The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).

The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.

The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.

Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.

Cabozantinib is marketed as Cabometyx by Exelixis.

lnikolaides@frontlinemedcom.com

The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).

The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.

The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.

Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.

Cabozantinib is marketed as Cabometyx by Exelixis.

lnikolaides@frontlinemedcom.com

The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).

The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.

The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.

Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.

Cabozantinib is marketed as Cabometyx by Exelixis.

lnikolaides@frontlinemedcom.com

REPORTING FROM SABCS 2017

SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.

Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.

He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.

I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.

As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10,  and 0.14, P less than .001 for each).

However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.

The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”

I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.

op@frontlinemedcom.com

SOURCE: Yee, D et al. SABCS Abstract GS3-08.

REPORTING FROM SABCS 2017

SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.

Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.

He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.

I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.

As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10,  and 0.14, P less than .001 for each).

However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.

The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”

I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.

op@frontlinemedcom.com

SOURCE: Yee, D et al. SABCS Abstract GS3-08.

REPORTING FROM SABCS 2017

SAN ANTONIO – Pathological complete response (pCR) is an accurate predictor of both event-free and distant recurrence-free survival in patients treated for stage 2 or 3 breast cancers with high risk for recurrence, according to investigators in the adaptive I-SPY2 trial.
Among 746 patients with various types of breast cancer evaluated in an intention-to-treat analysis, 3-year event-free survival (EFS) for those who had a pCR after chemotherapy and definitive surgery was 94%, compared with 76% for those who did not have a pCR.

Similarly, 3-year distant recurrence-free survival (DRFS) was 95% for patients who had a pCR after first-line therapy, compared with 79% for patients who did not, reported Douglas Yee, MD, of the Masonic Cancer Center at the University of Minnesota in Minneapolis.
“We find that path CR is a strong predictor of event-free survival and distance recurrence-free survival in the setting of a multiagent platform trial,” he said at the San Antonio Breast Cancer Symposium.

He explained that pCR is predictive of survival across all tumor subsets – regardless of hormone receptor status, HER2 status, and 70-gene signature (MammaPrint) status – and that pCR as a clinical trial endpoint allows investigators to rapidly evaluate novel therapeutic combinations, with the potential for identifying more effective and ideally less toxic regimens.

I-SPY 2 is a phase 2, adaptively randomized neoadjuvant clinical trial with a shared control arm in which patients receive standard neoadjuvant chemotherapy, and up to four simultaneous investigational arms. The primary endpoint is pCR, defined as no residual invasive cancer in the breast or lymph nodes, assessed according to the Residual Cancer Burden method. The goal is to match therapies with the most responsive breast cancer subtypes.
In the current analysis, the investigators looked at data on 245 patients with hormone receptor-negative and HER2– tumors (HR–/HER2–), 275 with HR-positive/HER2-negative tumors, 77 with HR–/HER2+ tumors, and 149 with tumors positive for both HR and HER2. Respective rates of pCR in these groups were 41%, 18%, 68% and 39%.

As noted, both EFS and DRFS were significantly better for patients with pCRs after initial therapy, with hazard ratios of 0.20 (P less than .001) for each comparison.
The predictive value of both EFS and DRFS held true for three of four subtypes studied, including triple-negative breast cancer (hazard ratios 0.17 and 0.16, P less than .001 for each), HR+/HER2– (HRs 0.21, P = .016 for EFS, and 0.22, P = .024 for DRFS), and HR–/HER2+ (HRs 0.10,  and 0.14, P less than .001 for each).

However, among patients with HR+/HER2+ (triple-positive) breast cancers, EFS and DRFS rates were high for both patients with pCRs and those without, and the differences did not reach statistical significance. In these patients, the 3-year EFS rates were 96% for pCR and 87% for non pCR (HR, 0.26, P = .054), and the 3-year DRFS was 97% vs. 92% (HR, 0.19, P = 0.80).
“We believe that achieving path CR doing any therapy for any subtype is a sufficient endpoint,” Dr. Yee said. “Given that, we need to develop minimally-invasive techniques such as MRI and biopsy to identify path CR prior to definitive surgery. We need to validate robust MRI and tissue predictors of path CR, and if we can do that, we can begin to de-escalate toxic therapies,” he said.

The converse is also true: For patients who do not experience a path CR, MRI and tissue predictors could help to identify early in the course of therapy those patients who may need alternative treatments, he added.
“I think that this very clearly validates path CR as an incredibly powerful biomarker,” Eric P. Winer, MD, of Dana-Farber Cancer Institute in Boston, said in the question-and-response session following Dr. Yee’s presentation.
Dr. Winer emphasized, however, “that this does not mean that we can use path CR in comparing treatment A and treatment B in a randomized trial to determine that one is better in terms of long-term outcome.”

I-SPY2 is sponsored by the Quantum Leap Healthcare Collaborative, with funding support from the William K Bowes Foundation, Give Breast Cancer the Boot, University of California San Francisco, The Biomarkers consortium, Quintiles, the Breast Cancer Research Foundation, and Safeway. Dr. Yee reported having no relevant disclosures.

op@frontlinemedcom.com

SOURCE: Yee, D et al. SABCS Abstract GS3-08.

MRI-guided stereotactic laser ablation (MRI-SLA) seems to offer advantages over more traditional open resection in patients requiring epileptic surgery, according to a recent review of the evidence.

• MRI-SLA has been found to improve several types of cognitive outcomes when compared to open surgery.
• Daniel Drane, MD, from Emory University points out that stereotactic laser ablation reduces collateral neurological damage.
• Stereotatic laser amygdalohippocampotomy may result in better neurological functioning in areas that include category related naming, verbal fluency, and object/familiar person recognition, when compared to traditional resection.
• The evidence suggests that using a neurosurgical technique like MRI-SLE offers advantages in patients undergoing epilepsy surgery by limiting the size of the surgical lesion zone.

Drane DL. MRI-Guided stereotactic laser ablation for epilepsy surgery: Promising preliminary results for cognitive outcome. [Published online ahead of print Sept 23, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.016

MRI-guided stereotactic laser ablation (MRI-SLA) seems to offer advantages over more traditional open resection in patients requiring epileptic surgery, according to a recent review of the evidence.

• MRI-SLA has been found to improve several types of cognitive outcomes when compared to open surgery.
• Daniel Drane, MD, from Emory University points out that stereotactic laser ablation reduces collateral neurological damage.
• Stereotatic laser amygdalohippocampotomy may result in better neurological functioning in areas that include category related naming, verbal fluency, and object/familiar person recognition, when compared to traditional resection.
• The evidence suggests that using a neurosurgical technique like MRI-SLE offers advantages in patients undergoing epilepsy surgery by limiting the size of the surgical lesion zone.

Drane DL. MRI-Guided stereotactic laser ablation for epilepsy surgery: Promising preliminary results for cognitive outcome. [Published online ahead of print Sept 23, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.016

MRI-guided stereotactic laser ablation (MRI-SLA) seems to offer advantages over more traditional open resection in patients requiring epileptic surgery, according to a recent review of the evidence.

• MRI-SLA has been found to improve several types of cognitive outcomes when compared to open surgery.
• Daniel Drane, MD, from Emory University points out that stereotactic laser ablation reduces collateral neurological damage.
• Stereotatic laser amygdalohippocampotomy may result in better neurological functioning in areas that include category related naming, verbal fluency, and object/familiar person recognition, when compared to traditional resection.
• The evidence suggests that using a neurosurgical technique like MRI-SLE offers advantages in patients undergoing epilepsy surgery by limiting the size of the surgical lesion zone.

