The extended-release version of the product that combines empagliflozin and metformin hydrochloride has received Food and Drug Administration approval for use in the management of blood sugar in adults with type 2 diabetes. The drug, to be marketed as Synjardy XR by Boehringer Ingelheim and Eli Lilly, is intended for use with a diet and exercise program.

Its standard release formulation was approved in August 2015.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

FDA approved the extended-release version on Dec. 12. The updated label includes a boxed warning regarding the risk of metformin-associated lactic acidosis

Empagliflozin recently received an FDA indication as a medication for use in reducing the risk of cardiovascular death in patients with type 2 diabetes and concomitant cardiovascular disease, the first drug for type 2 diabetes to do so.

The label includes information of the drug’s four doses, all of which contain 1,000 mg of metformin plus empagliflozin in strengths of 5 mg, 10 mg, 12.5 mg, and 25 mg.

Among patients who are already taking metformin and plan to begin a regimen of Synjardy XR, their best choice is to switch to the formulation containing a similar daily dose of metformin and a total daily dose of 10 mg empagliflozin. Those already on empagliflozin should switch to Synjardy XR containing the same daily dose of empagliflozin and a total daily dose of 1,000 mg metformin. Dosing may be adjusted upward on the basis of effectiveness and tolerability up to a maximum of 25 mg empagliflozin/2,000 mg metformin, taken once daily with a meal in the morning.

Synjardy XR is contraindicated in patients with an estimated glomerular filtration rate of less than 45 mL/min per 1.73 m². Renal function should be assessed in patients with impaired renal function before taking Synjardy XR.

Several clinical trials tested coadministration of metformin and empagliflozin. In the largest, 637 patients with type 2 diabetes who were inadequately controlled (hemoglobin A_1c of 7%-10%) with 1,500 mg metformin were randomized to receive placebo, 10 mg empagliflozin, or 25 mg empagliflozin for 24 weeks. Both the 10-mg and 25-mg dosages of empagliflozin resulted in significant reductions compared with placebo in HbA_1c (–0.7% and –0.8%, respectively) fasting glucose (–26 mg/dL and –29 mg/dL), and body weight (–2 kg and –2.5 kg).

The single-pill formulation of Synjardy XR was not tested in clinical trials for efficacy; however, several trials performed in healthy subjects showed bioequivalence of the fixed dose combination, compared with separate pills.
[email protected]

The extended-release version of the product that combines empagliflozin and metformin hydrochloride has received Food and Drug Administration approval for use in the management of blood sugar in adults with type 2 diabetes. The drug, to be marketed as Synjardy XR by Boehringer Ingelheim and Eli Lilly, is intended for use with a diet and exercise program.

Its standard release formulation was approved in August 2015.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

FDA approved the extended-release version on Dec. 12. The updated label includes a boxed warning regarding the risk of metformin-associated lactic acidosis

Empagliflozin recently received an FDA indication as a medication for use in reducing the risk of cardiovascular death in patients with type 2 diabetes and concomitant cardiovascular disease, the first drug for type 2 diabetes to do so.

The label includes information of the drug’s four doses, all of which contain 1,000 mg of metformin plus empagliflozin in strengths of 5 mg, 10 mg, 12.5 mg, and 25 mg.

Among patients who are already taking metformin and plan to begin a regimen of Synjardy XR, their best choice is to switch to the formulation containing a similar daily dose of metformin and a total daily dose of 10 mg empagliflozin. Those already on empagliflozin should switch to Synjardy XR containing the same daily dose of empagliflozin and a total daily dose of 1,000 mg metformin. Dosing may be adjusted upward on the basis of effectiveness and tolerability up to a maximum of 25 mg empagliflozin/2,000 mg metformin, taken once daily with a meal in the morning.

Synjardy XR is contraindicated in patients with an estimated glomerular filtration rate of less than 45 mL/min per 1.73 m². Renal function should be assessed in patients with impaired renal function before taking Synjardy XR.

