed electromagnetic fields device reduced pain intensity and improved physical functioning in patients with painful knee osteoarthritis (OA) in a double-blind, randomized trial.

The commercially available device (ActiPatch, Bioelectronics Corp.) did not improve patients’ mental health, but significantly reduced patients’ intake of NSAIDs and analgesics, compared with placebo.

“Although NSAIDs remain the gold standard for the treatment of pain in OA, there is increasing need to find conservative and alternative approaches, in order to avoid the toxicity associated with the chronic use of the analgesics, mostly in the elderly population,” wrote Dr. Gian Luca Bagnato of the University of Messina (Italy) and his colleagues (Rheumatology [Oxford]. 2015 Dec 24. doi: 10.1093/rheumatology/kev426).

courtesy BioElectronics Corporation

Pulsed electromagnetic fields (PEMF) therapy has been shown to reduce chondrocyte apoptosis and MMP-13 expression of knee cartilage and favorably affect cartilage homeostasis in animal models, but data regarding osteoarthritis (OA) pain and function in humans are mixed.

A recent systematic review found no effect in all 14 trials analyzed, but when only high-quality randomized clinical trials were included, PEMF provided significantly better pain relief at 4 and 8 weeks and better function at 8 weeks than did placebo (Rheumatology [Oxford]. 2013;52[5]:815-24).

Not only has the quality of trials varied, so has the PEMF pulse frequency and duration used in trials, “further limiting the possibility of comparing efficacy and safety,” Dr. Bagnato and associates observed.

The current study evenly randomized 60 patients with radiologic evidence of knee OA and persistent pain to wear the PEMF or a placebo device for a minimum of 12 hours, mainly at night, with the device kept in place with a wrap. The active device emits a form of non-ionizing electromagnetic radiation at a frequency of 27.12 MHz, a pulse rate of 1,000 Hz, and a burst width of 100 microsec.

Persistent pain was defined as a minimal mean score of 40 mm for global pain on the VAS (visual analog scale) and daily pain during the month prior to enrollment despite maximal tolerated doses of conventional medical therapy, including acetaminophen and/or an NSAID. The patients’ mean age was 67.7 years and mean OA duration 12 years.

The primary efficacy endpoint was reduction in pain intensity at 1 month on the VAS and WOMAC (Western Ontario and McMaster Universities Arthritis Index). The mean WOMAC total score at baseline was 132.9.

At 1 month, VAS pain scores were reduced 25.5% with the PEMF device and 3.6% with the placebo device. The standardized treatment effect size induced by PEMF therapy was –0.73 (95% confidence interval, –1.24 to –0.19), the investigators reported.

WOMAC pain subscale and total scores fell 23.4% and 18.4% with the PEMF device versus a 2.3% reduction for both scores with the placebo device. The standardized effect size was –0.61 for WOMAC pain (95% CI, –1.12 to –0.09) and –0.34 for WOMAC total score (95% CI, –0.85 to 0.17).

At 1 month, the mean Short Form-36 physical health score was significantly better in the PEMF group than in the placebo group (55.8 vs. 53.1; P = .024), while SF-36 mental health scores were nearly identical (43.8 vs. 43.6; P = .6).

Patients were allowed per protocol to take prescribed analgesic therapy as needed, but eight patients from the PEMF group stopped these medications, while one patient from the placebo group stopped medication and three started a new therapy for chronic pain. No adverse events were reported during the study.

“Given that our data are limited to a low number of participants and the long-term efficacy of the wearable device is unknown, the generalizability of the results needs to be confirmed in a larger clinical trial with a longer duration of treatment,” Dr. Bagnato and his coauthors concluded. “However, the use of a wearable PEMF therapy in knee OA can be considered as an alternative safe and effective therapy in knee OA, providing the possibility for home-based management of pain, compared with previous studies.”

[email protected]

A wearable pulsed electromagnetic fields device reduced pain intensity and improved physical functioning in patients with painful knee osteoarthritis (OA) in a double-blind, randomized trial.

The commercially available device (ActiPatch, Bioelectronics Corp.) did not improve patients’ mental health, but significantly reduced patients’ intake of NSAIDs and analgesics, compared with placebo.

“Although NSAIDs remain the gold standard for the treatment of pain in OA, there is increasing need to find conservative and alternative approaches, in order to avoid the toxicity associated with the chronic use of the analgesics, mostly in the elderly population,” wrote Dr. Gian Luca Bagnato of the University of Messina (Italy) and his colleagues (Rheumatology [Oxford]. 2015 Dec 24. doi: 10.1093/rheumatology/kev426).

courtesy BioElectronics Corporation

Pulsed electromagnetic fields (PEMF) therapy has been shown to reduce chondrocyte apoptosis and MMP-13 expression of knee cartilage and favorably affect cartilage homeostasis in animal models, but data regarding osteoarthritis (OA) pain and function in humans are mixed.

A recent systematic review found no effect in all 14 trials analyzed, but when only high-quality randomized clinical trials were included, PEMF provided significantly better pain relief at 4 and 8 weeks and better function at 8 weeks than did placebo (Rheumatology [Oxford]. 2013;52[5]:815-24).

Not only has the quality of trials varied, so has the PEMF pulse frequency and duration used in trials, “further limiting the possibility of comparing efficacy and safety,” Dr. Bagnato and associates observed.

The current study evenly randomized 60 patients with radiologic evidence of knee OA and persistent pain to wear the PEMF or a placebo device for a minimum of 12 hours, mainly at night, with the device kept in place with a wrap. The active device emits a form of non-ionizing electromagnetic radiation at a frequency of 27.12 MHz, a pulse rate of 1,000 Hz, and a burst width of 100 microsec.

Persistent pain was defined as a minimal mean score of 40 mm for global pain on the VAS (visual analog scale) and daily pain during the month prior to enrollment despite maximal tolerated doses of conventional medical therapy, including acetaminophen and/or an NSAID. The patients’ mean age was 67.7 years and mean OA duration 12 years.

