KAUAI, HAWAII – Children born with two or more melanocytic nevi of any size should have an MRI to check for brain lesions, ideally within the first 6 months, according to Jennifer Huang, MD, a pediatric dermatologist at Boston Children’s Hospital.

Two or more nevi increase the risk of CNS involvement, which in turn increases the risk of malignant conversion by more than 16-fold.

“If the scanning brain MRI is normal, [children] might not have congenital melanocytic nevus syndrome, and would be at low risk for melanoma,” Dr. Huang said. “If it’s abnormal, they might be at high risk for melanoma.” In the 2017 study, the odds ratio for melanoma with an abnormal MRI was 16.7 (P = .001).

Both melanocytes and neuronal cells arise from the embryonic neural crest, which explains the link between congenital nevi and brain lesions. Almost all congenital nevi are associated with early postzygotic mutations in the NRAS gene, and it’s possible the mutations affect other neural crest cell lines, including in the CNS, she said.

It’s also important to remember that childhood melanoma often doesn’t follow the ABCDE (asymmetry, border irregularity, color not uniform, diameter greater than 6 mm, and evolving) signs of melanoma common in adults.

In a retrospective study of 70 children with melanoma or ambiguous melanocytic tumors, 40% of pubertal subjects and 60% of prepubertal participants did not meet conventional adult ABCDE criteria. The majority of cases were raised, even in color, less than 6 mm across, symmetric, and de novo (J Am Acad Dermatol. 2013 Jun;68[6]:913-25).

It turns out that rapid evolution in size, shape, and color is the number one, unifying factor in childhood melanomas. Other key clues include raised lesions with uniform color or no pigmentation at all. A modified ABCDE for pediatric melanoma has been proposed: amelanotic, bump/bleeding, color uniform, diameter variable, de novo, and evolution.

“The lesson to learn is not to ignore the traditional ABCDEs of melanoma, but to recognize that pediatric melanoma may present with different clinical characteristics, and to incorporate this awareness into our practice,” Dr. Huang said.

She did not have any disclosures. SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Children born with two or more melanocytic nevi of any size should have an MRI to check for brain lesions, ideally within the first 6 months, according to Jennifer Huang, MD, a pediatric dermatologist at Boston Children’s Hospital.

Two or more nevi increase the risk of CNS involvement, which in turn increases the risk of malignant conversion by more than 16-fold.

“If the scanning brain MRI is normal, [children] might not have congenital melanocytic nevus syndrome, and would be at low risk for melanoma,” Dr. Huang said. “If it’s abnormal, they might be at high risk for melanoma.” In the 2017 study, the odds ratio for melanoma with an abnormal MRI was 16.7 (P = .001).

Both melanocytes and neuronal cells arise from the embryonic neural crest, which explains the link between congenital nevi and brain lesions. Almost all congenital nevi are associated with early postzygotic mutations in the NRAS gene, and it’s possible the mutations affect other neural crest cell lines, including in the CNS, she said.

It’s also important to remember that childhood melanoma often doesn’t follow the ABCDE (asymmetry, border irregularity, color not uniform, diameter greater than 6 mm, and evolving) signs of melanoma common in adults.

In a retrospective study of 70 children with melanoma or ambiguous melanocytic tumors, 40% of pubertal subjects and 60% of prepubertal participants did not meet conventional adult ABCDE criteria. The majority of cases were raised, even in color, less than 6 mm across, symmetric, and de novo (J Am Acad Dermatol. 2013 Jun;68[6]:913-25).

It turns out that rapid evolution in size, shape, and color is the number one, unifying factor in childhood melanomas. Other key clues include raised lesions with uniform color or no pigmentation at all. A modified ABCDE for pediatric melanoma has been proposed: amelanotic, bump/bleeding, color uniform, diameter variable, de novo, and evolution.

“The lesson to learn is not to ignore the traditional ABCDEs of melanoma, but to recognize that pediatric melanoma may present with different clinical characteristics, and to incorporate this awareness into our practice,” Dr. Huang said.

She did not have any disclosures. SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Children born with two or more melanocytic nevi of any size should have an MRI to check for brain lesions, ideally within the first 6 months, according to Jennifer Huang, MD, a pediatric dermatologist at Boston Children’s Hospital.

Two or more nevi increase the risk of CNS involvement, which in turn increases the risk of malignant conversion by more than 16-fold.

“If the scanning brain MRI is normal, [children] might not have congenital melanocytic nevus syndrome, and would be at low risk for melanoma,” Dr. Huang said. “If it’s abnormal, they might be at high risk for melanoma.” In the 2017 study, the odds ratio for melanoma with an abnormal MRI was 16.7 (P = .001).

Both melanocytes and neuronal cells arise from the embryonic neural crest, which explains the link between congenital nevi and brain lesions. Almost all congenital nevi are associated with early postzygotic mutations in the NRAS gene, and it’s possible the mutations affect other neural crest cell lines, including in the CNS, she said.

It’s also important to remember that childhood melanoma often doesn’t follow the ABCDE (asymmetry, border irregularity, color not uniform, diameter greater than 6 mm, and evolving) signs of melanoma common in adults.

In a retrospective study of 70 children with melanoma or ambiguous melanocytic tumors, 40% of pubertal subjects and 60% of prepubertal participants did not meet conventional adult ABCDE criteria. The majority of cases were raised, even in color, less than 6 mm across, symmetric, and de novo (J Am Acad Dermatol. 2013 Jun;68[6]:913-25).

It turns out that rapid evolution in size, shape, and color is the number one, unifying factor in childhood melanomas. Other key clues include raised lesions with uniform color or no pigmentation at all. A modified ABCDE for pediatric melanoma has been proposed: amelanotic, bump/bleeding, color uniform, diameter variable, de novo, and evolution.

“The lesson to learn is not to ignore the traditional ABCDEs of melanoma, but to recognize that pediatric melanoma may present with different clinical characteristics, and to incorporate this awareness into our practice,” Dr. Huang said.

She did not have any disclosures. SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

aotto@frontlinemedcom.com

Heart failure, with 42 medicines currently in development, is the leading area for new treatments of cardiovascular disease, according to Pharmaceutical Research and Manufacturers of America.

One of those 42 treatments is “a nonviral gene therapy that targets a tissue repair and regeneration pathway in the body,” PhRMA noted. A total of 200 medicines, including those for lipid disorders and hypertension, were either in clinical trials or undergoing regulatory review as of Jan. 24, 2018, the group reported. Some treatments are being considered for more than one condition.

rfranki@frontlinemedcom.com

Heart failure, with 42 medicines currently in development, is the leading area for new treatments of cardiovascular disease, according to Pharmaceutical Research and Manufacturers of America.