Drane DL. MRI-Guided stereotactic laser ablation for epilepsy surgery: Promising preliminary results for cognitive outcome. [Published online ahead of print Sept 23, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.016

Resting state functional magnetic resonance imaging (rsfMRI) may prove a valuable tool in evaluating patients with epilepsy postoperatively suggests this report from Epilepsy Research.

• Although task-based fMRI is often used to assess patients after surgery, Boerwinkle et al suggest resting state fMRI may be a useful adjunct and alternative after laser ablation of seizure foci, especially in pediatric patients.
• The researchers have developed software that can merge rsfMRI images with surgical navigation systems so that the technology can be more useful in a clinical setting.
• Boerwinkle et al postulate that performing rsfMRI after laser surgery may help clinicians detect changes in connectivity, determine the location of new seizure foci, and serve as a guide to determine the best course of antiepileptic therapy.

Boerwinkle VL,  Vedantam A, Lam S et al. Connectivity changes after laser ablation: Resting-state fMRI. [Published online ahead of print Sept 28, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.015

Resting state functional magnetic resonance imaging (rsfMRI) may prove a valuable tool in evaluating patients with epilepsy postoperatively suggests this report from Epilepsy Research.

• Although task-based fMRI is often used to assess patients after surgery, Boerwinkle et al suggest resting state fMRI may be a useful adjunct and alternative after laser ablation of seizure foci, especially in pediatric patients.
• The researchers have developed software that can merge rsfMRI images with surgical navigation systems so that the technology can be more useful in a clinical setting.
• Boerwinkle et al postulate that performing rsfMRI after laser surgery may help clinicians detect changes in connectivity, determine the location of new seizure foci, and serve as a guide to determine the best course of antiepileptic therapy.

Boerwinkle VL,  Vedantam A, Lam S et al. Connectivity changes after laser ablation: Resting-state fMRI. [Published online ahead of print Sept 28, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.015

Resting state functional magnetic resonance imaging (rsfMRI) may prove a valuable tool in evaluating patients with epilepsy postoperatively suggests this report from Epilepsy Research.

• Although task-based fMRI is often used to assess patients after surgery, Boerwinkle et al suggest resting state fMRI may be a useful adjunct and alternative after laser ablation of seizure foci, especially in pediatric patients.
• The researchers have developed software that can merge rsfMRI images with surgical navigation systems so that the technology can be more useful in a clinical setting.
• Boerwinkle et al postulate that performing rsfMRI after laser surgery may help clinicians detect changes in connectivity, determine the location of new seizure foci, and serve as a guide to determine the best course of antiepileptic therapy.

Boerwinkle VL,  Vedantam A, Lam S et al. Connectivity changes after laser ablation: Resting-state fMRI. [Published online ahead of print Sept 28, 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.09.015

Magnetic resonance-guided stereotactic laser amygdalohippocampotomy (SLAH) is emerging as a promising approach for patients with mesial temporal lobe epilepsy according to a recent review of the literature.

• Laser interstitial thermal therapy that is guided by MRI appears to be a safe, effective way to manage patients with mesial temporal lobe epilepsy—when used in properly selected patients.
• SLAH is less invasive than anterior temporal lobectomy and allows the surgeon to immediately destroy target tissue, which is not the case with radiosurgery.
• SLAH also has the advantage of allowing the surgeon to remove larger amounts of tissue than can be done with radiofrequency ablation.
• Bezchlibnyk et al state that MR-guided laser thermal therapy is less likely to cause neuropsychological deficits, when compared to open surgery.

Bezchlibnyk YB, Willie JT, Gross RE. A neurosurgeon`s view: Laser interstitial thermal therapy of mesial temporal lobe structures. [Published online ahead of print Oct 27 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.10.015

Magnetic resonance-guided stereotactic laser amygdalohippocampotomy (SLAH) is emerging as a promising approach for patients with mesial temporal lobe epilepsy according to a recent review of the literature.

• Laser interstitial thermal therapy that is guided by MRI appears to be a safe, effective way to manage patients with mesial temporal lobe epilepsy—when used in properly selected patients.
• SLAH is less invasive than anterior temporal lobectomy and allows the surgeon to immediately destroy target tissue, which is not the case with radiosurgery.
• SLAH also has the advantage of allowing the surgeon to remove larger amounts of tissue than can be done with radiofrequency ablation.
• Bezchlibnyk et al state that MR-guided laser thermal therapy is less likely to cause neuropsychological deficits, when compared to open surgery.

Bezchlibnyk YB, Willie JT, Gross RE. A neurosurgeon`s view: Laser interstitial thermal therapy of mesial temporal lobe structures. [Published online ahead of print Oct 27 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.10.015

Magnetic resonance-guided stereotactic laser amygdalohippocampotomy (SLAH) is emerging as a promising approach for patients with mesial temporal lobe epilepsy according to a recent review of the literature.

• Laser interstitial thermal therapy that is guided by MRI appears to be a safe, effective way to manage patients with mesial temporal lobe epilepsy—when used in properly selected patients.
• SLAH is less invasive than anterior temporal lobectomy and allows the surgeon to immediately destroy target tissue, which is not the case with radiosurgery.
• SLAH also has the advantage of allowing the surgeon to remove larger amounts of tissue than can be done with radiofrequency ablation.
• Bezchlibnyk et al state that MR-guided laser thermal therapy is less likely to cause neuropsychological deficits, when compared to open surgery.

Bezchlibnyk YB, Willie JT, Gross RE. A neurosurgeon`s view: Laser interstitial thermal therapy of mesial temporal lobe structures. [Published online ahead of print Oct 27 2017] Epilepsy Res. https://doi.org/10.1016/j.eplepsyres.2017.10.015

FROM THE AMERICAN JOURNAL OF PSYCHIATRY

Patients with schizophrenia showed signs of improvement in positive psychotic symptoms and clinician-rated improvement after treatment with cannabidiol, a component of cannabis thought to counteract the effects of tetrahydrocannabinol (THC), an industry-funded phase 2 study reported.
According to the authors, the study is only the second to examine the use of cannabidiol in schizophrenia. “Because cannabidiol acts in a way different from conventional antipsychotic medication, it may represent a new class of treatment for schizophrenia,” wrote the study authors, including several employees of the drugmaker that helped to fund the research.
The study, led by Philip McGuire, FMedSci., of King’s College London, was published online Dec. 15 in the American Journal of Psychiatry.
Researchers have long been interested in the relationship between aspects of schizophrenia – especially psychosis – and cannabis. There’s been less focus on the effects of individual cannabinoids – components of cannabis such as THC (which is psychoactive), cannabinol (which is linked to sleep), and cannabidiol.

Researchers have linked cannabidiol to anxiety relief, and it’s been used to treat a wide variety of conditions, particularly epilepsy.
For the current study, a randomized, double-blind parallel-group trial, researchers assigned patients with schizophrenia or related psychotic disorders to receive 1,000 mg/day of cannabidiol (n = 43) or placebo (n = 45) for 6 weeks. The patients took the drug (10 mL of a 100-mg/mL oral solution) or a matching placebo twice a day in divided doses. They continued to take their existing antipsychotic medication; the study did not accept anyone taking more than one medication for that purpose.
The patients, aged 18-65, were at 15 hospitals in the United Kingdom, Romania, and Poland; 93% of the subjects were white, and 58% were male. The subjects were allowed to continue the use of alcohol or cannabis.
Eighty-three patients finished the trial after two withdrew because of adverse events and three withdrew consent. The intention-to-treat analysis involved 86 patients: 42 who took cannabidiol (including 3 who took it for 21 or fewer days) and 44 who took the placebo. At the end of treatment, the researchers found that the positive score on the Positive and Negative Syndrome Scale (PANSS) fell from baseline by a mean –1.7 points in the placebo group and –3.2 points in the cannabidiol group, a difference of –1.4 points (P = .019). PANSS total and general scores also fell in both groups, as did the Scale for the Assessment of Negative Symptoms score, but the differences between the groups were not statistically significant. PANSS negative scores fell by about the same level in both groups.