The primary efficacy endpoint was reduction in pain intensity at 1 month on the VAS and WOMAC (Western Ontario and McMaster Universities Arthritis Index). The mean WOMAC total score at baseline was 132.9.

At 1 month, VAS pain scores were reduced 25.5% with the PEMF device and 3.6% with the placebo device. The standardized treatment effect size induced by PEMF therapy was –0.73 (95% confidence interval, –1.24 to –0.19), the investigators reported.

WOMAC pain subscale and total scores fell 23.4% and 18.4% with the PEMF device versus a 2.3% reduction for both scores with the placebo device. The standardized effect size was –0.61 for WOMAC pain (95% CI, –1.12 to –0.09) and –0.34 for WOMAC total score (95% CI, –0.85 to 0.17).

At 1 month, the mean Short Form-36 physical health score was significantly better in the PEMF group than in the placebo group (55.8 vs. 53.1; P = .024), while SF-36 mental health scores were nearly identical (43.8 vs. 43.6; P = .6).

Patients were allowed per protocol to take prescribed analgesic therapy as needed, but eight patients from the PEMF group stopped these medications, while one patient from the placebo group stopped medication and three started a new therapy for chronic pain. No adverse events were reported during the study.

“Given that our data are limited to a low number of participants and the long-term efficacy of the wearable device is unknown, the generalizability of the results needs to be confirmed in a larger clinical trial with a longer duration of treatment,” Dr. Bagnato and his coauthors concluded. “However, the use of a wearable PEMF therapy in knee OA can be considered as an alternative safe and effective therapy in knee OA, providing the possibility for home-based management of pain, compared with previous studies.”

[email protected]

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

[email protected]

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

[email protected]

The presence of minimal residual disease predicts relapse in patients with NMP1-mutated acute myeloid leukemia and is superior to currently used molecular genetic markers in determining whether these patients should be considered for stem cell transplantation, a new study has found.

At 3 years, patients with minimal residual disease (MRD) had a significantly greater risk of relapse than those with no MRD (82% vs. 30%; univariate hazard ratio, 4.80; P less than .001) and a lower rate of survival (24% vs. 75%; univariate HR, 4.38; P less than .001), Adam Ivey of King’s College London reported (N Engl J Med. 2016; doi:10.1056/NEJMoa1507471).

In an editorial that accompanied the study Dr. Michael J. Burke from the Children’s Hospital of Wisconsin in Milwaukee wrote, “Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML” (N Engl J Med. 2016; doi:10.1056/NEJMe1515525).

In adult AML, assessment of MRD has taken a back seat to analyses of cytogenetic and molecular lesions in determining a patient’s risk and treatment strategy. Typically, allogeneic stem cell transplantation is used for patients with high-risk features such as chromosome 3, 5, or 7 abnormalities or the FLT3-internal tandem duplication (ITD) mutation, while chemotherapy alone is used for low-risk disease.

The role of transplantation is unclear, however, for cytogenetically standard-risk patients, which includes those with a mutation in the gene encoding nucleophosmin (NPM1).

To address this issue, the investigators used a reverse-transcriptase quantitative polymerase chain reaction assay to evaluate 2,569 bone marrow and peripheral-blood samples from 346 patients with NPM1 mutations who had completed two cycles of induction chemotherapy in the U.K. National Cancer Research Institute AML17 trial.

MRD, defined as persistence of NPM1-mutated transcripts in peripheral blood, was present in 15% of patients after the second chemotherapy cycle.

Patients with MRD were significantly more likely than those without MRD to have a high U.K. Medical Research Council clinical risk score and to carry the FLT3-ITD mutation.

On univariate analysis, the risk of relapse was significantly higher with the presence of MRD in peripheral blood, an increased white cell count, and with the DNMT3A and FLT3-ITD mutations.

Only the presence of MRD and an elevated white cell count significantly predicted survival, Mr. Ivey reported.

“We could find no specific molecular subgroup consisting of 10 patients or more that had a rate of survival less than 52%; in contrast, the rate in the group with the presence of minimal residual disease was 24%,” he observed.

In multivariate analysis, the presence of MRD was the only significant prognostic factor for relapse (HR, 5.09; P less than .001) or death (HR, 4.84; P less than .001).

The results were validated in an independent cohort of 91 AML17 study patients. It confirmed that MRD in peripheral blood predicts worse outcome at 2 years than the absence of MRD, with a cumulative incidence of relapse of 70% vs. 31% (P = .001) and overall survival rates of 40% vs. 87% (P = .001), reported the investigators, including senior author Professor David Grimwade, also from King’s College London.

The clinical implications of these results “are substantive” because NPM-1 mutated AML is the most common subtype of AML and because of the uncertainty over the best treatment strategy for patients typically classified as standard risk, editorialist Dr. Burke observed.

“Now with the ability to reclassify standard-risk or low-risk patients as high-risk on the basis of the persistent expression of mutant NPM1 transcripts, it may be possible that stem-cell transplantation is a better approach in patients who otherwise would be treated with chemotherapy alone and that transplantation may be avoidable in high-risk patients who have no evidence of minimal residual disease,” he wrote. “Such predictions will need to be tested prospectively.”

The presence of MRD is also known to be an important independent prognostic factor in acute lymphoblastic leukemia, but since AML has a greater molecular heterogeneity, routine MRD assessment has not been as quickly adopted in AML, Dr. Burke noted.

The Children’s Oncology Group, however, recently adopted MRD assessment by flow cytometry to further stratify children with newly diagnosed AML after first induction therapy into low-risk or high-risk groups.

The study was supported by grants from Bloodwise and the National Institute for Health Research. Mr. Ivey and Dr. Burke reported having no disclosures.

[email protected]

CHICAGO – Microsurgery does not cure lymphedema, in most cases. But, in most cases, it does improve the severity of lymphedema and reduce the complications of this chronic and debilitating disease. And “it certainly improves patients’ quality of life,” lymphedema treatment pioneer Dr. David W. Chang said at the 40th annual Northwestern Vascular Symposium.