One of those 42 treatments is “a nonviral gene therapy that targets a tissue repair and regeneration pathway in the body,” PhRMA noted. A total of 200 medicines, including those for lipid disorders and hypertension, were either in clinical trials or undergoing regulatory review as of Jan. 24, 2018, the group reported. Some treatments are being considered for more than one condition.

rfranki@frontlinemedcom.com

Heart failure, with 42 medicines currently in development, is the leading area for new treatments of cardiovascular disease, according to Pharmaceutical Research and Manufacturers of America.

One of those 42 treatments is “a nonviral gene therapy that targets a tissue repair and regeneration pathway in the body,” PhRMA noted. A total of 200 medicines, including those for lipid disorders and hypertension, were either in clinical trials or undergoing regulatory review as of Jan. 24, 2018, the group reported. Some treatments are being considered for more than one condition.

rfranki@frontlinemedcom.com

Federal scientists advance a plan for a universal flu vaccine, making health care affordable has broad support, some encouraging news about proton pump inhibitors and myocardial infarction, and how obesity affects cardiovascular risk.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Federal scientists advance a plan for a universal flu vaccine, making health care affordable has broad support, some encouraging news about proton pump inhibitors and myocardial infarction, and how obesity affects cardiovascular risk.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Federal scientists advance a plan for a universal flu vaccine, making health care affordable has broad support, some encouraging news about proton pump inhibitors and myocardial infarction, and how obesity affects cardiovascular risk.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Photo from Business Wire

The European Commission (EC) has granted marketing authorization for emicizumab (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.

This means emicizumab is approved for use in the European Union for routine prophylaxis of bleeding episodes in patients of all ages who have hemophilia A and factor VIII inhibitors.

The recommended dose of emicizumab is 3 mg/kg once a week for the first 4 weeks, followed by 1.5 mg/kg once a week.

Emicizumab is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for patients with hemophilia A.

Emicizumab was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.

The EC’s decision to authorize marketing of emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

The European Commission (EC) has granted marketing authorization for emicizumab (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.

This means emicizumab is approved for use in the European Union for routine prophylaxis of bleeding episodes in patients of all ages who have hemophilia A and factor VIII inhibitors.

The recommended dose of emicizumab is 3 mg/kg once a week for the first 4 weeks, followed by 1.5 mg/kg once a week.

Emicizumab is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for patients with hemophilia A.

Emicizumab was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.

The EC’s decision to authorize marketing of emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

The European Commission (EC) has granted marketing authorization for emicizumab (Hemlibra®), a bispecific factor IXa- and factor X-directed antibody.

This means emicizumab is approved for use in the European Union for routine prophylaxis of bleeding episodes in patients of all ages who have hemophilia A and factor VIII inhibitors.

The recommended dose of emicizumab is 3 mg/kg once a week for the first 4 weeks, followed by 1.5 mg/kg once a week.

Emicizumab is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for patients with hemophilia A.

Emicizumab was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche, and Genentech.

The EC’s decision to authorize marketing of emicizumab is based on results from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from UAB Hospital

A study of US hospital discharges revealed a decrease in the use of red blood cell (RBC) and plasma transfusions—but not platelet transfusions—in recent years.

Researchers examined a sample of US hospital inpatient discharges from 1993 to 2014.

Overall, platelet, plasma, and RBC transfusions increased from 1993 to 2010.

However, from 2011 to 2014, there was a significant decrease in both plasma and RBC transfusions. Platelet transfusions remained stable over that period.

Aaron A. R. Tobian, MD, PhD, of Johns Hopkins University in Baltimore, Maryland, and his colleagues reported these findings in a letter to JAMA.

The researchers analyzed data from the National Inpatient Sample, which uses a stratified probability sample of 20% of all inpatient discharges in the US.

The team looked at transfusion trends from 1993 to 2014 but focused on trends from 2011 to 2014 because there was an inflection point in RBC transfusion in 2011. They used multivariable Poisson regression to estimate adjusted risk ratios (aRRs) comparing the risk of transfusion in 2011 and 2014.

The researchers found that RBC transfusions decreased from 6.8% in 2011 to 5.7% in 2014 (aRR=0.83; 95% confidence interval [CI], 0.78-0.88; P<0.001).

Plasma transfusions decreased from 1.0% to 0.87% (aRR=0.87; 95% CI, 0.80-0.95; P=0.003). And platelet transfusions remained stable (aRR=0.99; 95% CI, 0.89-1.10; P=0.93).

The researchers also conducted subgroup analyses to explore trends in RBC transfusion. They found that, from 2011 to 2014, there were significant reductions in RBC transfusions regardless of patients’ sex, race/ethnicity, risk severity, payer type, and admission type.

However, there was no significant reduction in RBC transfusions among patients younger than 18 years of age or in private investor–owned hospitals.

The researchers said the diagnostic coding used for this study was carried out primarily for billing purposes, and it was not possible to verify its accuracy. They also noted that the study only covered inpatient transfusions, so the results may not be generalizable to outpatient transfusions.

Photo from UAB Hospital

A study of US hospital discharges revealed a decrease in the use of red blood cell (RBC) and plasma transfusions—but not platelet transfusions—in recent years.

Researchers examined a sample of US hospital inpatient discharges from 1993 to 2014.

Overall, platelet, plasma, and RBC transfusions increased from 1993 to 2010.

However, from 2011 to 2014, there was a significant decrease in both plasma and RBC transfusions. Platelet transfusions remained stable over that period.

Aaron A. R. Tobian, MD, PhD, of Johns Hopkins University in Baltimore, Maryland, and his colleagues reported these findings in a letter to JAMA.

The researchers analyzed data from the National Inpatient Sample, which uses a stratified probability sample of 20% of all inpatient discharges in the US.

The team looked at transfusion trends from 1993 to 2014 but focused on trends from 2011 to 2014 because there was an inflection point in RBC transfusion in 2011. They used multivariable Poisson regression to estimate adjusted risk ratios (aRRs) comparing the risk of transfusion in 2011 and 2014.

The researchers found that RBC transfusions decreased from 6.8% in 2011 to 5.7% in 2014 (aRR=0.83; 95% confidence interval [CI], 0.78-0.88; P<0.001).