At the end of treatment, clinicians were more likely to rate subjects in the cannabidiol group as improved on the Clinical Global Impressions (CGI) Scale (P = 0.018), compared with those in the placebo group.
About 35% of patients in both groups reported adverse events, including gastrointestinal problems (21% of those in the cannabidiol group and 6.7% of those in the placebo group). Researchers determined that just 10 patients in each group had treatment-related adverse events.
The mechanism of action of cannabidiol is unclear. Its effects “do not appear to depend on dopamine D2 receptor antagonism,” the investigators said. Theories about its mechanism of action include inhibition of the fatty acid amide hydrolase, inhibition of adenosine reuptake, TRPV1 and 5-hydroxytryptamine 1A receptor agonism, and D2High partial agonism. “Because [cannabidiol] acts in a way different from conventional antipsychotic medication, it may represent a new class of treatment for schizophrenia,” the authors wrote.
The investigators acknowledged that the study has limitations. For example, nearly all the participants were white. And although research suggests that cannabis use is very common in patients with schizophrenia, the study authors reported that only three patients tested positive for THC at baseline. “Because so few patients tested positive for THC, it was not possible to assess whether the effects of cannabidiol were influenced by cannabis use,” the authors wrote.

GW Research funded the trial and supplied the investigational medicinal product. Other study funders included the National Institute for Health Research Biomedical Research Center at South London, Maudsley NHS Foundation Trust, and King’s College London. Four of the authors are employees of GW Pharmaceuticals and hold shares in the company; one of the four is a cosignatory on a patent for the use of cannabinoids in combination with aripiprazole. Two of the other authors reported various disclosures, including funding from GW Pharmaceuticals. Another two study authors reported no relevant disclosures.

cpnews@frontlinemedcom.com

SOURCE: McGuire P et al. Am J Psychiatry. 2017 Dec 15. doi: 10.1176/appi.ajp.2017.17030325

FROM THE AMERICAN JOURNAL OF PSYCHIATRY

Patients with schizophrenia showed signs of improvement in positive psychotic symptoms and clinician-rated improvement after treatment with cannabidiol, a component of cannabis thought to counteract the effects of tetrahydrocannabinol (THC), an industry-funded phase 2 study reported.
According to the authors, the study is only the second to examine the use of cannabidiol in schizophrenia. “Because cannabidiol acts in a way different from conventional antipsychotic medication, it may represent a new class of treatment for schizophrenia,” wrote the study authors, including several employees of the drugmaker that helped to fund the research.
The study, led by Philip McGuire, FMedSci., of King’s College London, was published online Dec. 15 in the American Journal of Psychiatry.
Researchers have long been interested in the relationship between aspects of schizophrenia – especially psychosis – and cannabis. There’s been less focus on the effects of individual cannabinoids – components of cannabis such as THC (which is psychoactive), cannabinol (which is linked to sleep), and cannabidiol.

Researchers have linked cannabidiol to anxiety relief, and it’s been used to treat a wide variety of conditions, particularly epilepsy.
For the current study, a randomized, double-blind parallel-group trial, researchers assigned patients with schizophrenia or related psychotic disorders to receive 1,000 mg/day of cannabidiol (n = 43) or placebo (n = 45) for 6 weeks. The patients took the drug (10 mL of a 100-mg/mL oral solution) or a matching placebo twice a day in divided doses. They continued to take their existing antipsychotic medication; the study did not accept anyone taking more than one medication for that purpose.
The patients, aged 18-65, were at 15 hospitals in the United Kingdom, Romania, and Poland; 93% of the subjects were white, and 58% were male. The subjects were allowed to continue the use of alcohol or cannabis.
Eighty-three patients finished the trial after two withdrew because of adverse events and three withdrew consent. The intention-to-treat analysis involved 86 patients: 42 who took cannabidiol (including 3 who took it for 21 or fewer days) and 44 who took the placebo. At the end of treatment, the researchers found that the positive score on the Positive and Negative Syndrome Scale (PANSS) fell from baseline by a mean –1.7 points in the placebo group and –3.2 points in the cannabidiol group, a difference of –1.4 points (P = .019). PANSS total and general scores also fell in both groups, as did the Scale for the Assessment of Negative Symptoms score, but the differences between the groups were not statistically significant. PANSS negative scores fell by about the same level in both groups.

At the end of treatment, clinicians were more likely to rate subjects in the cannabidiol group as improved on the Clinical Global Impressions (CGI) Scale (P = 0.018), compared with those in the placebo group.
About 35% of patients in both groups reported adverse events, including gastrointestinal problems (21% of those in the cannabidiol group and 6.7% of those in the placebo group). Researchers determined that just 10 patients in each group had treatment-related adverse events.
The mechanism of action of cannabidiol is unclear. Its effects “do not appear to depend on dopamine D2 receptor antagonism,” the investigators said. Theories about its mechanism of action include inhibition of the fatty acid amide hydrolase, inhibition of adenosine reuptake, TRPV1 and 5-hydroxytryptamine 1A receptor agonism, and D2High partial agonism. “Because [cannabidiol] acts in a way different from conventional antipsychotic medication, it may represent a new class of treatment for schizophrenia,” the authors wrote.
The investigators acknowledged that the study has limitations. For example, nearly all the participants were white. And although research suggests that cannabis use is very common in patients with schizophrenia, the study authors reported that only three patients tested positive for THC at baseline. “Because so few patients tested positive for THC, it was not possible to assess whether the effects of cannabidiol were influenced by cannabis use,” the authors wrote.

GW Research funded the trial and supplied the investigational medicinal product. Other study funders included the National Institute for Health Research Biomedical Research Center at South London, Maudsley NHS Foundation Trust, and King’s College London. Four of the authors are employees of GW Pharmaceuticals and hold shares in the company; one of the four is a cosignatory on a patent for the use of cannabinoids in combination with aripiprazole. Two of the other authors reported various disclosures, including funding from GW Pharmaceuticals. Another two study authors reported no relevant disclosures.

cpnews@frontlinemedcom.com

SOURCE: McGuire P et al. Am J Psychiatry. 2017 Dec 15. doi: 10.1176/appi.ajp.2017.17030325

FROM THE AMERICAN JOURNAL OF PSYCHIATRY

Patients with schizophrenia showed signs of improvement in positive psychotic symptoms and clinician-rated improvement after treatment with cannabidiol, a component of cannabis thought to counteract the effects of tetrahydrocannabinol (THC), an industry-funded phase 2 study reported.
According to the authors, the study is only the second to examine the use of cannabidiol in schizophrenia. “Because cannabidiol acts in a way different from conventional antipsychotic medication, it may represent a new class of treatment for schizophrenia,” wrote the study authors, including several employees of the drugmaker that helped to fund the research.
The study, led by Philip McGuire, FMedSci., of King’s College London, was published online Dec. 15 in the American Journal of Psychiatry.
Researchers have long been interested in the relationship between aspects of schizophrenia – especially psychosis – and cannabis. There’s been less focus on the effects of individual cannabinoids – components of cannabis such as THC (which is psychoactive), cannabinol (which is linked to sleep), and cannabidiol.