Surgical treatment for limb lymphedema has come into its own since a lymphovenous shunt was first used in a dog model in 1962, with Dr. Chang and others now anastomosing subdermal lymphatics to subdermal venules less than 0.8 mm in diameter. The rationale behind “super-microsurgery” is that venous pressure is low in the subdermal venules and has minimal back flow, he said.

Patrice Wendling/Frontline Medical News

One of the big problems early on was knowing exactly where the lymphatic vessels were, but newer technology like indocyanine green (ICG) lymphangiography helps visualize functioning lymphatic channels for potential bypass and determine the severity of the disease. Understanding the disease stage is key to selecting the appropriate surgical procedure.

Lymphovenous bypass (LVB) is best in patients with stage 1 or 2 upper extremity lymphedema, while lymph node transfer (LNT) works for patients who are poor candidates for LVB or require combined breast reconstruction, said Dr. Chang, a plastic surgeon with the University of Chicago.

More recently, Dr. Chang has begun combining LVB and LNT, particularly for the more severe cases with stage 3 or 4 upper or lower extremity disease.

In Dr. Chang’s first 100 consecutive LVB cases while at the M.D. Anderson Cancer Center in Houston, quantitative improvement occurred in 74% of patients, symptom improvement in 96%, and the average volume differential reduction was 42% at 12 months (Plast Reconstr Surg. 2013 Nov;132:1305-14). The reduction was significantly larger in patients with earlier stage 1 or 2 vs. later stage 3 or 4 disease (61% vs. 17%).

Images courtesy of Dr. David W. Chang

During lymphovenous bypass, ICG is injected into the dermis of the web space and the superficial lymphatics evaluated with near-infrared fluorescence. It is easy to identify discrete functioning lymphatic channels in early-stage disease, but in late-stage disease significant dermal back flow is present, Dr. Chang said.

Dissection is performed under the microscope in the superficial subcutaneous plane to locate a good venule and lymph channel. Lymphatics are confirmed with isosulfan blue and ICG, and once the bypass site is determined, the lymphatic is anastomosed to the venule using 11-0 or 12-0 nylon, preferably in an end-to-side fashion. It’s thought this creates a more favorable flow pattern for the lymph to empty into the venule than an end-to-end anastomosis, he observed.

After the anastomosis is complete, patency is confirmed with isosulfan blue and ICG and the incision is closed under the microscope to ensure that the delicate anastomosis isn’t damaged. To avoid shear injury to the anastomosis, the limb is wrapped postoperatively for about a month without use of compression garments, he said.

Lymph node transfer (LNT) is increasingly being offered at centers to provide relief from lymphedema, although the mechanism by which it works is yet unclear; either the healthy lymph nodes act as a sponge to absorb lymphatic fluid or they induce lymphangiogenesis. Experience has shown, however, that rather than just grafting the lymph nodes, they need to be harvested with a vascular pedicle before transfer and anastomosed to the recipient artery and vein, although reconnecting the actual lymphatics may not be necessary, Dr. Chang observed.

Despite its popularity as a donor site, Dr. Chang said he is reluctant to use the groin because of the potential for iatrogenic lymphedema and prefers to harvest the supraclavicular nodes based off the transverse cervical artery. The external jugular vein can be harvested with the nodes if adequate venae comitantes are not present with the artery. Dissection of this flap can be difficult and care should be taken not to injure the lymphatic ducts, he noted.

It is also important to excise all scar tissue in the recipient site as this can impair lymphatic flow and inhibits lymphangiogenesis. If it is difficult to access or remove the scar, the vascularized lymph nodes are best placed just distal on the limb to the site of lymphatic obstruction, he added.

A recent meta-analysis (Plast Reconstr Surg. 2014 Apr;133:905-13) in five LNT studies reported that 91% of patients had a quantitative improvement, 78% discontinued compression garments, and complications were infection (8%), lymphorrhea (15%), and need for additional procedures (36%). There was great heterogeneity between studies, so the results should be interpreted with caution, Dr. Chang advised.

LNT is frequently combined with autologous breast reconstruction in patients with breast cancer, who comprise a significant percentage of Dr. Chang’s practice. The overall incidence of arm lymphedema after breast cancer can range from 8% to 56% at 2 years’ post-surgery, with the risk higher among women undergoing axillary lymph node dissection and/or axillary radiation.

Outcomes with combined LNT and breast reconstruction have been favorable, with one series reporting evidence of improved lymphatic flow on lymphoscintigraphy in five of six cases and one-third of patients no longer needing compression therapy (Ann Surg. 2012 Mar;255:468-73).

In cases where the patient requires a large skin paddle or seeks breast reconstruction after a previous mastectomy, lateral superficial groin lymph nodes can be harvested for transfer, leaving the deeper lymph nodes that drain the leg behind, Dr. Chang said. The nodes are usually clustered at the junction of the superior inferior epigastric and superficial circumflex iliac veins.

When combining LNT with breast reconstruction, this tissue is harvested together with the free abdominal flap used to reconstruct the breast. The superficial circumflex iliac vein is anastomosed in the axilla in addition to the arterial and venous anastomosis of the deep inferior epigastric vessels to the internal mammary vessels for the breast reconstruction. Reverse lymphatic mapping with technetium and ICG is used to decrease the risk of donor site lymphedema.

An algorithmic approach to simultaneous LNT with microvascular breast reconstruction proposed by Dr. Chang resulted in a 47% reduction in mean volume differential 12 months after reconstruction in 29 consecutive patients with refractory lymphedema following breast cancer treatment. These early results also showed no flap losses or donor-site lymphedema and donor-site wound complications in six patients (21%) that resolved with conservative measures (Ann Surg Oncol. 2015 Sep;22:2919-24).

The holy grail may be to strike lymphedema before it develops. To that end, Italian surgeons have proposed the Lymphatic Microsurgical Preventing Healing Approach (LYMPHA), which involves anastomosing arm lymphatics to a collateral branch of the axillary vein at the time of nodal dissection.