Several clinical trials tested coadministration of metformin and empagliflozin. In the largest, 637 patients with type 2 diabetes who were inadequately controlled (hemoglobin A_1c of 7%-10%) with 1,500 mg metformin were randomized to receive placebo, 10 mg empagliflozin, or 25 mg empagliflozin for 24 weeks. Both the 10-mg and 25-mg dosages of empagliflozin resulted in significant reductions compared with placebo in HbA_1c (–0.7% and –0.8%, respectively) fasting glucose (–26 mg/dL and –29 mg/dL), and body weight (–2 kg and –2.5 kg).

The single-pill formulation of Synjardy XR was not tested in clinical trials for efficacy; however, several trials performed in healthy subjects showed bioequivalence of the fixed dose combination, compared with separate pills.
[email protected]

The extended-release version of the product that combines empagliflozin and metformin hydrochloride has received Food and Drug Administration approval for use in the management of blood sugar in adults with type 2 diabetes. The drug, to be marketed as Synjardy XR by Boehringer Ingelheim and Eli Lilly, is intended for use with a diet and exercise program.

Its standard release formulation was approved in August 2015.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

FDA approved the extended-release version on Dec. 12. The updated label includes a boxed warning regarding the risk of metformin-associated lactic acidosis

Empagliflozin recently received an FDA indication as a medication for use in reducing the risk of cardiovascular death in patients with type 2 diabetes and concomitant cardiovascular disease, the first drug for type 2 diabetes to do so.

The label includes information of the drug’s four doses, all of which contain 1,000 mg of metformin plus empagliflozin in strengths of 5 mg, 10 mg, 12.5 mg, and 25 mg.

Among patients who are already taking metformin and plan to begin a regimen of Synjardy XR, their best choice is to switch to the formulation containing a similar daily dose of metformin and a total daily dose of 10 mg empagliflozin. Those already on empagliflozin should switch to Synjardy XR containing the same daily dose of empagliflozin and a total daily dose of 1,000 mg metformin. Dosing may be adjusted upward on the basis of effectiveness and tolerability up to a maximum of 25 mg empagliflozin/2,000 mg metformin, taken once daily with a meal in the morning.

Synjardy XR is contraindicated in patients with an estimated glomerular filtration rate of less than 45 mL/min per 1.73 m². Renal function should be assessed in patients with impaired renal function before taking Synjardy XR.

Several clinical trials tested coadministration of metformin and empagliflozin. In the largest, 637 patients with type 2 diabetes who were inadequately controlled (hemoglobin A_1c of 7%-10%) with 1,500 mg metformin were randomized to receive placebo, 10 mg empagliflozin, or 25 mg empagliflozin for 24 weeks. Both the 10-mg and 25-mg dosages of empagliflozin resulted in significant reductions compared with placebo in HbA_1c (–0.7% and –0.8%, respectively) fasting glucose (–26 mg/dL and –29 mg/dL), and body weight (–2 kg and –2.5 kg).

The single-pill formulation of Synjardy XR was not tested in clinical trials for efficacy; however, several trials performed in healthy subjects showed bioequivalence of the fixed dose combination, compared with separate pills.
[email protected]

SAN ANTONIO – About half of the women with stage 1 or 2 breast cancer who were treated using a scalp cooling device during chemotherapy retained their hair in the prospective, randomized Scalp Cooling Alopecia Prevention (SCALP) trial.

Of 229 women who were enrolled from seven U.S. sites between December 2013 and September 2016 and who planned to undergo at least four cycles of anthracycline- or taxane-based chemotherapy, 182 met eligibility criteria; 119 were randomized to undergo scalp cooling using the Orbis Paxman Hair Loss Prevention System (OPHLPS; Paxman Coolers) and 63 were assigned to a control group. Of those, 95 and 47, respectively, were evaluable and had completed four cycles of chemotherapy at the time of a preplanned interim analysis.

Baylor College of Medicine

[email protected]

SAN ANTONIO – About half of the women with stage 1 or 2 breast cancer who were treated using a scalp cooling device during chemotherapy retained their hair in the prospective, randomized Scalp Cooling Alopecia Prevention (SCALP) trial.