Researchers have linked cannabidiol to anxiety relief, and it’s been used to treat a wide variety of conditions, particularly epilepsy.
For the current study, a randomized, double-blind parallel-group trial, researchers assigned patients with schizophrenia or related psychotic disorders to receive 1,000 mg/day of cannabidiol (n = 43) or placebo (n = 45) for 6 weeks. The patients took the drug (10 mL of a 100-mg/mL oral solution) or a matching placebo twice a day in divided doses. They continued to take their existing antipsychotic medication; the study did not accept anyone taking more than one medication for that purpose.
The patients, aged 18-65, were at 15 hospitals in the United Kingdom, Romania, and Poland; 93% of the subjects were white, and 58% were male. The subjects were allowed to continue the use of alcohol or cannabis.
Eighty-three patients finished the trial after two withdrew because of adverse events and three withdrew consent. The intention-to-treat analysis involved 86 patients: 42 who took cannabidiol (including 3 who took it for 21 or fewer days) and 44 who took the placebo. At the end of treatment, the researchers found that the positive score on the Positive and Negative Syndrome Scale (PANSS) fell from baseline by a mean –1.7 points in the placebo group and –3.2 points in the cannabidiol group, a difference of –1.4 points (P = .019). PANSS total and general scores also fell in both groups, as did the Scale for the Assessment of Negative Symptoms score, but the differences between the groups were not statistically significant. PANSS negative scores fell by about the same level in both groups.

At the end of treatment, clinicians were more likely to rate subjects in the cannabidiol group as improved on the Clinical Global Impressions (CGI) Scale (P = 0.018), compared with those in the placebo group.
About 35% of patients in both groups reported adverse events, including gastrointestinal problems (21% of those in the cannabidiol group and 6.7% of those in the placebo group). Researchers determined that just 10 patients in each group had treatment-related adverse events.
The mechanism of action of cannabidiol is unclear. Its effects “do not appear to depend on dopamine D2 receptor antagonism,” the investigators said. Theories about its mechanism of action include inhibition of the fatty acid amide hydrolase, inhibition of adenosine reuptake, TRPV1 and 5-hydroxytryptamine 1A receptor agonism, and D2High partial agonism. “Because [cannabidiol] acts in a way different from conventional antipsychotic medication, it may represent a new class of treatment for schizophrenia,” the authors wrote.
The investigators acknowledged that the study has limitations. For example, nearly all the participants were white. And although research suggests that cannabis use is very common in patients with schizophrenia, the study authors reported that only three patients tested positive for THC at baseline. “Because so few patients tested positive for THC, it was not possible to assess whether the effects of cannabidiol were influenced by cannabis use,” the authors wrote.

GW Research funded the trial and supplied the investigational medicinal product. Other study funders included the National Institute for Health Research Biomedical Research Center at South London, Maudsley NHS Foundation Trust, and King’s College London. Four of the authors are employees of GW Pharmaceuticals and hold shares in the company; one of the four is a cosignatory on a patent for the use of cannabinoids in combination with aripiprazole. Two of the other authors reported various disclosures, including funding from GW Pharmaceuticals. Another two study authors reported no relevant disclosures.

cpnews@frontlinemedcom.com

SOURCE: McGuire P et al. Am J Psychiatry. 2017 Dec 15. doi: 10.1176/appi.ajp.2017.17030325

Compared to the adult population with a prevalence of lower extremity ulcers reaching approximately 1% to 2%, pediatric leg ulcers are much less common and require dermatologists to think outside the box for differential diagnoses.¹ Although the most common types of lower extremity ulcers in the adult population include venous leg ulcers, arterial ulcers, and diabetic foot ulcers, the etiology for pediatric ulcers is vastly different, and thus these statistics cannot be extrapolated to this younger group. Additionally, scant research has been conducted to construct a systemic algorithm for helping these patients. In 1998, Dangoisse and Song² concluded that juvenile leg ulcers secondary to causes other than trauma are uncommon, with the infectious origin fairly frequent; however, they stated further workup should be pursued to investigate for underlying vascular, metabolic, hematologic, and immunologic disorders. They also added that an infectious etiology must be ruled out with foremost priority, and a subsequent biopsy could assist in the ultimate diagnosis.²

To further investigate pediatric leg ulcers and their unique causes, a PubMed search of articles indexed for MEDLINE published from 1995 to present was performed using the term pediatric leg ulcers. The search yielded approximately 100 relevant articles. The search generated more than 47 different causes of leg ulcers and produced unusual etiologies such as trophic ulcers of Lesch-Nyhan syndrome, ulcers secondary to disabling pansclerotic morphea of childhood, dracunculiasis, and dengue hemorrhagic fever, among others.^3-6 The articles were further divided into 4 categories to better characterize the causes—hematologic, infectious, genodermatoses, and autoimmune—which are reviewed here.

Hematologic Causes

Hematologic causes predominated in this juvenile arena, with sickle cell disease specifically comprising the vast majority of causes of pediatric leg ulcers.^7,8 Sickle cell disease is a chronic disease with anemia and sickling crises contributing to a myriad of health problems. In a 13-year study following 44 patients with sickle cell disease, Silva et al⁸ found that leg ulcers affected approximately 5% of pediatric patients; however, the authors noted that this statistic may underestimate the accurate prevalence, as the ulcers typically affect older children and their study population was a younger distribution. The lesions manifest as painful, well-demarcated ulcers with surrounding hyperpigmentation mimicking venous ulcers.⁹ The ulcers may be readily diagnosed if the history is known, and it is critical to maximize care of these lesions, as they may heal at least 10 times slower than venous leg ulcers and frequently recur, with the vast majority recurring in less than 1 year. Furthermore, the presence of leg ulcers in sickle cell disease may be associated with increased hemolysis and pulmonary hypertension, demonstrating the severity of disease in these patients.¹⁰ Local wound care is the mainstay of therapy including compression, leg elevation, and adjuvant wound dressings. Systemic therapies such as hydroxyurea, zinc supplementation, pentoxifylline, and transfusion therapy may be pursued in refractory cases, though an ideal systemic regimen is still under exploration.^9,10 Other major hematologic abnormalities leading to leg ulcers included additional causes of anemia, such as thalassemia and hereditary spherocytosis. These patients additionally were treated with local wound care to maximize healing.^11,12

Infectious Causes

Infectious causes of pediatric ulcers were much more varied with a myriad of etiologies such as ulcers from ecthyma gangrenosum caused by Pseudomonas aeruginosa to leishmaniasis and tularemia. The most commonly reported infection causing leg ulcers in the pediatric literature was Mycobacterium ulcerans, which led to the characteristic Buruli ulcer; however, this infection is likely grossly overrepresented, as more common etiologies are underreported; the geographic location for a Buruli ulcer also is important, as cases are rare in the United States.^13,14 A Buruli ulcer presents as a well-defined, painless, chronic skin ulceration and most commonly affects children.¹⁵ Exposure to stagnant water in tropical climates is thought to play a role in the pathogenesis of this slow-growing, acid-fast bacillus. The bacteria produces a potent cytotoxin called mycolactone, which then induces tissue necrosis and ulceration, leading to the clinical manifestations of disease.¹⁵ The ulcers may heal spontaneously; however, up to 15% can be associated with osteomyelitis; treatment includes surgical excision and prolonged antibiotics.¹⁴ Given the numerous additional causes of pediatric leg ulcers harboring infections, it is critical to be cognizant of the travel history and immune status of the patient. The infectious cause of leg ulcers likely predominates, making a biopsy with culture necessary in any nonhealing wound in this population prior to pursuing further workup.