Over more than 4 years’ follow-up, only 3 of 74 breast cancer patients who underwent axillary nodal dissection with LYMPHA developed lymphedema, translating into a an exceptionally low 4% risk of lymphedema (Microsurgery. 2014 Sep;34:421-4). However, this approach is controversial because of unknown oncological risk and the uncertainty of its effectiveness in patients who may receive radiation after the surgery, Dr. Chang said in an interview.

Although these techniques show promise, currently no optimal solution exists and more research is needed to better understand lymphatic anatomy and physiology and the pathophysiology of lymphedema, concluded Dr. Chang, who reported no relevant conflicts of interest.

[email protected]

CHICAGO – Microsurgery does not cure lymphedema, in most cases. But, in most cases, it does improve the severity of lymphedema and reduce the complications of this chronic and debilitating disease. And “it certainly improves patients’ quality of life,” lymphedema treatment pioneer Dr. David W. Chang said at the 40th annual Northwestern Vascular Symposium.

Surgical treatment for limb lymphedema has come into its own since a lymphovenous shunt was first used in a dog model in 1962, with Dr. Chang and others now anastomosing subdermal lymphatics to subdermal venules less than 0.8 mm in diameter. The rationale behind “super-microsurgery” is that venous pressure is low in the subdermal venules and has minimal back flow, he said.

Patrice Wendling/Frontline Medical News

One of the big problems early on was knowing exactly where the lymphatic vessels were, but newer technology like indocyanine green (ICG) lymphangiography helps visualize functioning lymphatic channels for potential bypass and determine the severity of the disease. Understanding the disease stage is key to selecting the appropriate surgical procedure.

Lymphovenous bypass (LVB) is best in patients with stage 1 or 2 upper extremity lymphedema, while lymph node transfer (LNT) works for patients who are poor candidates for LVB or require combined breast reconstruction, said Dr. Chang, a plastic surgeon with the University of Chicago.

More recently, Dr. Chang has begun combining LVB and LNT, particularly for the more severe cases with stage 3 or 4 upper or lower extremity disease.

In Dr. Chang’s first 100 consecutive LVB cases while at the M.D. Anderson Cancer Center in Houston, quantitative improvement occurred in 74% of patients, symptom improvement in 96%, and the average volume differential reduction was 42% at 12 months (Plast Reconstr Surg. 2013 Nov;132:1305-14). The reduction was significantly larger in patients with earlier stage 1 or 2 vs. later stage 3 or 4 disease (61% vs. 17%).

Images courtesy of Dr. David W. Chang

During lymphovenous bypass, ICG is injected into the dermis of the web space and the superficial lymphatics evaluated with near-infrared fluorescence. It is easy to identify discrete functioning lymphatic channels in early-stage disease, but in late-stage disease significant dermal back flow is present, Dr. Chang said.

Dissection is performed under the microscope in the superficial subcutaneous plane to locate a good venule and lymph channel. Lymphatics are confirmed with isosulfan blue and ICG, and once the bypass site is determined, the lymphatic is anastomosed to the venule using 11-0 or 12-0 nylon, preferably in an end-to-side fashion. It’s thought this creates a more favorable flow pattern for the lymph to empty into the venule than an end-to-end anastomosis, he observed.

After the anastomosis is complete, patency is confirmed with isosulfan blue and ICG and the incision is closed under the microscope to ensure that the delicate anastomosis isn’t damaged. To avoid shear injury to the anastomosis, the limb is wrapped postoperatively for about a month without use of compression garments, he said.

Lymph node transfer (LNT) is increasingly being offered at centers to provide relief from lymphedema, although the mechanism by which it works is yet unclear; either the healthy lymph nodes act as a sponge to absorb lymphatic fluid or they induce lymphangiogenesis. Experience has shown, however, that rather than just grafting the lymph nodes, they need to be harvested with a vascular pedicle before transfer and anastomosed to the recipient artery and vein, although reconnecting the actual lymphatics may not be necessary, Dr. Chang observed.

Despite its popularity as a donor site, Dr. Chang said he is reluctant to use the groin because of the potential for iatrogenic lymphedema and prefers to harvest the supraclavicular nodes based off the transverse cervical artery. The external jugular vein can be harvested with the nodes if adequate venae comitantes are not present with the artery. Dissection of this flap can be difficult and care should be taken not to injure the lymphatic ducts, he noted.

It is also important to excise all scar tissue in the recipient site as this can impair lymphatic flow and inhibits lymphangiogenesis. If it is difficult to access or remove the scar, the vascularized lymph nodes are best placed just distal on the limb to the site of lymphatic obstruction, he added.

A recent meta-analysis (Plast Reconstr Surg. 2014 Apr;133:905-13) in five LNT studies reported that 91% of patients had a quantitative improvement, 78% discontinued compression garments, and complications were infection (8%), lymphorrhea (15%), and need for additional procedures (36%). There was great heterogeneity between studies, so the results should be interpreted with caution, Dr. Chang advised.

LNT is frequently combined with autologous breast reconstruction in patients with breast cancer, who comprise a significant percentage of Dr. Chang’s practice. The overall incidence of arm lymphedema after breast cancer can range from 8% to 56% at 2 years’ post-surgery, with the risk higher among women undergoing axillary lymph node dissection and/or axillary radiation.

Outcomes with combined LNT and breast reconstruction have been favorable, with one series reporting evidence of improved lymphatic flow on lymphoscintigraphy in five of six cases and one-third of patients no longer needing compression therapy (Ann Surg. 2012 Mar;255:468-73).

In cases where the patient requires a large skin paddle or seeks breast reconstruction after a previous mastectomy, lateral superficial groin lymph nodes can be harvested for transfer, leaving the deeper lymph nodes that drain the leg behind, Dr. Chang said. The nodes are usually clustered at the junction of the superior inferior epigastric and superficial circumflex iliac veins.

When combining LNT with breast reconstruction, this tissue is harvested together with the free abdominal flap used to reconstruct the breast. The superficial circumflex iliac vein is anastomosed in the axilla in addition to the arterial and venous anastomosis of the deep inferior epigastric vessels to the internal mammary vessels for the breast reconstruction. Reverse lymphatic mapping with technetium and ICG is used to decrease the risk of donor site lymphedema.