Of 229 women who were enrolled from seven U.S. sites between December 2013 and September 2016 and who planned to undergo at least four cycles of anthracycline- or taxane-based chemotherapy, 182 met eligibility criteria; 119 were randomized to undergo scalp cooling using the Orbis Paxman Hair Loss Prevention System (OPHLPS; Paxman Coolers) and 63 were assigned to a control group. Of those, 95 and 47, respectively, were evaluable and had completed four cycles of chemotherapy at the time of a preplanned interim analysis.

Baylor College of Medicine

[email protected]

SAN ANTONIO – About half of the women with stage 1 or 2 breast cancer who were treated using a scalp cooling device during chemotherapy retained their hair in the prospective, randomized Scalp Cooling Alopecia Prevention (SCALP) trial.

Of 229 women who were enrolled from seven U.S. sites between December 2013 and September 2016 and who planned to undergo at least four cycles of anthracycline- or taxane-based chemotherapy, 182 met eligibility criteria; 119 were randomized to undergo scalp cooling using the Orbis Paxman Hair Loss Prevention System (OPHLPS; Paxman Coolers) and 63 were assigned to a control group. Of those, 95 and 47, respectively, were evaluable and had completed four cycles of chemotherapy at the time of a preplanned interim analysis.

Baylor College of Medicine

[email protected]

Though a 10-year epidemiologic study did not find an increased risk of bladder cancer with pioglitazone use, the Food and Drug Administration has chosen to affirm the warning on the label of the type 2 diabetes drug following an updated review of several studies.

The FDA issued a warning about the possible risk of bladder cancer based on interim results from the 10-year epidemiologic study in 2010, and it changed the labels of pioglitazone-containing medicines in 2011 to include warnings about this risk.

There was a modest trend toward higher risk with increasing duration of use, but the trend was not statistically significant. Compared with the interim 5-year results, these final 10-year results found weaker associations that were not statistically significant.

The directions of the associations, however, remained unchanged. Based on these findings and other reviewed studies with conflicting results, the FDA has concluded that use of pioglitazone may be linked to an increased risk of bladder cancer.

The labels of pioglitazone-containing medicines already contain warnings about this risk, but the FDA has now approved label updates to describe the additional studies reviewed.

Read the FDA update and data summary here.

[email protected]

On Twitter @nikolaideslaura

Though a 10-year epidemiologic study did not find an increased risk of bladder cancer with pioglitazone use, the Food and Drug Administration has chosen to affirm the warning on the label of the type 2 diabetes drug following an updated review of several studies.

The FDA issued a warning about the possible risk of bladder cancer based on interim results from the 10-year epidemiologic study in 2010, and it changed the labels of pioglitazone-containing medicines in 2011 to include warnings about this risk.

There was a modest trend toward higher risk with increasing duration of use, but the trend was not statistically significant. Compared with the interim 5-year results, these final 10-year results found weaker associations that were not statistically significant.

The directions of the associations, however, remained unchanged. Based on these findings and other reviewed studies with conflicting results, the FDA has concluded that use of pioglitazone may be linked to an increased risk of bladder cancer.

The labels of pioglitazone-containing medicines already contain warnings about this risk, but the FDA has now approved label updates to describe the additional studies reviewed.

Read the FDA update and data summary here.

[email protected]

On Twitter @nikolaideslaura

Though a 10-year epidemiologic study did not find an increased risk of bladder cancer with pioglitazone use, the Food and Drug Administration has chosen to affirm the warning on the label of the type 2 diabetes drug following an updated review of several studies.

The FDA issued a warning about the possible risk of bladder cancer based on interim results from the 10-year epidemiologic study in 2010, and it changed the labels of pioglitazone-containing medicines in 2011 to include warnings about this risk.

There was a modest trend toward higher risk with increasing duration of use, but the trend was not statistically significant. Compared with the interim 5-year results, these final 10-year results found weaker associations that were not statistically significant.