Plasma transfusions decreased from 1.0% to 0.87% (aRR=0.87; 95% CI, 0.80-0.95; P=0.003). And platelet transfusions remained stable (aRR=0.99; 95% CI, 0.89-1.10; P=0.93).

The researchers also conducted subgroup analyses to explore trends in RBC transfusion. They found that, from 2011 to 2014, there were significant reductions in RBC transfusions regardless of patients’ sex, race/ethnicity, risk severity, payer type, and admission type.

However, there was no significant reduction in RBC transfusions among patients younger than 18 years of age or in private investor–owned hospitals.

The researchers said the diagnostic coding used for this study was carried out primarily for billing purposes, and it was not possible to verify its accuracy. They also noted that the study only covered inpatient transfusions, so the results may not be generalizable to outpatient transfusions.

Photo from UAB Hospital

A study of US hospital discharges revealed a decrease in the use of red blood cell (RBC) and plasma transfusions—but not platelet transfusions—in recent years.

Researchers examined a sample of US hospital inpatient discharges from 1993 to 2014.

Overall, platelet, plasma, and RBC transfusions increased from 1993 to 2010.

However, from 2011 to 2014, there was a significant decrease in both plasma and RBC transfusions. Platelet transfusions remained stable over that period.

Aaron A. R. Tobian, MD, PhD, of Johns Hopkins University in Baltimore, Maryland, and his colleagues reported these findings in a letter to JAMA.

The researchers analyzed data from the National Inpatient Sample, which uses a stratified probability sample of 20% of all inpatient discharges in the US.

The team looked at transfusion trends from 1993 to 2014 but focused on trends from 2011 to 2014 because there was an inflection point in RBC transfusion in 2011. They used multivariable Poisson regression to estimate adjusted risk ratios (aRRs) comparing the risk of transfusion in 2011 and 2014.

The researchers found that RBC transfusions decreased from 6.8% in 2011 to 5.7% in 2014 (aRR=0.83; 95% confidence interval [CI], 0.78-0.88; P<0.001).

Plasma transfusions decreased from 1.0% to 0.87% (aRR=0.87; 95% CI, 0.80-0.95; P=0.003). And platelet transfusions remained stable (aRR=0.99; 95% CI, 0.89-1.10; P=0.93).

The researchers also conducted subgroup analyses to explore trends in RBC transfusion. They found that, from 2011 to 2014, there were significant reductions in RBC transfusions regardless of patients’ sex, race/ethnicity, risk severity, payer type, and admission type.

However, there was no significant reduction in RBC transfusions among patients younger than 18 years of age or in private investor–owned hospitals.

The researchers said the diagnostic coding used for this study was carried out primarily for billing purposes, and it was not possible to verify its accuracy. They also noted that the study only covered inpatient transfusions, so the results may not be generalizable to outpatient transfusions.

Pinkerton, J. V., et al, Menopause 24(10):1099, October 2017

The authors, writing for the North American Menopause Society (NAMS), protest the recent guideline recommendations regarding postmenopausal hormone therapy (HT) from the US Preventive Services Task Force (USPSTF). The USPSTF draft guidance gives HT (both combined regimens and estrogen alone) a D recommendation for preventing chronic disease because of harms outweighing benefits. The NAMS panel contends that the USPSTF opinion does not distinguish between approved and unapproved indications for HT. They note that the conclusions are based on the Women’s Health Initiative (WHI) trial, from which certain patient populations who may benefit (bothersome hot flashes, high osteoporosis risk, genitourinary symptoms) were omitted. The WHI tested a single dose of a single formulation in women having an average age of 63 who were 13 years past menopause. According to NAMS, the USPSTF should acknowledge that HT relieves vasomotor symptoms, helps prevent bone loss and fracture, and may improve quality of life in women younger than 60 years who take HT within ten years of menopause. Women younger than 60 years who have had a hysterectomy benefit from early estrogen monotherapy, having a lower incidence of breast cancer, cardiovascular disease and mortality. Further, the panel feels that the USPSTF should state that the findings of harm were based on higher-dose formulations, and that the results may not apply to lower doses, different and newer formulations (e.g., natural progesterone, bazedoxifene), and different dosing routes (e.g., transdermal administration). NAMS agrees that HT does not prevent heart disease, but indicates that its use (and insurance coverage) should not be precluded for women with early menopause, bothersome hot flashes, genitourinary symptoms and/or a high risk of fracture. 12 references

Pinkerton, J. V., et al, Menopause 24(10):1099, October 2017

The authors, writing for the North American Menopause Society (NAMS), protest the recent guideline recommendations regarding postmenopausal hormone therapy (HT) from the US Preventive Services Task Force (USPSTF). The USPSTF draft guidance gives HT (both combined regimens and estrogen alone) a D recommendation for preventing chronic disease because of harms outweighing benefits. The NAMS panel contends that the USPSTF opinion does not distinguish between approved and unapproved indications for HT. They note that the conclusions are based on the Women’s Health Initiative (WHI) trial, from which certain patient populations who may benefit (bothersome hot flashes, high osteoporosis risk, genitourinary symptoms) were omitted. The WHI tested a single dose of a single formulation in women having an average age of 63 who were 13 years past menopause. According to NAMS, the USPSTF should acknowledge that HT relieves vasomotor symptoms, helps prevent bone loss and fracture, and may improve quality of life in women younger than 60 years who take HT within ten years of menopause. Women younger than 60 years who have had a hysterectomy benefit from early estrogen monotherapy, having a lower incidence of breast cancer, cardiovascular disease and mortality. Further, the panel feels that the USPSTF should state that the findings of harm were based on higher-dose formulations, and that the results may not apply to lower doses, different and newer formulations (e.g., natural progesterone, bazedoxifene), and different dosing routes (e.g., transdermal administration). NAMS agrees that HT does not prevent heart disease, but indicates that its use (and insurance coverage) should not be precluded for women with early menopause, bothersome hot flashes, genitourinary symptoms and/or a high risk of fracture. 12 references