An algorithmic approach to simultaneous LNT with microvascular breast reconstruction proposed by Dr. Chang resulted in a 47% reduction in mean volume differential 12 months after reconstruction in 29 consecutive patients with refractory lymphedema following breast cancer treatment. These early results also showed no flap losses or donor-site lymphedema and donor-site wound complications in six patients (21%) that resolved with conservative measures (Ann Surg Oncol. 2015 Sep;22:2919-24).

The holy grail may be to strike lymphedema before it develops. To that end, Italian surgeons have proposed the Lymphatic Microsurgical Preventing Healing Approach (LYMPHA), which involves anastomosing arm lymphatics to a collateral branch of the axillary vein at the time of nodal dissection.

Over more than 4 years’ follow-up, only 3 of 74 breast cancer patients who underwent axillary nodal dissection with LYMPHA developed lymphedema, translating into a an exceptionally low 4% risk of lymphedema (Microsurgery. 2014 Sep;34:421-4). However, this approach is controversial because of unknown oncological risk and the uncertainty of its effectiveness in patients who may receive radiation after the surgery, Dr. Chang said in an interview.

Although these techniques show promise, currently no optimal solution exists and more research is needed to better understand lymphatic anatomy and physiology and the pathophysiology of lymphedema, concluded Dr. Chang, who reported no relevant conflicts of interest.

[email protected]

CHICAGO – Microsurgery does not cure lymphedema, in most cases. But, in most cases, it does improve the severity of lymphedema and reduce the complications of this chronic and debilitating disease. And “it certainly improves patients’ quality of life,” lymphedema treatment pioneer Dr. David W. Chang said at the 40th annual Northwestern Vascular Symposium.

Surgical treatment for limb lymphedema has come into its own since a lymphovenous shunt was first used in a dog model in 1962, with Dr. Chang and others now anastomosing subdermal lymphatics to subdermal venules less than 0.8 mm in diameter. The rationale behind “super-microsurgery” is that venous pressure is low in the subdermal venules and has minimal back flow, he said.

Patrice Wendling/Frontline Medical News

One of the big problems early on was knowing exactly where the lymphatic vessels were, but newer technology like indocyanine green (ICG) lymphangiography helps visualize functioning lymphatic channels for potential bypass and determine the severity of the disease. Understanding the disease stage is key to selecting the appropriate surgical procedure.

Lymphovenous bypass (LVB) is best in patients with stage 1 or 2 upper extremity lymphedema, while lymph node transfer (LNT) works for patients who are poor candidates for LVB or require combined breast reconstruction, said Dr. Chang, a plastic surgeon with the University of Chicago.

More recently, Dr. Chang has begun combining LVB and LNT, particularly for the more severe cases with stage 3 or 4 upper or lower extremity disease.

In Dr. Chang’s first 100 consecutive LVB cases while at the M.D. Anderson Cancer Center in Houston, quantitative improvement occurred in 74% of patients, symptom improvement in 96%, and the average volume differential reduction was 42% at 12 months (Plast Reconstr Surg. 2013 Nov;132:1305-14). The reduction was significantly larger in patients with earlier stage 1 or 2 vs. later stage 3 or 4 disease (61% vs. 17%).

Images courtesy of Dr. David W. Chang

During lymphovenous bypass, ICG is injected into the dermis of the web space and the superficial lymphatics evaluated with near-infrared fluorescence. It is easy to identify discrete functioning lymphatic channels in early-stage disease, but in late-stage disease significant dermal back flow is present, Dr. Chang said.

Dissection is performed under the microscope in the superficial subcutaneous plane to locate a good venule and lymph channel. Lymphatics are confirmed with isosulfan blue and ICG, and once the bypass site is determined, the lymphatic is anastomosed to the venule using 11-0 or 12-0 nylon, preferably in an end-to-side fashion. It’s thought this creates a more favorable flow pattern for the lymph to empty into the venule than an end-to-end anastomosis, he observed.

After the anastomosis is complete, patency is confirmed with isosulfan blue and ICG and the incision is closed under the microscope to ensure that the delicate anastomosis isn’t damaged. To avoid shear injury to the anastomosis, the limb is wrapped postoperatively for about a month without use of compression garments, he said.

Lymph node transfer (LNT) is increasingly being offered at centers to provide relief from lymphedema, although the mechanism by which it works is yet unclear; either the healthy lymph nodes act as a sponge to absorb lymphatic fluid or they induce lymphangiogenesis. Experience has shown, however, that rather than just grafting the lymph nodes, they need to be harvested with a vascular pedicle before transfer and anastomosed to the recipient artery and vein, although reconnecting the actual lymphatics may not be necessary, Dr. Chang observed.

Despite its popularity as a donor site, Dr. Chang said he is reluctant to use the groin because of the potential for iatrogenic lymphedema and prefers to harvest the supraclavicular nodes based off the transverse cervical artery. The external jugular vein can be harvested with the nodes if adequate venae comitantes are not present with the artery. Dissection of this flap can be difficult and care should be taken not to injure the lymphatic ducts, he noted.

It is also important to excise all scar tissue in the recipient site as this can impair lymphatic flow and inhibits lymphangiogenesis. If it is difficult to access or remove the scar, the vascularized lymph nodes are best placed just distal on the limb to the site of lymphatic obstruction, he added.

A recent meta-analysis (Plast Reconstr Surg. 2014 Apr;133:905-13) in five LNT studies reported that 91% of patients had a quantitative improvement, 78% discontinued compression garments, and complications were infection (8%), lymphorrhea (15%), and need for additional procedures (36%). There was great heterogeneity between studies, so the results should be interpreted with caution, Dr. Chang advised.

LNT is frequently combined with autologous breast reconstruction in patients with breast cancer, who comprise a significant percentage of Dr. Chang’s practice. The overall incidence of arm lymphedema after breast cancer can range from 8% to 56% at 2 years’ post-surgery, with the risk higher among women undergoing axillary lymph node dissection and/or axillary radiation.