The directions of the associations, however, remained unchanged. Based on these findings and other reviewed studies with conflicting results, the FDA has concluded that use of pioglitazone may be linked to an increased risk of bladder cancer.

The labels of pioglitazone-containing medicines already contain warnings about this risk, but the FDA has now approved label updates to describe the additional studies reviewed.

Read the FDA update and data summary here.

[email protected]

On Twitter @nikolaideslaura

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

There has been a significant increase over time in the proportion of deliveries to women living with HIV aged 40 years and older, which has implications for pregnancy management, according to a study in HIV Medicine.

HIV-positive older adults have higher cystatin C levels than do HIV-negative older adults, according to a recent study, and cystatin C may be associated with neurocognitive impairment in this population, particularly if they use tenofovir.

alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

There has been a significant increase over time in the proportion of deliveries to women living with HIV aged 40 years and older, which has implications for pregnancy management, according to a study in HIV Medicine.

HIV-positive older adults have higher cystatin C levels than do HIV-negative older adults, according to a recent study, and cystatin C may be associated with neurocognitive impairment in this population, particularly if they use tenofovir.

alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

A great volume of HIV and AIDS research enters the medical literature every month. It’s difficult to monitor everything, so here’s a quick look at some notable news items and journal articles published over the past few weeks.

There has been a significant increase over time in the proportion of deliveries to women living with HIV aged 40 years and older, which has implications for pregnancy management, according to a study in HIV Medicine.

HIV-positive older adults have higher cystatin C levels than do HIV-negative older adults, according to a recent study, and cystatin C may be associated with neurocognitive impairment in this population, particularly if they use tenofovir.

alexskopje/Thinkstock

[email protected]

On Twitter @richpizzi

SAN DIEGO – Anti-CD19 chimeric antigen receptor (CAR) T cells engineered with a “safety switch” yielded high rates of complete response and an acceptable toxicity profile in chemotherapy-resistant B cell acute lymphoblastic leukemia, according to a multicenter phase I/II trial.

Importantly, high tumor burden did not increase the risk of cytokine release syndrome, said Lung-Ji Chang, PhD, of Shenzhen (China) Genoimmune Medical Institute and the University of Florida in Gainesville. “This reliable, standardized CAR T-cell preparation protocol has now served more than 30 major medical centers in China,” he said at the annual meeting of the American Society of Hematology.

Anti-CD19 CAR T cells have shown dramatic potential for treating B-cell malignancies, but toxicities have been a concern. One potentially serious adverse reaction is cytokine release syndrome, in which patients develop marked rises in blood levels of several types of cytokines. Another problem is that anti-CD19 CAR T cells can trigger loss of CD19 B cells, ultimately leading to humoral deficiencies, Dr. Chang noted. Consequently, researchers have searched for ways to continue controlling the activity of CAR T cells even after infusing them into patients.

As part of that effort, Dr. Chang and his associates developed a standardized protocol for engineering next-generation anti-CD19 CAR T cells based on the established concept of a “safety switch.” After collecting T cells from patients with chemotherapy-resistant ALL, they used a lentiviral vector to transform them into CAR T cells with fusion proteins consisting of a proapoptotic molecule called caspase-9 that is linked to modified human FK506-binding proteins, or FKBP. The addition of iCaspase9-FKBP enables clinicians to induce CAR T cell apoptosis by treating patients with a synthetic dimerizer called AP1903.

Apoptosis occurs about 45 minutes after this drug is given, according to Dr. Chang. This “safety switch” also enables clinicians to eliminate anti-CD19 CAR T cells after tumor cells are eradicated so that patients can recover their humoral immunity. He and his associates further modified these anti-CD19 CAR T cells by introducing four intracellular signaling domains that are associated with T-cell activation, survival, and longevity, he said.

A total of 22 treatment centers helped test this approach in a phase I/II trial of 110 leukemia patients, about half of whom were children with a median age of 9 years. The median age of adults was 37 years, and the oldest patient was 70. Cancer types included Philadelphia chromosome–positive ALL, Philadelphia chromosome–negative ALL, and chronic myeloid leukemia with blast crisis. About a third of patients had bone marrow samples with at least 50% blasts, and a similar proportion had already undergone hematopoietic stem cell transplantation.