Pinkerton, J. V., et al, Menopause 24(10):1099, October 2017

The authors, writing for the North American Menopause Society (NAMS), protest the recent guideline recommendations regarding postmenopausal hormone therapy (HT) from the US Preventive Services Task Force (USPSTF). The USPSTF draft guidance gives HT (both combined regimens and estrogen alone) a D recommendation for preventing chronic disease because of harms outweighing benefits. The NAMS panel contends that the USPSTF opinion does not distinguish between approved and unapproved indications for HT. They note that the conclusions are based on the Women’s Health Initiative (WHI) trial, from which certain patient populations who may benefit (bothersome hot flashes, high osteoporosis risk, genitourinary symptoms) were omitted. The WHI tested a single dose of a single formulation in women having an average age of 63 who were 13 years past menopause. According to NAMS, the USPSTF should acknowledge that HT relieves vasomotor symptoms, helps prevent bone loss and fracture, and may improve quality of life in women younger than 60 years who take HT within ten years of menopause. Women younger than 60 years who have had a hysterectomy benefit from early estrogen monotherapy, having a lower incidence of breast cancer, cardiovascular disease and mortality. Further, the panel feels that the USPSTF should state that the findings of harm were based on higher-dose formulations, and that the results may not apply to lower doses, different and newer formulations (e.g., natural progesterone, bazedoxifene), and different dosing routes (e.g., transdermal administration). NAMS agrees that HT does not prevent heart disease, but indicates that its use (and insurance coverage) should not be precluded for women with early menopause, bothersome hot flashes, genitourinary symptoms and/or a high risk of fracture. 12 references

IN THIS ARTICLE

• Diagnosis
• Treatment
• Care outcome

A 57-year-old horticulturist is working on a ladder leaned up against a tree trunk when the ladder slips, causing her to fall six feet onto concrete. Her right foot and ankle sustain the force of the fall; she is in excruciating pain and unable to bear weight on the foot. She is immediately transported to a local emergency department for evaluation.

Physical exam reveals a tearful middle-aged female in moderate distress and acute pain. There is moderate swelling of the right medial and lateral malleolus, as well as the midfoot, with blue and purple discoloration on the medial and lateral malleolus. Radiographs of the right ankle identify nondisplaced fractures of the distal fibula and tibia. Foot x-rays are unremarkable. A splint is ordered. The patient is given crutches (non-weight-bearing status), pain medication, and a referral to orthopedics.

On day 3, the patient presents to orthopedics, where the splint is removed. An irregular, 4 × 3–in (at largest diameter), serohemorrhagic blister is discovered on the medial aspect of the lower leg, above the right malleolus (see Figure 1). Multiple 1- to 3-mm vesicles surround much of the anterior border. Moderate edema is noted from the top of the lesion to the midfoot, concentrated around the lateral and medial malleolus. Extensive blue, purple, and black discoloration is seen below the malleolus. The patient is diagnosed with a fracture blister.

DISCUSSION

Fracture blisters are taut, bullous, subepidermal vesicles that can accompany fractures or severe twisting injuries. They overlie markedly edematous soft tissue and histologically resemble a second-degree burn.^1,2

Physiologically, blisters are caused by increased interstitial pressure due to swelling, with subsequent increased filtration pressure and colloid osmotic pressure in the epidermal gap.³ This causes a disruption that allows fluid to move into the weakened area.³ Areas most at risk for fracture blister formation are those with tight, closely adhered skin without muscle or enveloping fascia, where there is less soft tissue between the skin and bone prominences (eg, ankle, elbow, foot, distal tibia).^2-4

Approximately 3% of all patients with acute fractures requiring hospitalization develop a fracture blister.⁴ Any condition that predisposes a patient to poor wound healing (eg, peripheral vascular disease, diabetes, hypertension) increases risk for a fracture blister.² Recognizing which patients are at greatest risk is vital, as implementing prevention strategies and intervening when fracture blisters do form can help decrease complications—including infection and delayed surgery—and improve fracture resolution. In this patient’s case, the extent of the injury and force of the fall caused the fracture blister to form.

Diagnosis

Diagnosis of a fracture blister is based on clinical presentation. There are two types: hemorrhagic blisters and clear fluid-filled blisters. Hemorrhagic blisters indicate more severe injury and longer healing time (approximately 16 d), while clear fluid-filled blisters demonstrate minimal injury and therefore are quicker to heal.^2,4

The differential diagnosis for fracture blisters includes friction blisters and disorders such as epidermolysis bullosa and bullous pemphigoid. Friction blisters form when the epidermis is subjected to repeated friction or shear forces (eg, from a cast or splint).^5,6 These forces mechanically separate epidermal cells at the stratum spinosum layer.⁷ The pressure that moves across the skin forces fluid into the deeper open spaces, filling them but leaving the surface layer intact.¹

Epidermolysis bullosa (EB) is a group of rare inherited cutaneous and mucus membrane disorders. EB involves fragility and detachment of subepithelial tissues, which results in blistering and erosions.^8,9 The blisters tend to develop in areas subject to minor trauma, such as the extensor aspects of the elbows and the dorsal aspects of the hands and feet.⁹ They can also be triggered by exposure to heat, friction, scratching, and adhesive tape.¹⁰

Bullous pemphigoid, a chronic autoimmune skin disorder, is characterized by pruritic, bullous lesions. When IgG autoantibodies bind to certain hemidesmosomal antigens, complement activation causes a subepidermal blister.¹¹ While bullous pemphigoid most commonly affects those older than 60, it can also occur in children. Diagnosis is confirmed by skin biopsy and immunofluorescence testing.¹¹

Treatment and management

Although several recommendations have been published, there is no gold standard and treatment of fracture blisters remains controversial. Early surgical intervention for fractures could decrease the incidence of fracture blisters.^1,3

The goal of treatment is to achieve re-epithelialization of the dermis.^3,12,13 Once a blister forms, management techniques vary. Some recommend keeping closed blisters covered with a dry dressing to protect them from damage.³ Strauss et al recommend unroofing to avoid traumatic rupture; however, this does increase risk for infection.¹² Recommendations differ depending on provider preference and each patient’s individual situation. 

Elective unroofing of a blister is typically followed with one of several treatment options. These include covering the open blister with a topical antibiotic cream (eg, silver sulfadiazine 2%); applying a nonadherent, occlusive bismuth-tribromophenate-petroleum gauze dressing; or elevating and immobilizing the affected extremity.^12,13

Treatment of spontaneously ruptured fracture blisters entails

• Unroofing the blister completely and applying a topical antimicrobial (eg, silver sulfadiazine, polymyxin B, neomycin, bacitracin).
• Applying a hydrocolloid dressing to keep the environment moist.
• Using a first-aid gel containing melaleuca (tea tree) oil.
• Initiating prophylactic oral antibiotics.
• Using whirlpool treatments.
• Elevating and immobilizing the affected extremity.^3,12,14

OUTCOME FOR THE CASE PATIENT

The fracture blister was electively unroofed (see Figure 2) based on provider preference. The patient was instructed to clean the wound daily and apply topical cream (silver sulfadiazine 2% bid) to the wound and cover it with gauze. The patient was made non-weight-bearing to the right lower extremity. Continuous elevation was highly encouraged except for bathing and restroom use, and an NSAID was recommended as needed for pain. She was reassessed the following day and, due to partial refilling, the blister required additional unroofing. The patient was instructed to resume previous wound care orders.