Outcomes with combined LNT and breast reconstruction have been favorable, with one series reporting evidence of improved lymphatic flow on lymphoscintigraphy in five of six cases and one-third of patients no longer needing compression therapy (Ann Surg. 2012 Mar;255:468-73).

In cases where the patient requires a large skin paddle or seeks breast reconstruction after a previous mastectomy, lateral superficial groin lymph nodes can be harvested for transfer, leaving the deeper lymph nodes that drain the leg behind, Dr. Chang said. The nodes are usually clustered at the junction of the superior inferior epigastric and superficial circumflex iliac veins.

When combining LNT with breast reconstruction, this tissue is harvested together with the free abdominal flap used to reconstruct the breast. The superficial circumflex iliac vein is anastomosed in the axilla in addition to the arterial and venous anastomosis of the deep inferior epigastric vessels to the internal mammary vessels for the breast reconstruction. Reverse lymphatic mapping with technetium and ICG is used to decrease the risk of donor site lymphedema.

An algorithmic approach to simultaneous LNT with microvascular breast reconstruction proposed by Dr. Chang resulted in a 47% reduction in mean volume differential 12 months after reconstruction in 29 consecutive patients with refractory lymphedema following breast cancer treatment. These early results also showed no flap losses or donor-site lymphedema and donor-site wound complications in six patients (21%) that resolved with conservative measures (Ann Surg Oncol. 2015 Sep;22:2919-24).

The holy grail may be to strike lymphedema before it develops. To that end, Italian surgeons have proposed the Lymphatic Microsurgical Preventing Healing Approach (LYMPHA), which involves anastomosing arm lymphatics to a collateral branch of the axillary vein at the time of nodal dissection.

Over more than 4 years’ follow-up, only 3 of 74 breast cancer patients who underwent axillary nodal dissection with LYMPHA developed lymphedema, translating into a an exceptionally low 4% risk of lymphedema (Microsurgery. 2014 Sep;34:421-4). However, this approach is controversial because of unknown oncological risk and the uncertainty of its effectiveness in patients who may receive radiation after the surgery, Dr. Chang said in an interview.

Although these techniques show promise, currently no optimal solution exists and more research is needed to better understand lymphatic anatomy and physiology and the pathophysiology of lymphedema, concluded Dr. Chang, who reported no relevant conflicts of interest.

[email protected]

New guidelines on the diagnosis and management of primary adrenal insufficiency stress the importance of early recognition and the need to prevent life-threatening adrenal crises in these patients.

©SomkiatFakmee/thinkstockphotos.com

These are the first clinical practice guidelines on primary adrenal insufficiency (PAI), also known as Addison’s disease, issued by Endocrine Society (J Clin Endocrinol Metab. 2016 Jan 13:jc20151710 [Epub ahead of print]).

“Because it’s a rare disease and symptoms can mimic common conditions, adrenal insufficiency is often, at least initially, overlooked,” guideline co-author Dr. Deborah Merke, a senior investigator with the National Institutes of Health Clinical Center in Bethesda, Md., said. “So the main goal of these clinical practice guidelines is to improve patient care.”

The guidelines suggest clinicians should have a low diagnostic threshold in acutely ill patients with unexplained symptoms or signs suggestive of PAI such as volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.

This low diagnostic threshold for PAI should also be extended to pregnant women with unexplained persistent nausea, fatigue, and hypotension.

For adult patients with a suspected adrenal crisis, an immediate parenteral injection of hydrocortisone 100 mg should be given, followed by appropriate fluid resuscitation and 200 mg of hydrocortisone for 24 hours, according to the guidelines, which were co-sponsored by the European Society of Endocrinology and American Association for Clinical Chemistry.

Despite a known association between adrenal crisis and mortality, there is a knowledge gap regarding how to prevent, recognize, and reduce the risk of these life-threatening events, Dr. Merke said.

To that end, the task force has taken a page from the diabetes community in recommending all PAI patients carry steroid emergency identification cards and be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.

The guidelines also advocate education about stress dosing to counter the increased demand for corticosteroids during periods of stress, which can encompass something as common as the flu.

“Just like diabetics carry around emergency medicines, it’s important for patients with adrenal insufficiency to carry around an emergency kit and to realize that should they start to get sick, they need to increase their doses,” she said. “There often seems to be a lack of awareness among physicians as well that these patients have a potentially life-threatening condition, should they get a common illness.”

One of the key unanswered clinical questions the task force sought to address was whether the widely used high-dose (250 mcg) corticotropin stimulation test, also known as the adrenocorticotropin (ACTH) or short Synacthen test, should be replaced by the low-dose test (1 mcg) to diagnosis PAI.

Despite a review of published data and a systematic review commissioned by the task force, “We didn’t come up with much scientific evidence to say we should be changing the historic standard,” Dr. Merke said.

The systematic review identified only five studies of high-dose corticotropin testing specifically in PAI and none of low-dose testing. The low-dose test has shown higher sensitivity in the detection of adrenal insufficiency in critically ill patients and secondary adrenal insufficiency, but the limited available data suggest it does not provide better diagnostic accuracy for PAI than the high-dose test.

As a result, the guidelines recommend the standard, short corticotropin test (250 mcg for adults and children aged at least 2 years) as the “gold standard” diagnostic test to establish a PAI diagnosis.

The low-dose (1 mcg) test is recommended only when corticotropin is in short supply, which is not typically a problem in the United States, she said.

If corticotropin testing isn’t feasible, a combination of a morning plasma ACTH and cortisol levels (less than 5 mcg/dL) can be used as an initial screening, though confirmatory testing with corticotropin stimulation is strongly recommended.

Glucocorticoid therapy is recommended in all patients with confirmed PAI based on the highest quality of evidence, with a clear preference given for the short-acting steroids, Dr. Merke observed.

Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative.

Hydrocortisone is also suggested over cortisone acetate, prednisolone, or prednisone for pregnant women and recommended for children (about 8 mg/m² per day), but the evidence supporting these items was of low quality.