Cytokine release syndrome affected 86% of patients with low or no tumor burden, but only 53% of patients with bone marrow blasts exceeding 5%, Dr. Chang reported. He emphasized that patients with high tumor burden were no more likely to develop moderate or severe cytokine release syndrome than were patients with little or no tumor burden (P = .3). Furthermore, among 17 patients with more than 80% bone marrow involvement, only three developed grade 3-4 cytokine release syndrome, while eight developed grade 1 cytokine release syndrome.

A total of 96 patients (87%) had a complete response to this CAR T cell regimen, including 51 children and 45 adults, Dr. Chang reported. Median overall survival was 222 days (range, 23-1,041 days), and 60% of patients lived at least 400 days after treatment. Patients survived a median of 115 days without relapsing (range, 0-455 days), and 55% ultimately relapsed. Age did not appear to predict relapse, he noted.

Kaplan-Meier curves revealed no major differences in rates of overall survival (OS) between adults and children at 400-day data cutoff, Dr. Chang said. However, patients with more than 50% blast cells in their bone marrow had significantly lower rates of survival (P = .02) than did patients with less advanced ALL. A lower T-cell dose predicted lower survival in children (P = .04), but not in adults. Dr. Chang and his colleagues now dose patients of all ages with 106 cells per kilogram, he said.

Survival was significantly more likely when CAR T cell recipients went on to allogeneic hematopoietic stem cell transplantation (P = .0002) than otherwise. Based on the findings, Dr. Chang particularly recommends this approach for highly chemotherapy-resistant disease with a high tumor burden. Among patients who relapsed, repeating CAR T cell therapy led to better survival than administering combination chemotherapy-tyrosine kinase inhibitor therapy (P = .01).

These safety and efficacy results suggest that CAR T cell immunotherapy can benefit patients if they have very high-burden leukemia, Dr. Chang concluded. Patients outcomes remained consistent across centers due to a “highly standardized CAR T cell preparation profile,” he said.

Dr. Chang did not report funding sources. He reported having no relevant conflicts of interest.

SAN DIEGO – Anti-CD19 chimeric antigen receptor (CAR) T cells engineered with a “safety switch” yielded high rates of complete response and an acceptable toxicity profile in chemotherapy-resistant B cell acute lymphoblastic leukemia, according to a multicenter phase I/II trial.

Importantly, high tumor burden did not increase the risk of cytokine release syndrome, said Lung-Ji Chang, PhD, of Shenzhen (China) Genoimmune Medical Institute and the University of Florida in Gainesville. “This reliable, standardized CAR T-cell preparation protocol has now served more than 30 major medical centers in China,” he said at the annual meeting of the American Society of Hematology.

Anti-CD19 CAR T cells have shown dramatic potential for treating B-cell malignancies, but toxicities have been a concern. One potentially serious adverse reaction is cytokine release syndrome, in which patients develop marked rises in blood levels of several types of cytokines. Another problem is that anti-CD19 CAR T cells can trigger loss of CD19 B cells, ultimately leading to humoral deficiencies, Dr. Chang noted. Consequently, researchers have searched for ways to continue controlling the activity of CAR T cells even after infusing them into patients.

As part of that effort, Dr. Chang and his associates developed a standardized protocol for engineering next-generation anti-CD19 CAR T cells based on the established concept of a “safety switch.” After collecting T cells from patients with chemotherapy-resistant ALL, they used a lentiviral vector to transform them into CAR T cells with fusion proteins consisting of a proapoptotic molecule called caspase-9 that is linked to modified human FK506-binding proteins, or FKBP. The addition of iCaspase9-FKBP enables clinicians to induce CAR T cell apoptosis by treating patients with a synthetic dimerizer called AP1903.