Genodermatoses

A number of genodermatoses also contribute to persistent wounds in the pediatric population; specifically, genodermatoses that predispose to neuropathies and decreased pain sensation, which affect the child’s ability to detect sensation in the lower extremities, can result in inadvertent trauma leading to refractory wounds. For example, hereditary, sensory, and autonomic neuropathies are rare disorders causing progressive distal sensory loss, leading to ulcerations, osteomyelitis, arthritis, and even amputation.¹⁶ Hereditary, sensory, and autonomic neuropathies are further categorized into several different types; however, the unifying theme of diminished sensation is the culprit for troublesome wounds. Therapeutic endeavors to maximize preventative care with orthotics are vital in allaying recurrent wounds in these patients. Another uncommon hereditary disorder that promotes poor wound healing is caused by an inborn error of collagen synthesis. Prolidase deficiency is an autosomal-recessive condition resulting in characteristic facies, recurrent infections, and recalcitrant leg ulcerations due to impaired collagen formation.¹⁷ More than 50% of affected patients experience leg ulcers comprised of irregular borders with prominent granulation tissue. Treatment is aimed at restoring collagen synthesis and optimizing wound healing with the use of topical proline, glycine, and even growth hormone to promote repair.¹⁸ Additional genodermatoses predisposing to leg ulcerations include Lesch-Nyhan syndrome due to self-mutilating behaviors and epidermolysis bullosa due to impaired barrier and a decreased ability to repair cutaneous defects.

Autoimmune Causes

Although a much smaller category, ulcers due to autoimmune etiologies were reported in the literature. Fibrosing disorders including morphea and scleroderma can cause extensive disease in severe cases. Disabling pansclerotic morphea of childhood can cause sclerosis that extends into muscle, fascia, and even bone, resulting in contractures and ulcerations.⁴ The initial areas of involvement are the arms and legs, followed by spread to the trunk and head and neck area.⁴ Immunosuppressant therapy is needed to halt disease progression. Pediatric cases of systemic lupus erythematosus also have been associated with digital ulcers. One case was thought to be due to vasculitis,¹⁹ and another resulted from peripheral gangrene in association with Raynaud phenomenon.²⁰ Albeit rare, it is important to consider autoimmune connective tissue diseases when faced with recurrent wounds and to search for additional symptoms that might yield the underlying diagnosis.

Conclusion

Pediatric leg ulcers are a relatively uncommon phenomenon; however, the etiologies are vastly different than adult leg ulcers and require careful contemplation surrounding the cardinal etiology. The main categories of disease in pediatric leg ulcers after trauma include hematologic abnormalities, infection, genodermatoses, and autoimmune diseases. The evaluation requires obtaining a thorough history and physical examination, including pertinent family histories for associated inheritable disorders. If the clinical picture remains elusive and the ulceration fails conservative management, a biopsy with tissue culture may be necessary to rule out an infectious etiology.

Compared to the adult population with a prevalence of lower extremity ulcers reaching approximately 1% to 2%, pediatric leg ulcers are much less common and require dermatologists to think outside the box for differential diagnoses.¹ Although the most common types of lower extremity ulcers in the adult population include venous leg ulcers, arterial ulcers, and diabetic foot ulcers, the etiology for pediatric ulcers is vastly different, and thus these statistics cannot be extrapolated to this younger group. Additionally, scant research has been conducted to construct a systemic algorithm for helping these patients. In 1998, Dangoisse and Song² concluded that juvenile leg ulcers secondary to causes other than trauma are uncommon, with the infectious origin fairly frequent; however, they stated further workup should be pursued to investigate for underlying vascular, metabolic, hematologic, and immunologic disorders. They also added that an infectious etiology must be ruled out with foremost priority, and a subsequent biopsy could assist in the ultimate diagnosis.²

To further investigate pediatric leg ulcers and their unique causes, a PubMed search of articles indexed for MEDLINE published from 1995 to present was performed using the term pediatric leg ulcers. The search yielded approximately 100 relevant articles. The search generated more than 47 different causes of leg ulcers and produced unusual etiologies such as trophic ulcers of Lesch-Nyhan syndrome, ulcers secondary to disabling pansclerotic morphea of childhood, dracunculiasis, and dengue hemorrhagic fever, among others.^3-6 The articles were further divided into 4 categories to better characterize the causes—hematologic, infectious, genodermatoses, and autoimmune—which are reviewed here.

Hematologic Causes

Hematologic causes predominated in this juvenile arena, with sickle cell disease specifically comprising the vast majority of causes of pediatric leg ulcers.^7,8 Sickle cell disease is a chronic disease with anemia and sickling crises contributing to a myriad of health problems. In a 13-year study following 44 patients with sickle cell disease, Silva et al⁸ found that leg ulcers affected approximately 5% of pediatric patients; however, the authors noted that this statistic may underestimate the accurate prevalence, as the ulcers typically affect older children and their study population was a younger distribution. The lesions manifest as painful, well-demarcated ulcers with surrounding hyperpigmentation mimicking venous ulcers.⁹ The ulcers may be readily diagnosed if the history is known, and it is critical to maximize care of these lesions, as they may heal at least 10 times slower than venous leg ulcers and frequently recur, with the vast majority recurring in less than 1 year. Furthermore, the presence of leg ulcers in sickle cell disease may be associated with increased hemolysis and pulmonary hypertension, demonstrating the severity of disease in these patients.¹⁰ Local wound care is the mainstay of therapy including compression, leg elevation, and adjuvant wound dressings. Systemic therapies such as hydroxyurea, zinc supplementation, pentoxifylline, and transfusion therapy may be pursued in refractory cases, though an ideal systemic regimen is still under exploration.^9,10 Other major hematologic abnormalities leading to leg ulcers included additional causes of anemia, such as thalassemia and hereditary spherocytosis. These patients additionally were treated with local wound care to maximize healing.^11,12

Infectious Causes

Infectious causes of pediatric ulcers were much more varied with a myriad of etiologies such as ulcers from ecthyma gangrenosum caused by Pseudomonas aeruginosa to leishmaniasis and tularemia. The most commonly reported infection causing leg ulcers in the pediatric literature was Mycobacterium ulcerans, which led to the characteristic Buruli ulcer; however, this infection is likely grossly overrepresented, as more common etiologies are underreported; the geographic location for a Buruli ulcer also is important, as cases are rare in the United States.^13,14 A Buruli ulcer presents as a well-defined, painless, chronic skin ulceration and most commonly affects children.¹⁵ Exposure to stagnant water in tropical climates is thought to play a role in the pathogenesis of this slow-growing, acid-fast bacillus. The bacteria produces a potent cytotoxin called mycolactone, which then induces tissue necrosis and ulceration, leading to the clinical manifestations of disease.¹⁵ The ulcers may heal spontaneously; however, up to 15% can be associated with osteomyelitis; treatment includes surgical excision and prolonged antibiotics.¹⁴ Given the numerous additional causes of pediatric leg ulcers harboring infections, it is critical to be cognizant of the travel history and immune status of the patient. The infectious cause of leg ulcers likely predominates, making a biopsy with culture necessary in any nonhealing wound in this population prior to pursuing further workup.