The guidelines suggest against using dexamethasone, the longest-acting glucocorticoid, because of the potential long-term side effects of overt-treatment and the frequent appearance of cushingoid side effects. They also recommend against dexamethasone in pregnant women because it is not inactivated in the placenta.

The guidelines are also quite clear in their suggestion against hormonal monitoring of glucocorticoid replacement and instead favor adjusting treatment based only on clinical response.

“This is a very important suggestion that we made because often clinicians use ACTH to adjust doses and this commonly results in overreplacement and there are side effects to overreplacement,” including weight gain, insomnia, and peripheral edema, Dr. Merke said.

A second systematic review commissioned by the task force involving 15 observational studies of glucocorticoid replacement regimens uncovered very sparse data on mortality, bone density, and incidence of adrenal crisis.

It has been suggested that newer extended-release and dual-release glucocorticoid formulations may result in higher health-reality quality of life than once-, twice-, or thrice-daily regimens, but once again, the evidence was insufficient to support a specific recommendation.

Dr. Merke acknowledged that many of the guidelines recommendations were ungraded or best practices, reflecting the lack of randomized clinical trials in PAI.

“I think that’s why it was so important for us to do this,” she said. “We had a group of experts that were very familiar with this disease providing guidance, but I think it’s also one reason why physicians out there in practice get confused about exactly what to do because of the lack of hard evidence. ... It does certainly cry for the need for more studies in these rare diseases.”

The guidelines were funded by the Endocrine Society, and the authors reported receiving no external funding or remuneration.

[email protected]

New guidelines on the diagnosis and management of primary adrenal insufficiency stress the importance of early recognition and the need to prevent life-threatening adrenal crises in these patients.

©SomkiatFakmee/thinkstockphotos.com

These are the first clinical practice guidelines on primary adrenal insufficiency (PAI), also known as Addison’s disease, issued by Endocrine Society (J Clin Endocrinol Metab. 2016 Jan 13:jc20151710 [Epub ahead of print]).

“Because it’s a rare disease and symptoms can mimic common conditions, adrenal insufficiency is often, at least initially, overlooked,” guideline co-author Dr. Deborah Merke, a senior investigator with the National Institutes of Health Clinical Center in Bethesda, Md., said. “So the main goal of these clinical practice guidelines is to improve patient care.”

The guidelines suggest clinicians should have a low diagnostic threshold in acutely ill patients with unexplained symptoms or signs suggestive of PAI such as volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.

This low diagnostic threshold for PAI should also be extended to pregnant women with unexplained persistent nausea, fatigue, and hypotension.

For adult patients with a suspected adrenal crisis, an immediate parenteral injection of hydrocortisone 100 mg should be given, followed by appropriate fluid resuscitation and 200 mg of hydrocortisone for 24 hours, according to the guidelines, which were co-sponsored by the European Society of Endocrinology and American Association for Clinical Chemistry.

Despite a known association between adrenal crisis and mortality, there is a knowledge gap regarding how to prevent, recognize, and reduce the risk of these life-threatening events, Dr. Merke said.

To that end, the task force has taken a page from the diabetes community in recommending all PAI patients carry steroid emergency identification cards and be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.

The guidelines also advocate education about stress dosing to counter the increased demand for corticosteroids during periods of stress, which can encompass something as common as the flu.

“Just like diabetics carry around emergency medicines, it’s important for patients with adrenal insufficiency to carry around an emergency kit and to realize that should they start to get sick, they need to increase their doses,” she said. “There often seems to be a lack of awareness among physicians as well that these patients have a potentially life-threatening condition, should they get a common illness.”

One of the key unanswered clinical questions the task force sought to address was whether the widely used high-dose (250 mcg) corticotropin stimulation test, also known as the adrenocorticotropin (ACTH) or short Synacthen test, should be replaced by the low-dose test (1 mcg) to diagnosis PAI.

Despite a review of published data and a systematic review commissioned by the task force, “We didn’t come up with much scientific evidence to say we should be changing the historic standard,” Dr. Merke said.

The systematic review identified only five studies of high-dose corticotropin testing specifically in PAI and none of low-dose testing. The low-dose test has shown higher sensitivity in the detection of adrenal insufficiency in critically ill patients and secondary adrenal insufficiency, but the limited available data suggest it does not provide better diagnostic accuracy for PAI than the high-dose test.

As a result, the guidelines recommend the standard, short corticotropin test (250 mcg for adults and children aged at least 2 years) as the “gold standard” diagnostic test to establish a PAI diagnosis.

The low-dose (1 mcg) test is recommended only when corticotropin is in short supply, which is not typically a problem in the United States, she said.

If corticotropin testing isn’t feasible, a combination of a morning plasma ACTH and cortisol levels (less than 5 mcg/dL) can be used as an initial screening, though confirmatory testing with corticotropin stimulation is strongly recommended.

Glucocorticoid therapy is recommended in all patients with confirmed PAI based on the highest quality of evidence, with a clear preference given for the short-acting steroids, Dr. Merke observed.

Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative.

Hydrocortisone is also suggested over cortisone acetate, prednisolone, or prednisone for pregnant women and recommended for children (about 8 mg/m² per day), but the evidence supporting these items was of low quality.

The guidelines suggest against using dexamethasone, the longest-acting glucocorticoid, because of the potential long-term side effects of overt-treatment and the frequent appearance of cushingoid side effects. They also recommend against dexamethasone in pregnant women because it is not inactivated in the placenta.

The guidelines are also quite clear in their suggestion against hormonal monitoring of glucocorticoid replacement and instead favor adjusting treatment based only on clinical response.

“This is a very important suggestion that we made because often clinicians use ACTH to adjust doses and this commonly results in overreplacement and there are side effects to overreplacement,” including weight gain, insomnia, and peripheral edema, Dr. Merke said.

A second systematic review commissioned by the task force involving 15 observational studies of glucocorticoid replacement regimens uncovered very sparse data on mortality, bone density, and incidence of adrenal crisis.