Apoptosis occurs about 45 minutes after this drug is given, according to Dr. Chang. This “safety switch” also enables clinicians to eliminate anti-CD19 CAR T cells after tumor cells are eradicated so that patients can recover their humoral immunity. He and his associates further modified these anti-CD19 CAR T cells by introducing four intracellular signaling domains that are associated with T-cell activation, survival, and longevity, he said.

A total of 22 treatment centers helped test this approach in a phase I/II trial of 110 leukemia patients, about half of whom were children with a median age of 9 years. The median age of adults was 37 years, and the oldest patient was 70. Cancer types included Philadelphia chromosome–positive ALL, Philadelphia chromosome–negative ALL, and chronic myeloid leukemia with blast crisis. About a third of patients had bone marrow samples with at least 50% blasts, and a similar proportion had already undergone hematopoietic stem cell transplantation.

Cytokine release syndrome affected 86% of patients with low or no tumor burden, but only 53% of patients with bone marrow blasts exceeding 5%, Dr. Chang reported. He emphasized that patients with high tumor burden were no more likely to develop moderate or severe cytokine release syndrome than were patients with little or no tumor burden (P = .3). Furthermore, among 17 patients with more than 80% bone marrow involvement, only three developed grade 3-4 cytokine release syndrome, while eight developed grade 1 cytokine release syndrome.

A total of 96 patients (87%) had a complete response to this CAR T cell regimen, including 51 children and 45 adults, Dr. Chang reported. Median overall survival was 222 days (range, 23-1,041 days), and 60% of patients lived at least 400 days after treatment. Patients survived a median of 115 days without relapsing (range, 0-455 days), and 55% ultimately relapsed. Age did not appear to predict relapse, he noted.

Kaplan-Meier curves revealed no major differences in rates of overall survival (OS) between adults and children at 400-day data cutoff, Dr. Chang said. However, patients with more than 50% blast cells in their bone marrow had significantly lower rates of survival (P = .02) than did patients with less advanced ALL. A lower T-cell dose predicted lower survival in children (P = .04), but not in adults. Dr. Chang and his colleagues now dose patients of all ages with 106 cells per kilogram, he said.

Survival was significantly more likely when CAR T cell recipients went on to allogeneic hematopoietic stem cell transplantation (P = .0002) than otherwise. Based on the findings, Dr. Chang particularly recommends this approach for highly chemotherapy-resistant disease with a high tumor burden. Among patients who relapsed, repeating CAR T cell therapy led to better survival than administering combination chemotherapy-tyrosine kinase inhibitor therapy (P = .01).

These safety and efficacy results suggest that CAR T cell immunotherapy can benefit patients if they have very high-burden leukemia, Dr. Chang concluded. Patients outcomes remained consistent across centers due to a “highly standardized CAR T cell preparation profile,” he said.

Dr. Chang did not report funding sources. He reported having no relevant conflicts of interest.

SAN DIEGO – Anti-CD19 chimeric antigen receptor (CAR) T cells engineered with a “safety switch” yielded high rates of complete response and an acceptable toxicity profile in chemotherapy-resistant B cell acute lymphoblastic leukemia, according to a multicenter phase I/II trial.

Importantly, high tumor burden did not increase the risk of cytokine release syndrome, said Lung-Ji Chang, PhD, of Shenzhen (China) Genoimmune Medical Institute and the University of Florida in Gainesville. “This reliable, standardized CAR T-cell preparation protocol has now served more than 30 major medical centers in China,” he said at the annual meeting of the American Society of Hematology.

Anti-CD19 CAR T cells have shown dramatic potential for treating B-cell malignancies, but toxicities have been a concern. One potentially serious adverse reaction is cytokine release syndrome, in which patients develop marked rises in blood levels of several types of cytokines. Another problem is that anti-CD19 CAR T cells can trigger loss of CD19 B cells, ultimately leading to humoral deficiencies, Dr. Chang noted. Consequently, researchers have searched for ways to continue controlling the activity of CAR T cells even after infusing them into patients.