Genodermatoses

A number of genodermatoses also contribute to persistent wounds in the pediatric population; specifically, genodermatoses that predispose to neuropathies and decreased pain sensation, which affect the child’s ability to detect sensation in the lower extremities, can result in inadvertent trauma leading to refractory wounds. For example, hereditary, sensory, and autonomic neuropathies are rare disorders causing progressive distal sensory loss, leading to ulcerations, osteomyelitis, arthritis, and even amputation.¹⁶ Hereditary, sensory, and autonomic neuropathies are further categorized into several different types; however, the unifying theme of diminished sensation is the culprit for troublesome wounds. Therapeutic endeavors to maximize preventative care with orthotics are vital in allaying recurrent wounds in these patients. Another uncommon hereditary disorder that promotes poor wound healing is caused by an inborn error of collagen synthesis. Prolidase deficiency is an autosomal-recessive condition resulting in characteristic facies, recurrent infections, and recalcitrant leg ulcerations due to impaired collagen formation.¹⁷ More than 50% of affected patients experience leg ulcers comprised of irregular borders with prominent granulation tissue. Treatment is aimed at restoring collagen synthesis and optimizing wound healing with the use of topical proline, glycine, and even growth hormone to promote repair.¹⁸ Additional genodermatoses predisposing to leg ulcerations include Lesch-Nyhan syndrome due to self-mutilating behaviors and epidermolysis bullosa due to impaired barrier and a decreased ability to repair cutaneous defects.

Autoimmune Causes

Although a much smaller category, ulcers due to autoimmune etiologies were reported in the literature. Fibrosing disorders including morphea and scleroderma can cause extensive disease in severe cases. Disabling pansclerotic morphea of childhood can cause sclerosis that extends into muscle, fascia, and even bone, resulting in contractures and ulcerations.⁴ The initial areas of involvement are the arms and legs, followed by spread to the trunk and head and neck area.⁴ Immunosuppressant therapy is needed to halt disease progression. Pediatric cases of systemic lupus erythematosus also have been associated with digital ulcers. One case was thought to be due to vasculitis,¹⁹ and another resulted from peripheral gangrene in association with Raynaud phenomenon.²⁰ Albeit rare, it is important to consider autoimmune connective tissue diseases when faced with recurrent wounds and to search for additional symptoms that might yield the underlying diagnosis.

Conclusion

Pediatric leg ulcers are a relatively uncommon phenomenon; however, the etiologies are vastly different than adult leg ulcers and require careful contemplation surrounding the cardinal etiology. The main categories of disease in pediatric leg ulcers after trauma include hematologic abnormalities, infection, genodermatoses, and autoimmune diseases. The evaluation requires obtaining a thorough history and physical examination, including pertinent family histories for associated inheritable disorders. If the clinical picture remains elusive and the ulceration fails conservative management, a biopsy with tissue culture may be necessary to rule out an infectious etiology.

Compared to the adult population with a prevalence of lower extremity ulcers reaching approximately 1% to 2%, pediatric leg ulcers are much less common and require dermatologists to think outside the box for differential diagnoses.¹ Although the most common types of lower extremity ulcers in the adult population include venous leg ulcers, arterial ulcers, and diabetic foot ulcers, the etiology for pediatric ulcers is vastly different, and thus these statistics cannot be extrapolated to this younger group. Additionally, scant research has been conducted to construct a systemic algorithm for helping these patients. In 1998, Dangoisse and Song² concluded that juvenile leg ulcers secondary to causes other than trauma are uncommon, with the infectious origin fairly frequent; however, they stated further workup should be pursued to investigate for underlying vascular, metabolic, hematologic, and immunologic disorders. They also added that an infectious etiology must be ruled out with foremost priority, and a subsequent biopsy could assist in the ultimate diagnosis.²

To further investigate pediatric leg ulcers and their unique causes, a PubMed search of articles indexed for MEDLINE published from 1995 to present was performed using the term pediatric leg ulcers. The search yielded approximately 100 relevant articles. The search generated more than 47 different causes of leg ulcers and produced unusual etiologies such as trophic ulcers of Lesch-Nyhan syndrome, ulcers secondary to disabling pansclerotic morphea of childhood, dracunculiasis, and dengue hemorrhagic fever, among others.^3-6 The articles were further divided into 4 categories to better characterize the causes—hematologic, infectious, genodermatoses, and autoimmune—which are reviewed here.

Hematologic Causes

Hematologic causes predominated in this juvenile arena, with sickle cell disease specifically comprising the vast majority of causes of pediatric leg ulcers.^7,8 Sickle cell disease is a chronic disease with anemia and sickling crises contributing to a myriad of health problems. In a 13-year study following 44 patients with sickle cell disease, Silva et al⁸ found that leg ulcers affected approximately 5% of pediatric patients; however, the authors noted that this statistic may underestimate the accurate prevalence, as the ulcers typically affect older children and their study population was a younger distribution. The lesions manifest as painful, well-demarcated ulcers with surrounding hyperpigmentation mimicking venous ulcers.⁹ The ulcers may be readily diagnosed if the history is known, and it is critical to maximize care of these lesions, as they may heal at least 10 times slower than venous leg ulcers and frequently recur, with the vast majority recurring in less than 1 year. Furthermore, the presence of leg ulcers in sickle cell disease may be associated with increased hemolysis and pulmonary hypertension, demonstrating the severity of disease in these patients.¹⁰ Local wound care is the mainstay of therapy including compression, leg elevation, and adjuvant wound dressings. Systemic therapies such as hydroxyurea, zinc supplementation, pentoxifylline, and transfusion therapy may be pursued in refractory cases, though an ideal systemic regimen is still under exploration.^9,10 Other major hematologic abnormalities leading to leg ulcers included additional causes of anemia, such as thalassemia and hereditary spherocytosis. These patients additionally were treated with local wound care to maximize healing.^11,12

Infectious Causes

Infectious causes of pediatric ulcers were much more varied with a myriad of etiologies such as ulcers from ecthyma gangrenosum caused by Pseudomonas aeruginosa to leishmaniasis and tularemia. The most commonly reported infection causing leg ulcers in the pediatric literature was Mycobacterium ulcerans, which led to the characteristic Buruli ulcer; however, this infection is likely grossly overrepresented, as more common etiologies are underreported; the geographic location for a Buruli ulcer also is important, as cases are rare in the United States.^13,14 A Buruli ulcer presents as a well-defined, painless, chronic skin ulceration and most commonly affects children.¹⁵ Exposure to stagnant water in tropical climates is thought to play a role in the pathogenesis of this slow-growing, acid-fast bacillus. The bacteria produces a potent cytotoxin called mycolactone, which then induces tissue necrosis and ulceration, leading to the clinical manifestations of disease.¹⁵ The ulcers may heal spontaneously; however, up to 15% can be associated with osteomyelitis; treatment includes surgical excision and prolonged antibiotics.¹⁴ Given the numerous additional causes of pediatric leg ulcers harboring infections, it is critical to be cognizant of the travel history and immune status of the patient. The infectious cause of leg ulcers likely predominates, making a biopsy with culture necessary in any nonhealing wound in this population prior to pursuing further workup.

Genodermatoses

A number of genodermatoses also contribute to persistent wounds in the pediatric population; specifically, genodermatoses that predispose to neuropathies and decreased pain sensation, which affect the child’s ability to detect sensation in the lower extremities, can result in inadvertent trauma leading to refractory wounds. For example, hereditary, sensory, and autonomic neuropathies are rare disorders causing progressive distal sensory loss, leading to ulcerations, osteomyelitis, arthritis, and even amputation.¹⁶ Hereditary, sensory, and autonomic neuropathies are further categorized into several different types; however, the unifying theme of diminished sensation is the culprit for troublesome wounds. Therapeutic endeavors to maximize preventative care with orthotics are vital in allaying recurrent wounds in these patients. Another uncommon hereditary disorder that promotes poor wound healing is caused by an inborn error of collagen synthesis. Prolidase deficiency is an autosomal-recessive condition resulting in characteristic facies, recurrent infections, and recalcitrant leg ulcerations due to impaired collagen formation.¹⁷ More than 50% of affected patients experience leg ulcers comprised of irregular borders with prominent granulation tissue. Treatment is aimed at restoring collagen synthesis and optimizing wound healing with the use of topical proline, glycine, and even growth hormone to promote repair.¹⁸ Additional genodermatoses predisposing to leg ulcerations include Lesch-Nyhan syndrome due to self-mutilating behaviors and epidermolysis bullosa due to impaired barrier and a decreased ability to repair cutaneous defects.