It has been suggested that newer extended-release and dual-release glucocorticoid formulations may result in higher health-reality quality of life than once-, twice-, or thrice-daily regimens, but once again, the evidence was insufficient to support a specific recommendation.

Dr. Merke acknowledged that many of the guidelines recommendations were ungraded or best practices, reflecting the lack of randomized clinical trials in PAI.

“I think that’s why it was so important for us to do this,” she said. “We had a group of experts that were very familiar with this disease providing guidance, but I think it’s also one reason why physicians out there in practice get confused about exactly what to do because of the lack of hard evidence. ... It does certainly cry for the need for more studies in these rare diseases.”

The guidelines were funded by the Endocrine Society, and the authors reported receiving no external funding or remuneration.

[email protected]

New guidelines on the diagnosis and management of primary adrenal insufficiency stress the importance of early recognition and the need to prevent life-threatening adrenal crises in these patients.

©SomkiatFakmee/thinkstockphotos.com

These are the first clinical practice guidelines on primary adrenal insufficiency (PAI), also known as Addison’s disease, issued by Endocrine Society (J Clin Endocrinol Metab. 2016 Jan 13:jc20151710 [Epub ahead of print]).

“Because it’s a rare disease and symptoms can mimic common conditions, adrenal insufficiency is often, at least initially, overlooked,” guideline co-author Dr. Deborah Merke, a senior investigator with the National Institutes of Health Clinical Center in Bethesda, Md., said. “So the main goal of these clinical practice guidelines is to improve patient care.”

The guidelines suggest clinicians should have a low diagnostic threshold in acutely ill patients with unexplained symptoms or signs suggestive of PAI such as volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or, especially in children, hypoglycemia.

This low diagnostic threshold for PAI should also be extended to pregnant women with unexplained persistent nausea, fatigue, and hypotension.

For adult patients with a suspected adrenal crisis, an immediate parenteral injection of hydrocortisone 100 mg should be given, followed by appropriate fluid resuscitation and 200 mg of hydrocortisone for 24 hours, according to the guidelines, which were co-sponsored by the European Society of Endocrinology and American Association for Clinical Chemistry.

Despite a known association between adrenal crisis and mortality, there is a knowledge gap regarding how to prevent, recognize, and reduce the risk of these life-threatening events, Dr. Merke said.

To that end, the task force has taken a page from the diabetes community in recommending all PAI patients carry steroid emergency identification cards and be equipped with a glucocorticoid injection kit for emergency use and be educated on how to use it.

The guidelines also advocate education about stress dosing to counter the increased demand for corticosteroids during periods of stress, which can encompass something as common as the flu.

“Just like diabetics carry around emergency medicines, it’s important for patients with adrenal insufficiency to carry around an emergency kit and to realize that should they start to get sick, they need to increase their doses,” she said. “There often seems to be a lack of awareness among physicians as well that these patients have a potentially life-threatening condition, should they get a common illness.”

One of the key unanswered clinical questions the task force sought to address was whether the widely used high-dose (250 mcg) corticotropin stimulation test, also known as the adrenocorticotropin (ACTH) or short Synacthen test, should be replaced by the low-dose test (1 mcg) to diagnosis PAI.

Despite a review of published data and a systematic review commissioned by the task force, “We didn’t come up with much scientific evidence to say we should be changing the historic standard,” Dr. Merke said.

The systematic review identified only five studies of high-dose corticotropin testing specifically in PAI and none of low-dose testing. The low-dose test has shown higher sensitivity in the detection of adrenal insufficiency in critically ill patients and secondary adrenal insufficiency, but the limited available data suggest it does not provide better diagnostic accuracy for PAI than the high-dose test.

As a result, the guidelines recommend the standard, short corticotropin test (250 mcg for adults and children aged at least 2 years) as the “gold standard” diagnostic test to establish a PAI diagnosis.

The low-dose (1 mcg) test is recommended only when corticotropin is in short supply, which is not typically a problem in the United States, she said.

If corticotropin testing isn’t feasible, a combination of a morning plasma ACTH and cortisol levels (less than 5 mcg/dL) can be used as an initial screening, though confirmatory testing with corticotropin stimulation is strongly recommended.

Glucocorticoid therapy is recommended in all patients with confirmed PAI based on the highest quality of evidence, with a clear preference given for the short-acting steroids, Dr. Merke observed.

Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative.

Hydrocortisone is also suggested over cortisone acetate, prednisolone, or prednisone for pregnant women and recommended for children (about 8 mg/m² per day), but the evidence supporting these items was of low quality.

The guidelines suggest against using dexamethasone, the longest-acting glucocorticoid, because of the potential long-term side effects of overt-treatment and the frequent appearance of cushingoid side effects. They also recommend against dexamethasone in pregnant women because it is not inactivated in the placenta.

The guidelines are also quite clear in their suggestion against hormonal monitoring of glucocorticoid replacement and instead favor adjusting treatment based only on clinical response.

“This is a very important suggestion that we made because often clinicians use ACTH to adjust doses and this commonly results in overreplacement and there are side effects to overreplacement,” including weight gain, insomnia, and peripheral edema, Dr. Merke said.

A second systematic review commissioned by the task force involving 15 observational studies of glucocorticoid replacement regimens uncovered very sparse data on mortality, bone density, and incidence of adrenal crisis.

It has been suggested that newer extended-release and dual-release glucocorticoid formulations may result in higher health-reality quality of life than once-, twice-, or thrice-daily regimens, but once again, the evidence was insufficient to support a specific recommendation.

Dr. Merke acknowledged that many of the guidelines recommendations were ungraded or best practices, reflecting the lack of randomized clinical trials in PAI.

“I think that’s why it was so important for us to do this,” she said. “We had a group of experts that were very familiar with this disease providing guidance, but I think it’s also one reason why physicians out there in practice get confused about exactly what to do because of the lack of hard evidence. ... It does certainly cry for the need for more studies in these rare diseases.”

The guidelines were funded by the Endocrine Society, and the authors reported receiving no external funding or remuneration.

[email protected]