No surgical intervention was required. CT of the right foot and ankle without contrast (performed on day 4 postinjury) confirmed a nondisplaced transverse fracture of the medial malleolus and a sagittal avulsion fracture of the anterior-inferior lateral malleolus. Multiple smaller fracture fragments were noted posterior and medial to the medial malleolus as well as inferiorly along the course of the deltoid ligament. There was a small, nondisplaced avulsion fracture of the medial malleolus at the anterolateral and posterolateral tibial plafond.

Due to the extent of the swelling, multiple fractures, and blister formation, the patient was essentially bed bound for the first three weeks; complete resolution of the fracture blister occurred 21 days after initial discovery (see Figure 3). The patient did not experience cutaneous complications. Her lower extremity was then casted in a short-leg removable cast for 10 weeks. She underwent physical therapy, and after 12 weeks, the patient was weight-bearing and was discharged from orthopedics. The patient reported refractory pain and swelling for an additional eight weeks following injury, warranting daily ibuprofen.

CONCLUSION

Fracture blisters are rare, and experience and knowledge about them in primary care is lacking. But clinicians need to be able to identify, diagnose, and refer at-risk patients to orthopedics in a timely manner.

Current management and treatment recommendations are inconsistent. Treatment varies depending on the site, severity, type, and status of the blister and the overall health of the patient. Fracture blisters may be left intact, electively unroofed, or treated after spontaneous rupture. More research is needed to clarify management recommendations, specifically regarding the decision to unroof a blister or leave it intact. Early surgical intervention may prevent the development of a fracture blister.

IN THIS ARTICLE

• Diagnosis
• Treatment
• Care outcome

A 57-year-old horticulturist is working on a ladder leaned up against a tree trunk when the ladder slips, causing her to fall six feet onto concrete. Her right foot and ankle sustain the force of the fall; she is in excruciating pain and unable to bear weight on the foot. She is immediately transported to a local emergency department for evaluation.

Physical exam reveals a tearful middle-aged female in moderate distress and acute pain. There is moderate swelling of the right medial and lateral malleolus, as well as the midfoot, with blue and purple discoloration on the medial and lateral malleolus. Radiographs of the right ankle identify nondisplaced fractures of the distal fibula and tibia. Foot x-rays are unremarkable. A splint is ordered. The patient is given crutches (non-weight-bearing status), pain medication, and a referral to orthopedics.

On day 3, the patient presents to orthopedics, where the splint is removed. An irregular, 4 × 3–in (at largest diameter), serohemorrhagic blister is discovered on the medial aspect of the lower leg, above the right malleolus (see Figure 1). Multiple 1- to 3-mm vesicles surround much of the anterior border. Moderate edema is noted from the top of the lesion to the midfoot, concentrated around the lateral and medial malleolus. Extensive blue, purple, and black discoloration is seen below the malleolus. The patient is diagnosed with a fracture blister.

DISCUSSION

Fracture blisters are taut, bullous, subepidermal vesicles that can accompany fractures or severe twisting injuries. They overlie markedly edematous soft tissue and histologically resemble a second-degree burn.^1,2

Physiologically, blisters are caused by increased interstitial pressure due to swelling, with subsequent increased filtration pressure and colloid osmotic pressure in the epidermal gap.³ This causes a disruption that allows fluid to move into the weakened area.³ Areas most at risk for fracture blister formation are those with tight, closely adhered skin without muscle or enveloping fascia, where there is less soft tissue between the skin and bone prominences (eg, ankle, elbow, foot, distal tibia).^2-4

Approximately 3% of all patients with acute fractures requiring hospitalization develop a fracture blister.⁴ Any condition that predisposes a patient to poor wound healing (eg, peripheral vascular disease, diabetes, hypertension) increases risk for a fracture blister.² Recognizing which patients are at greatest risk is vital, as implementing prevention strategies and intervening when fracture blisters do form can help decrease complications—including infection and delayed surgery—and improve fracture resolution. In this patient’s case, the extent of the injury and force of the fall caused the fracture blister to form.

Diagnosis

Diagnosis of a fracture blister is based on clinical presentation. There are two types: hemorrhagic blisters and clear fluid-filled blisters. Hemorrhagic blisters indicate more severe injury and longer healing time (approximately 16 d), while clear fluid-filled blisters demonstrate minimal injury and therefore are quicker to heal.^2,4

The differential diagnosis for fracture blisters includes friction blisters and disorders such as epidermolysis bullosa and bullous pemphigoid. Friction blisters form when the epidermis is subjected to repeated friction or shear forces (eg, from a cast or splint).^5,6 These forces mechanically separate epidermal cells at the stratum spinosum layer.⁷ The pressure that moves across the skin forces fluid into the deeper open spaces, filling them but leaving the surface layer intact.¹

Epidermolysis bullosa (EB) is a group of rare inherited cutaneous and mucus membrane disorders. EB involves fragility and detachment of subepithelial tissues, which results in blistering and erosions.^8,9 The blisters tend to develop in areas subject to minor trauma, such as the extensor aspects of the elbows and the dorsal aspects of the hands and feet.⁹ They can also be triggered by exposure to heat, friction, scratching, and adhesive tape.¹⁰

Bullous pemphigoid, a chronic autoimmune skin disorder, is characterized by pruritic, bullous lesions. When IgG autoantibodies bind to certain hemidesmosomal antigens, complement activation causes a subepidermal blister.¹¹ While bullous pemphigoid most commonly affects those older than 60, it can also occur in children. Diagnosis is confirmed by skin biopsy and immunofluorescence testing.¹¹

Treatment and management

Although several recommendations have been published, there is no gold standard and treatment of fracture blisters remains controversial. Early surgical intervention for fractures could decrease the incidence of fracture blisters.^1,3

The goal of treatment is to achieve re-epithelialization of the dermis.^3,12,13 Once a blister forms, management techniques vary. Some recommend keeping closed blisters covered with a dry dressing to protect them from damage.³ Strauss et al recommend unroofing to avoid traumatic rupture; however, this does increase risk for infection.¹² Recommendations differ depending on provider preference and each patient’s individual situation. 