Autoimmune Causes

Although a much smaller category, ulcers due to autoimmune etiologies were reported in the literature. Fibrosing disorders including morphea and scleroderma can cause extensive disease in severe cases. Disabling pansclerotic morphea of childhood can cause sclerosis that extends into muscle, fascia, and even bone, resulting in contractures and ulcerations.⁴ The initial areas of involvement are the arms and legs, followed by spread to the trunk and head and neck area.⁴ Immunosuppressant therapy is needed to halt disease progression. Pediatric cases of systemic lupus erythematosus also have been associated with digital ulcers. One case was thought to be due to vasculitis,¹⁹ and another resulted from peripheral gangrene in association with Raynaud phenomenon.²⁰ Albeit rare, it is important to consider autoimmune connective tissue diseases when faced with recurrent wounds and to search for additional symptoms that might yield the underlying diagnosis.

Conclusion

Pediatric leg ulcers are a relatively uncommon phenomenon; however, the etiologies are vastly different than adult leg ulcers and require careful contemplation surrounding the cardinal etiology. The main categories of disease in pediatric leg ulcers after trauma include hematologic abnormalities, infection, genodermatoses, and autoimmune diseases. The evaluation requires obtaining a thorough history and physical examination, including pertinent family histories for associated inheritable disorders. If the clinical picture remains elusive and the ulceration fails conservative management, a biopsy with tissue culture may be necessary to rule out an infectious etiology.

Researchers examined 5,152 people who died due to opioid overdose in Maine, Massachusetts, Missouri, New Hampshire, New Mexico, Ohio, Oklahoma, Rhode Island, West Virginia, and Wisconsin and found that nearly 3,000 were fentanyl positive. In addition, > 700 tested positive for drugs with similar chemical structures to fentanyl, including an extremely potent analog, carfentanil, which is used to sedate large animals.

The findings are from the first report on data from the State Unintentional Drug Overdose Reporting System (SUDORS). According to the CDC, SUDORS makes it possible to use toxicology and death scene investigation data previously unavailable across states to provide insights into specific substances and circumstances driving overdoses. That information can help pinpoint changes in the opioid epidemic and inform interventions.

Starting in late 2017, the CDC’s Enhanced State Opioid Overdose Surveillance program is funding expanded forensic toxicology testing of opioid overdose deaths to detect fentanyl analogs and other illicitly manufactured synthetic opioid drugs.

Researchers examined 5,152 people who died due to opioid overdose in Maine, Massachusetts, Missouri, New Hampshire, New Mexico, Ohio, Oklahoma, Rhode Island, West Virginia, and Wisconsin and found that nearly 3,000 were fentanyl positive. In addition, > 700 tested positive for drugs with similar chemical structures to fentanyl, including an extremely potent analog, carfentanil, which is used to sedate large animals.

The findings are from the first report on data from the State Unintentional Drug Overdose Reporting System (SUDORS). According to the CDC, SUDORS makes it possible to use toxicology and death scene investigation data previously unavailable across states to provide insights into specific substances and circumstances driving overdoses. That information can help pinpoint changes in the opioid epidemic and inform interventions.

Starting in late 2017, the CDC’s Enhanced State Opioid Overdose Surveillance program is funding expanded forensic toxicology testing of opioid overdose deaths to detect fentanyl analogs and other illicitly manufactured synthetic opioid drugs.

Researchers examined 5,152 people who died due to opioid overdose in Maine, Massachusetts, Missouri, New Hampshire, New Mexico, Ohio, Oklahoma, Rhode Island, West Virginia, and Wisconsin and found that nearly 3,000 were fentanyl positive. In addition, > 700 tested positive for drugs with similar chemical structures to fentanyl, including an extremely potent analog, carfentanil, which is used to sedate large animals.

The findings are from the first report on data from the State Unintentional Drug Overdose Reporting System (SUDORS). According to the CDC, SUDORS makes it possible to use toxicology and death scene investigation data previously unavailable across states to provide insights into specific substances and circumstances driving overdoses. That information can help pinpoint changes in the opioid epidemic and inform interventions.

Starting in late 2017, the CDC’s Enhanced State Opioid Overdose Surveillance program is funding expanded forensic toxicology testing of opioid overdose deaths to detect fentanyl analogs and other illicitly manufactured synthetic opioid drugs.

Extreme weight gain during pregnancy may contribute to  risk factors for early childhood asthma, say researchers from University of South Carolina. They found obesity nearly doubled a woman’s chances of having a child who developed asthma by age 4. Extreme-low weight gain (<5 kg) and extreme-high weight gain (≥25 kg) were both associated with increased risk of asthma.

At 9 months, 2 years, and 4 years, 5%, 8%, and 12% of children, respectively, were diagnosed with asthma. Overall, 15% of children were diagnosed with asthma by age 4. Every 1.0 unit increase in maternal body mass index was associated with increased odds of asthma in children.

Childhood asthma already is believed to have inutero origins, the researchers say. They cite a study that found 40% of children with a diagnosis of asthma by age 7 had reduced airflow and bronchial responsiveness as neonates. Research suggests that maternal weight and gestational weight gain may change the intrauterine environment and affect the development of asthma.

The researchers say, to their knowledge, no studies have examined the association between gestational weight gain and asthma in offspring in a nationally representative sample of children in the U.S. Moreover, previous studies did not account for gestational age, which can affect the amount of weight gained.

Although the researchers note that no single risk factor can entirely account for childhood asthma, maternal obesity is one that is modifiable.

Extreme weight gain during pregnancy may contribute to  risk factors for early childhood asthma, say researchers from University of South Carolina. They found obesity nearly doubled a woman’s chances of having a child who developed asthma by age 4. Extreme-low weight gain (<5 kg) and extreme-high weight gain (≥25 kg) were both associated with increased risk of asthma.

At 9 months, 2 years, and 4 years, 5%, 8%, and 12% of children, respectively, were diagnosed with asthma. Overall, 15% of children were diagnosed with asthma by age 4. Every 1.0 unit increase in maternal body mass index was associated with increased odds of asthma in children.

Childhood asthma already is believed to have inutero origins, the researchers say. They cite a study that found 40% of children with a diagnosis of asthma by age 7 had reduced airflow and bronchial responsiveness as neonates. Research suggests that maternal weight and gestational weight gain may change the intrauterine environment and affect the development of asthma.

The researchers say, to their knowledge, no studies have examined the association between gestational weight gain and asthma in offspring in a nationally representative sample of children in the U.S. Moreover, previous studies did not account for gestational age, which can affect the amount of weight gained.

Although the researchers note that no single risk factor can entirely account for childhood asthma, maternal obesity is one that is modifiable.

Extreme weight gain during pregnancy may contribute to  risk factors for early childhood asthma, say researchers from University of South Carolina. They found obesity nearly doubled a woman’s chances of having a child who developed asthma by age 4. Extreme-low weight gain (<5 kg) and extreme-high weight gain (≥25 kg) were both associated with increased risk of asthma.