As part of that effort, Dr. Chang and his associates developed a standardized protocol for engineering next-generation anti-CD19 CAR T cells based on the established concept of a “safety switch.” After collecting T cells from patients with chemotherapy-resistant ALL, they used a lentiviral vector to transform them into CAR T cells with fusion proteins consisting of a proapoptotic molecule called caspase-9 that is linked to modified human FK506-binding proteins, or FKBP. The addition of iCaspase9-FKBP enables clinicians to induce CAR T cell apoptosis by treating patients with a synthetic dimerizer called AP1903.

Apoptosis occurs about 45 minutes after this drug is given, according to Dr. Chang. This “safety switch” also enables clinicians to eliminate anti-CD19 CAR T cells after tumor cells are eradicated so that patients can recover their humoral immunity. He and his associates further modified these anti-CD19 CAR T cells by introducing four intracellular signaling domains that are associated with T-cell activation, survival, and longevity, he said.

A total of 22 treatment centers helped test this approach in a phase I/II trial of 110 leukemia patients, about half of whom were children with a median age of 9 years. The median age of adults was 37 years, and the oldest patient was 70. Cancer types included Philadelphia chromosome–positive ALL, Philadelphia chromosome–negative ALL, and chronic myeloid leukemia with blast crisis. About a third of patients had bone marrow samples with at least 50% blasts, and a similar proportion had already undergone hematopoietic stem cell transplantation.

Cytokine release syndrome affected 86% of patients with low or no tumor burden, but only 53% of patients with bone marrow blasts exceeding 5%, Dr. Chang reported. He emphasized that patients with high tumor burden were no more likely to develop moderate or severe cytokine release syndrome than were patients with little or no tumor burden (P = .3). Furthermore, among 17 patients with more than 80% bone marrow involvement, only three developed grade 3-4 cytokine release syndrome, while eight developed grade 1 cytokine release syndrome.

A total of 96 patients (87%) had a complete response to this CAR T cell regimen, including 51 children and 45 adults, Dr. Chang reported. Median overall survival was 222 days (range, 23-1,041 days), and 60% of patients lived at least 400 days after treatment. Patients survived a median of 115 days without relapsing (range, 0-455 days), and 55% ultimately relapsed. Age did not appear to predict relapse, he noted.

Kaplan-Meier curves revealed no major differences in rates of overall survival (OS) between adults and children at 400-day data cutoff, Dr. Chang said. However, patients with more than 50% blast cells in their bone marrow had significantly lower rates of survival (P = .02) than did patients with less advanced ALL. A lower T-cell dose predicted lower survival in children (P = .04), but not in adults. Dr. Chang and his colleagues now dose patients of all ages with 106 cells per kilogram, he said.

Survival was significantly more likely when CAR T cell recipients went on to allogeneic hematopoietic stem cell transplantation (P = .0002) than otherwise. Based on the findings, Dr. Chang particularly recommends this approach for highly chemotherapy-resistant disease with a high tumor burden. Among patients who relapsed, repeating CAR T cell therapy led to better survival than administering combination chemotherapy-tyrosine kinase inhibitor therapy (P = .01).

These safety and efficacy results suggest that CAR T cell immunotherapy can benefit patients if they have very high-burden leukemia, Dr. Chang concluded. Patients outcomes remained consistent across centers due to a “highly standardized CAR T cell preparation profile,” he said.

Dr. Chang did not report funding sources. He reported having no relevant conflicts of interest.

VIENNA – Stereotactic body radiotherapy (SBRT) proved too toxic for many of patients recruited into a multinational phase II trial with centrally-located lung tumors.

The majority of patients experienced some type of adverse effect, with 28% experiencing serious (grade 3-5) adverse effects.

“Our major concern now is that we had six cases of grade 5 bleedings,” Karen Lindberg, MD, said at the World Conference on Lung Cancer. “Tumor location seems to be a risk factor for bleeding,” she added, with five of the six cases seen in patients who had tumors close to a main bronchus (group A). The other case was in patient who had tumors close to a lobular bronchus (group B).