Elective unroofing of a blister is typically followed with one of several treatment options. These include covering the open blister with a topical antibiotic cream (eg, silver sulfadiazine 2%); applying a nonadherent, occlusive bismuth-tribromophenate-petroleum gauze dressing; or elevating and immobilizing the affected extremity.^12,13

Treatment of spontaneously ruptured fracture blisters entails

• Unroofing the blister completely and applying a topical antimicrobial (eg, silver sulfadiazine, polymyxin B, neomycin, bacitracin).
• Applying a hydrocolloid dressing to keep the environment moist.
• Using a first-aid gel containing melaleuca (tea tree) oil.
• Initiating prophylactic oral antibiotics.
• Using whirlpool treatments.
• Elevating and immobilizing the affected extremity.^3,12,14

OUTCOME FOR THE CASE PATIENT

The fracture blister was electively unroofed (see Figure 2) based on provider preference. The patient was instructed to clean the wound daily and apply topical cream (silver sulfadiazine 2% bid) to the wound and cover it with gauze. The patient was made non-weight-bearing to the right lower extremity. Continuous elevation was highly encouraged except for bathing and restroom use, and an NSAID was recommended as needed for pain. She was reassessed the following day and, due to partial refilling, the blister required additional unroofing. The patient was instructed to resume previous wound care orders.

No surgical intervention was required. CT of the right foot and ankle without contrast (performed on day 4 postinjury) confirmed a nondisplaced transverse fracture of the medial malleolus and a sagittal avulsion fracture of the anterior-inferior lateral malleolus. Multiple smaller fracture fragments were noted posterior and medial to the medial malleolus as well as inferiorly along the course of the deltoid ligament. There was a small, nondisplaced avulsion fracture of the medial malleolus at the anterolateral and posterolateral tibial plafond.

Due to the extent of the swelling, multiple fractures, and blister formation, the patient was essentially bed bound for the first three weeks; complete resolution of the fracture blister occurred 21 days after initial discovery (see Figure 3). The patient did not experience cutaneous complications. Her lower extremity was then casted in a short-leg removable cast for 10 weeks. She underwent physical therapy, and after 12 weeks, the patient was weight-bearing and was discharged from orthopedics. The patient reported refractory pain and swelling for an additional eight weeks following injury, warranting daily ibuprofen.

CONCLUSION

Fracture blisters are rare, and experience and knowledge about them in primary care is lacking. But clinicians need to be able to identify, diagnose, and refer at-risk patients to orthopedics in a timely manner.

Current management and treatment recommendations are inconsistent. Treatment varies depending on the site, severity, type, and status of the blister and the overall health of the patient. Fracture blisters may be left intact, electively unroofed, or treated after spontaneous rupture. More research is needed to clarify management recommendations, specifically regarding the decision to unroof a blister or leave it intact. Early surgical intervention may prevent the development of a fracture blister.

IN THIS ARTICLE

• Diagnosis
• Treatment
• Care outcome

A 57-year-old horticulturist is working on a ladder leaned up against a tree trunk when the ladder slips, causing her to fall six feet onto concrete. Her right foot and ankle sustain the force of the fall; she is in excruciating pain and unable to bear weight on the foot. She is immediately transported to a local emergency department for evaluation.

Physical exam reveals a tearful middle-aged female in moderate distress and acute pain. There is moderate swelling of the right medial and lateral malleolus, as well as the midfoot, with blue and purple discoloration on the medial and lateral malleolus. Radiographs of the right ankle identify nondisplaced fractures of the distal fibula and tibia. Foot x-rays are unremarkable. A splint is ordered. The patient is given crutches (non-weight-bearing status), pain medication, and a referral to orthopedics.

On day 3, the patient presents to orthopedics, where the splint is removed. An irregular, 4 × 3–in (at largest diameter), serohemorrhagic blister is discovered on the medial aspect of the lower leg, above the right malleolus (see Figure 1). Multiple 1- to 3-mm vesicles surround much of the anterior border. Moderate edema is noted from the top of the lesion to the midfoot, concentrated around the lateral and medial malleolus. Extensive blue, purple, and black discoloration is seen below the malleolus. The patient is diagnosed with a fracture blister.

DISCUSSION

Fracture blisters are taut, bullous, subepidermal vesicles that can accompany fractures or severe twisting injuries. They overlie markedly edematous soft tissue and histologically resemble a second-degree burn.^1,2

Physiologically, blisters are caused by increased interstitial pressure due to swelling, with subsequent increased filtration pressure and colloid osmotic pressure in the epidermal gap.³ This causes a disruption that allows fluid to move into the weakened area.³ Areas most at risk for fracture blister formation are those with tight, closely adhered skin without muscle or enveloping fascia, where there is less soft tissue between the skin and bone prominences (eg, ankle, elbow, foot, distal tibia).^2-4

Approximately 3% of all patients with acute fractures requiring hospitalization develop a fracture blister.⁴ Any condition that predisposes a patient to poor wound healing (eg, peripheral vascular disease, diabetes, hypertension) increases risk for a fracture blister.² Recognizing which patients are at greatest risk is vital, as implementing prevention strategies and intervening when fracture blisters do form can help decrease complications—including infection and delayed surgery—and improve fracture resolution. In this patient’s case, the extent of the injury and force of the fall caused the fracture blister to form.

Diagnosis

Diagnosis of a fracture blister is based on clinical presentation. There are two types: hemorrhagic blisters and clear fluid-filled blisters. Hemorrhagic blisters indicate more severe injury and longer healing time (approximately 16 d), while clear fluid-filled blisters demonstrate minimal injury and therefore are quicker to heal.^2,4

The differential diagnosis for fracture blisters includes friction blisters and disorders such as epidermolysis bullosa and bullous pemphigoid. Friction blisters form when the epidermis is subjected to repeated friction or shear forces (eg, from a cast or splint).^5,6 These forces mechanically separate epidermal cells at the stratum spinosum layer.⁷ The pressure that moves across the skin forces fluid into the deeper open spaces, filling them but leaving the surface layer intact.¹

Epidermolysis bullosa (EB) is a group of rare inherited cutaneous and mucus membrane disorders. EB involves fragility and detachment of subepithelial tissues, which results in blistering and erosions.^8,9 The blisters tend to develop in areas subject to minor trauma, such as the extensor aspects of the elbows and the dorsal aspects of the hands and feet.⁹ They can also be triggered by exposure to heat, friction, scratching, and adhesive tape.¹⁰

Bullous pemphigoid, a chronic autoimmune skin disorder, is characterized by pruritic, bullous lesions. When IgG autoantibodies bind to certain hemidesmosomal antigens, complement activation causes a subepidermal blister.¹¹ While bullous pemphigoid most commonly affects those older than 60, it can also occur in children. Diagnosis is confirmed by skin biopsy and immunofluorescence testing.¹¹

Treatment and management

Although several recommendations have been published, there is no gold standard and treatment of fracture blisters remains controversial. Early surgical intervention for fractures could decrease the incidence of fracture blisters.^1,3

The goal of treatment is to achieve re-epithelialization of the dermis.^3,12,13 Once a blister forms, management techniques vary. Some recommend keeping closed blisters covered with a dry dressing to protect them from damage.³ Strauss et al recommend unroofing to avoid traumatic rupture; however, this does increase risk for infection.¹² Recommendations differ depending on provider preference and each patient’s individual situation. 