At 9 months, 2 years, and 4 years, 5%, 8%, and 12% of children, respectively, were diagnosed with asthma. Overall, 15% of children were diagnosed with asthma by age 4. Every 1.0 unit increase in maternal body mass index was associated with increased odds of asthma in children.

Childhood asthma already is believed to have inutero origins, the researchers say. They cite a study that found 40% of children with a diagnosis of asthma by age 7 had reduced airflow and bronchial responsiveness as neonates. Research suggests that maternal weight and gestational weight gain may change the intrauterine environment and affect the development of asthma.

The researchers say, to their knowledge, no studies have examined the association between gestational weight gain and asthma in offspring in a nationally representative sample of children in the U.S. Moreover, previous studies did not account for gestational age, which can affect the amount of weight gained.

Although the researchers note that no single risk factor can entirely account for childhood asthma, maternal obesity is one that is modifiable.

Recently, a 57-year-old woman was informed by her husband that she has a discolored area of skin on her back. This discovery followed a prolonged period of back pain, for which she was prescribed an NSAID. When this yielded no relief, she started sleeping with an electric heating pad, held in place by an elastic bandage, to ease the pain.

She reports mild itching in the affected area. She claims to be in good health otherwise and is not taking any medication.

EXAMINATION
The patient is in no acute distress but has obvious difficulty walking without pain. Covering her back, from the bra strap down, is modest erythema, a reticular pattern of modest hyperpigmentation, and focal areas of mild scaling.

No tenderness or increased warmth is detected on palpation. No notable changes are seen elsewhere on her skin.

What is the diagnosis?

Today, the condition can develop in a variety of contexts, all of which involve prolonged, repeated exposure to infrared radiation (eg, electric blankets, hot water bottles, electric space heaters, laptop computers). EAI can also affect the faces and arms of bakers, chefs, welders, and silversmiths working in close proximity to radiation.

This type of heat increases vasodilation in the superficial venous plexus (located in the papillary dermis), which causes hemosiderin to leak into the superficial dermis over time. This permanently stains the skin with a characteristic reticular pattern that mimics the affected vascular pattern. Generally, the darker the patient’s skin, the darker the pattern appears.

EAI more commonly affects women than men, and its diagnosis should prompt further investigation for underlying conditions. Musculoskeletal problems, chronic infection, anemia, or hypothyroidism could be involved.

Treatment, besides avoidance of radiation, includes topical application of retinoids or use of lasers.

In this case, the changes were discovered early enough to be at least partially reversible. In more advanced cases, focal areas of scaling can coalesce into papules or nodules that can undergo malignant transformation to squamous cell carcinoma.

TAKE-HOME LEARNING POINTS

• Erythema ab igne (EAI) is a fairly common condition caused by close proximity to infrared radiation (eg, heating pads, laptop computers, electric space heaters).
• This radiation causes chronic vasodilatation of the superficial venous plexus, which leads to leakage of hemosiderin pigment, permanently staining the skin in a reticular pattern.
• EAI can affect the faces and arms of bakers, welders, chefs, and silversmiths.
• Treatment can be attempted with topical application of retinoids or with use of lasers.

Recently, a 57-year-old woman was informed by her husband that she has a discolored area of skin on her back. This discovery followed a prolonged period of back pain, for which she was prescribed an NSAID. When this yielded no relief, she started sleeping with an electric heating pad, held in place by an elastic bandage, to ease the pain.

She reports mild itching in the affected area. She claims to be in good health otherwise and is not taking any medication.

EXAMINATION
The patient is in no acute distress but has obvious difficulty walking without pain. Covering her back, from the bra strap down, is modest erythema, a reticular pattern of modest hyperpigmentation, and focal areas of mild scaling.

No tenderness or increased warmth is detected on palpation. No notable changes are seen elsewhere on her skin.

What is the diagnosis?

Today, the condition can develop in a variety of contexts, all of which involve prolonged, repeated exposure to infrared radiation (eg, electric blankets, hot water bottles, electric space heaters, laptop computers). EAI can also affect the faces and arms of bakers, chefs, welders, and silversmiths working in close proximity to radiation.

This type of heat increases vasodilation in the superficial venous plexus (located in the papillary dermis), which causes hemosiderin to leak into the superficial dermis over time. This permanently stains the skin with a characteristic reticular pattern that mimics the affected vascular pattern. Generally, the darker the patient’s skin, the darker the pattern appears.

EAI more commonly affects women than men, and its diagnosis should prompt further investigation for underlying conditions. Musculoskeletal problems, chronic infection, anemia, or hypothyroidism could be involved.

Treatment, besides avoidance of radiation, includes topical application of retinoids or use of lasers.

In this case, the changes were discovered early enough to be at least partially reversible. In more advanced cases, focal areas of scaling can coalesce into papules or nodules that can undergo malignant transformation to squamous cell carcinoma.

TAKE-HOME LEARNING POINTS

• Erythema ab igne (EAI) is a fairly common condition caused by close proximity to infrared radiation (eg, heating pads, laptop computers, electric space heaters).
• This radiation causes chronic vasodilatation of the superficial venous plexus, which leads to leakage of hemosiderin pigment, permanently staining the skin in a reticular pattern.
• EAI can affect the faces and arms of bakers, welders, chefs, and silversmiths.
• Treatment can be attempted with topical application of retinoids or with use of lasers.

Recently, a 57-year-old woman was informed by her husband that she has a discolored area of skin on her back. This discovery followed a prolonged period of back pain, for which she was prescribed an NSAID. When this yielded no relief, she started sleeping with an electric heating pad, held in place by an elastic bandage, to ease the pain.

She reports mild itching in the affected area. She claims to be in good health otherwise and is not taking any medication.

EXAMINATION
The patient is in no acute distress but has obvious difficulty walking without pain. Covering her back, from the bra strap down, is modest erythema, a reticular pattern of modest hyperpigmentation, and focal areas of mild scaling.

No tenderness or increased warmth is detected on palpation. No notable changes are seen elsewhere on her skin.

What is the diagnosis?

Today, the condition can develop in a variety of contexts, all of which involve prolonged, repeated exposure to infrared radiation (eg, electric blankets, hot water bottles, electric space heaters, laptop computers). EAI can also affect the faces and arms of bakers, chefs, welders, and silversmiths working in close proximity to radiation.

This type of heat increases vasodilation in the superficial venous plexus (located in the papillary dermis), which causes hemosiderin to leak into the superficial dermis over time. This permanently stains the skin with a characteristic reticular pattern that mimics the affected vascular pattern. Generally, the darker the patient’s skin, the darker the pattern appears.

EAI more commonly affects women than men, and its diagnosis should prompt further investigation for underlying conditions. Musculoskeletal problems, chronic infection, anemia, or hypothyroidism could be involved.

Treatment, besides avoidance of radiation, includes topical application of retinoids or use of lasers.

In this case, the changes were discovered early enough to be at least partially reversible. In more advanced cases, focal areas of scaling can coalesce into papules or nodules that can undergo malignant transformation to squamous cell carcinoma.

TAKE-HOME LEARNING POINTS

• Erythema ab igne (EAI) is a fairly common condition caused by close proximity to infrared radiation (eg, heating pads, laptop computers, electric space heaters).
• This radiation causes chronic vasodilatation of the superficial venous plexus, which leads to leakage of hemosiderin pigment, permanently staining the skin in a reticular pattern.
• EAI can affect the faces and arms of bakers, welders, chefs, and silversmiths.
• Treatment can be attempted with topical application of retinoids or with use of lasers.