Elective unroofing of a blister is typically followed with one of several treatment options. These include covering the open blister with a topical antibiotic cream (eg, silver sulfadiazine 2%); applying a nonadherent, occlusive bismuth-tribromophenate-petroleum gauze dressing; or elevating and immobilizing the affected extremity.^12,13

Treatment of spontaneously ruptured fracture blisters entails

• Unroofing the blister completely and applying a topical antimicrobial (eg, silver sulfadiazine, polymyxin B, neomycin, bacitracin).
• Applying a hydrocolloid dressing to keep the environment moist.
• Using a first-aid gel containing melaleuca (tea tree) oil.
• Initiating prophylactic oral antibiotics.
• Using whirlpool treatments.
• Elevating and immobilizing the affected extremity.^3,12,14

OUTCOME FOR THE CASE PATIENT

The fracture blister was electively unroofed (see Figure 2) based on provider preference. The patient was instructed to clean the wound daily and apply topical cream (silver sulfadiazine 2% bid) to the wound and cover it with gauze. The patient was made non-weight-bearing to the right lower extremity. Continuous elevation was highly encouraged except for bathing and restroom use, and an NSAID was recommended as needed for pain. She was reassessed the following day and, due to partial refilling, the blister required additional unroofing. The patient was instructed to resume previous wound care orders.

No surgical intervention was required. CT of the right foot and ankle without contrast (performed on day 4 postinjury) confirmed a nondisplaced transverse fracture of the medial malleolus and a sagittal avulsion fracture of the anterior-inferior lateral malleolus. Multiple smaller fracture fragments were noted posterior and medial to the medial malleolus as well as inferiorly along the course of the deltoid ligament. There was a small, nondisplaced avulsion fracture of the medial malleolus at the anterolateral and posterolateral tibial plafond.

Due to the extent of the swelling, multiple fractures, and blister formation, the patient was essentially bed bound for the first three weeks; complete resolution of the fracture blister occurred 21 days after initial discovery (see Figure 3). The patient did not experience cutaneous complications. Her lower extremity was then casted in a short-leg removable cast for 10 weeks. She underwent physical therapy, and after 12 weeks, the patient was weight-bearing and was discharged from orthopedics. The patient reported refractory pain and swelling for an additional eight weeks following injury, warranting daily ibuprofen.

CONCLUSION

Fracture blisters are rare, and experience and knowledge about them in primary care is lacking. But clinicians need to be able to identify, diagnose, and refer at-risk patients to orthopedics in a timely manner.

Current management and treatment recommendations are inconsistent. Treatment varies depending on the site, severity, type, and status of the blister and the overall health of the patient. Fracture blisters may be left intact, electively unroofed, or treated after spontaneous rupture. More research is needed to clarify management recommendations, specifically regarding the decision to unroof a blister or leave it intact. Early surgical intervention may prevent the development of a fracture blister.

KAUAI, HAWAII – Intermittent dosing of vismodegib (Erivedge) for locally advanced/metastatic basal cell carcinoma appears to preserve efficacy, but reduces treatment-related side effects, according to Kishwer Nehal, MD, director of Mohs micrographic and dermatologic surgery at Memorial Sloan Kettering Cancer Center, New York.

That’s important because, although some patients have a good response to vismodegib, more – about 80% – have side effects that make it necessary to stop treatment, including muscle spasms and weight loss, among other problems. Side effects often come on quickly and can become intolerable after a few months of treatment, so physicians have looked for alternative dosing regimens to hold them off, with some success.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Intermittent dosing of vismodegib (Erivedge) for locally advanced/metastatic basal cell carcinoma appears to preserve efficacy, but reduces treatment-related side effects, according to Kishwer Nehal, MD, director of Mohs micrographic and dermatologic surgery at Memorial Sloan Kettering Cancer Center, New York.

That’s important because, although some patients have a good response to vismodegib, more – about 80% – have side effects that make it necessary to stop treatment, including muscle spasms and weight loss, among other problems. Side effects often come on quickly and can become intolerable after a few months of treatment, so physicians have looked for alternative dosing regimens to hold them off, with some success.

aotto@frontlinemedcom.com

KAUAI, HAWAII – Intermittent dosing of vismodegib (Erivedge) for locally advanced/metastatic basal cell carcinoma appears to preserve efficacy, but reduces treatment-related side effects, according to Kishwer Nehal, MD, director of Mohs micrographic and dermatologic surgery at Memorial Sloan Kettering Cancer Center, New York.

That’s important because, although some patients have a good response to vismodegib, more – about 80% – have side effects that make it necessary to stop treatment, including muscle spasms and weight loss, among other problems. Side effects often come on quickly and can become intolerable after a few months of treatment, so physicians have looked for alternative dosing regimens to hold them off, with some success.

aotto@frontlinemedcom.com

In the year 2017, a plethora of articles and commentaries on the “opioid crisis” have appeared in major medical journals, alongside the ongoing hyperbole seen daily in the lay media. But the pressing concern remains: How best to manage patients who are 1.) already taking opioids and 2.) those newly requesting relief of serious and chronic pain.

Opioid for Pain and Its Misuse

In this article by Volkow and Collins, both of whom are titans in neuroscience, we are reminded that despite all the warnings, opioids are being widely prescribed in the U.S. In a weighted national sample of over 50,000 adults, the investigators concluded that more than one-third of the adult population has taken an opioid at some point during 2015. Among these, 12.5% confirmed that they misused the drug, e.g., used them without a prescription or in any way contrary to the prescribed directions. Of these, 16.7% developed an opioid-use disorder, as defined in the DSM-IV.

In response, Volkow and Collins note that an increasing number of clinicians are attempting to control chronic or intractable pain with new anticonvulsants such as Pregabalin (Lyrica) and Gabapentin. Yet, these drugs have only been shown to be effective only for fibromyalgia and certain forms of neurogenic pain. In addition, the authors note that a multidisciplinary workgroup convened by the NIH Office of Disease Prevention (2014) found that there had been no randomized trials to evaluate the efficacy of long-term (>1 year) opioid treatment. Accordingly, the authors recommend short-term strategy to develop abuse-deterrent formulations that can minimize diversion and misuse.

What About Cannabis?

In a 2017 report from the National Academies of Sciences, Engineering, and Medicine, substantial evidence supports the effectiveness of cannabinoids in treating some types of pain. However, again there is scant research on phytocannabinoids as medicine. In addition, there are abundant research and legitimate concerns related to cognitive, motor and motivational impairment and the effects on brain development. However, the therapeutic potential of cannabinoids and mediators of the abundant endocannabinoid system warrants further exploration for alternatives to opioids.

Lastly, non-pharmacologic interventions, including behavioral, self-management interventions, may play an important role in pain management. The initiative described by the authors supports partnerships between the NIH and pharmaceutical and biotechnology companies to hasten medication and device development.

Why Does This Matter?

If these data are true, and one-third of the U.S. adult population suffers from chronic pain, we are duty bound to find therapeutic options with less risk, addictive potential and mortality. As I have argued for nearly 40 years, basic and translational research is desperately needed, as clinicians are in a conundrum between the worthy goals of alleviating pain and suffering and decreasing the risk for addiction and mortality. We can, and must do better.

In the year 2017, a plethora of articles and commentaries on the “opioid crisis” have appeared in major medical journals, alongside the ongoing hyperbole seen daily in the lay media. But the pressing concern remains: How best to manage patients who are 1.) already taking opioids and 2.) those newly requesting relief of serious and chronic pain.

Opioid for Pain and Its Misuse

In this article by Volkow and Collins, both of whom are titans in neuroscience, we are reminded that despite all the warnings, opioids are being widely prescribed in the U.S. In a weighted national sample of over 50,000 adults, the investigators concluded that more than one-third of the adult population has taken an opioid at some point during 2015. Among these, 12.5% confirmed that they misused the drug, e.g., used them without a prescription or in any way contrary to the prescribed directions. Of these, 16.7% developed an opioid-use disorder, as defined in the DSM-IV.

In response, Volkow and Collins note that an increasing number of clinicians are attempting to control chronic or intractable pain with new anticonvulsants such as Pregabalin (Lyrica) and Gabapentin. Yet, these drugs have only been shown to be effective only for fibromyalgia and certain forms of neurogenic pain. In addition, the authors note that a multidisciplinary workgroup convened by the NIH Office of Disease Prevention (2014) found that there had been no randomized trials to evaluate the efficacy of long-term (>1 year) opioid treatment. Accordingly, the authors recommend short-term strategy to develop abuse-deterrent formulations that can minimize diversion and misuse.

What About Cannabis?

In a 2017 report from the National Academies of Sciences, Engineering, and Medicine, substantial evidence supports the effectiveness of cannabinoids in treating some types of pain. However, again there is scant research on phytocannabinoids as medicine. In addition, there are abundant research and legitimate concerns related to cognitive, motor and motivational impairment and the effects on brain development. However, the therapeutic potential of cannabinoids and mediators of the abundant endocannabinoid system warrants further exploration for alternatives to opioids.

Lastly, non-pharmacologic interventions, including behavioral, self-management interventions, may play an important role in pain management. The initiative described by the authors supports partnerships between the NIH and pharmaceutical and biotechnology companies to hasten medication and device development.

Why Does This Matter?

If these data are true, and one-third of the U.S. adult population suffers from chronic pain, we are duty bound to find therapeutic options with less risk, addictive potential and mortality. As I have argued for nearly 40 years, basic and translational research is desperately needed, as clinicians are in a conundrum between the worthy goals of alleviating pain and suffering and decreasing the risk for addiction and mortality. We can, and must do better.

In the year 2017, a plethora of articles and commentaries on the “opioid crisis” have appeared in major medical journals, alongside the ongoing hyperbole seen daily in the lay media. But the pressing concern remains: How best to manage patients who are 1.) already taking opioids and 2.) those newly requesting relief of serious and chronic pain.

Opioid for Pain and Its Misuse

In this article by Volkow and Collins, both of whom are titans in neuroscience, we are reminded that despite all the warnings, opioids are being widely prescribed in the U.S. In a weighted national sample of over 50,000 adults, the investigators concluded that more than one-third of the adult population has taken an opioid at some point during 2015. Among these, 12.5% confirmed that they misused the drug, e.g., used them without a prescription or in any way contrary to the prescribed directions. Of these, 16.7% developed an opioid-use disorder, as defined in the DSM-IV.

In response, Volkow and Collins note that an increasing number of clinicians are attempting to control chronic or intractable pain with new anticonvulsants such as Pregabalin (Lyrica) and Gabapentin. Yet, these drugs have only been shown to be effective only for fibromyalgia and certain forms of neurogenic pain. In addition, the authors note that a multidisciplinary workgroup convened by the NIH Office of Disease Prevention (2014) found that there had been no randomized trials to evaluate the efficacy of long-term (>1 year) opioid treatment. Accordingly, the authors recommend short-term strategy to develop abuse-deterrent formulations that can minimize diversion and misuse.

What About Cannabis?

In a 2017 report from the National Academies of Sciences, Engineering, and Medicine, substantial evidence supports the effectiveness of cannabinoids in treating some types of pain. However, again there is scant research on phytocannabinoids as medicine. In addition, there are abundant research and legitimate concerns related to cognitive, motor and motivational impairment and the effects on brain development. However, the therapeutic potential of cannabinoids and mediators of the abundant endocannabinoid system warrants further exploration for alternatives to opioids.

Lastly, non-pharmacologic interventions, including behavioral, self-management interventions, may play an important role in pain management. The initiative described by the authors supports partnerships between the NIH and pharmaceutical and biotechnology companies to hasten medication and device development.

Why Does This Matter?

If these data are true, and one-third of the U.S. adult population suffers from chronic pain, we are duty bound to find therapeutic options with less risk, addictive potential and mortality. As I have argued for nearly 40 years, basic and translational research is desperately needed, as clinicians are in a conundrum between the worthy goals of alleviating pain and suffering and decreasing the risk for addiction and mortality. We can, and must do better.