“The classical definition of a centrally-located lung tumor is a tumor residing within or touching an imaginary zone 2 cm around the proximal bronchial tree,” explained Dr. Lindberg of Karolinska University Hospital and the Karolinska Institutet in Stockholm, who presented the first results of the Nordic HILUS Trial.

“When we designed this study we wanted to look at very centrally located tumors, so we tightened up this definition to look at tumors that occurred within 1 cm around the proximal bronchial tree,” she said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

During the trial, SBRT was to be delivered at a dose of 7 Gray (Gy) in 8 fractions at 65%-75% isodose lines to ultra-centrally-located tumors. Dose constraints were stipulated for tumors situated very close to the spinal cord, contralateral main bronchus, and trachea, with some dosing recommendations on reducing the dose delivered to tumors that were ipsilateral to the main bronchus, or very close to the esophagus or heart.

A total of 74 patients with centrally-located, locally progressive tumors, which were less than 5 cm in size and due to non–small-cell lung cancer (NSCLC) or metastatic lung disease from another solid tumor, were recruited. Patients had to have a good performance status and life expectancy of 3 months.

Patients with brain metastases or tumors that reached through the wall of a main bronchus were excluded as were those who were taking any concomitant systemic therapy.

The mean age of the recruited patients was 71 years; 58 (78%) had NSCLC, of which 20 (27%) had adenomas and 19 (26%) had squamous cell cancers. Of those with secondary lung tumors, eight (11%), had primary renal cell carcinoma and four (5%) had colorectal cancer.

After a follow-up of 18.6 months, 31 (42%) patients had died.

The most common adverse events reported were grade 1-2 dyspnea, cough, and fatigue. However, there was a high rate of grade 3 (dyspnea, fatigue, pain, pneumonitis, and heart rhythm disturbance), 4 (pain, lung infection, fever, heart rhythm disturbance, fistula, and pneumothorax) and 5 toxicities (pneumonitis and bleeding).

Bleeding often occurred without warning and had an acute onset and toll.

Seven patients (six in group A and one in group B) may have suffered grade 5 side effects; six patients experienced lethal hemoptysis after a median of 15.5 months (2.5-21 months) and one patient suffered from a lethal pneumonitis 5 months post study treatment. The reintroduction of TKIs may also have played a role, Dr. Lindberg suggested.

SBRT for early stage NSCLC is very effective and “generates outstanding tumor control”, said Feng-Ming Kong, MD, of Indiana University, Indianapolis, who was invited to comment on the findings.

Most studies of SBRT have looked at peripherally-located tumors, however, so the study by the NORDIC Study Group provides valuable information on a more centrally-located approach. The big question of course is what caused the bleeding.

“What percentage of TKI patients had bleeding and how many of them had a TKI without bleeding?” Dr. Kong asked. Other questions around dosing remain: How much radiation was delivered to the great vessels such as the pulmonary artery, and how much of the dose hit critical structures? And, were tumors invading the pulmonary artery?

“SBRT may be applied for centrally-located tumors safely with other prescription regimens, she suggested, such as 10-11 Gy given in 5 fractions. That is assuming that “the dose limits of normal tissues are strictly controlled and the patients are carefully selected to exclude T4 diseases for adjacent organ invasion.”

The NORDIC SBRT Study Group conducted the study. Dr. Lindberg had no conflicts of interest to disclose. Dr. Kong has received research grants from the National Cancer Institute (part of the National Institutes of Health) and speakers honorarium and travel support from Varian Medical.

VIENNA – Stereotactic body radiotherapy (SBRT) proved too toxic for many of patients recruited into a multinational phase II trial with centrally-located lung tumors.

The majority of patients experienced some type of adverse effect, with 28% experiencing serious (grade 3-5) adverse effects.

“Our major concern now is that we had six cases of grade 5 bleedings,” Karen Lindberg, MD, said at the World Conference on Lung Cancer. “Tumor location seems to be a risk factor for bleeding,” she added, with five of the six cases seen in patients who had tumors close to a main bronchus (group A). The other case was in patient who had tumors close to a lobular bronchus (group B).

“The classical definition of a centrally-located lung tumor is a tumor residing within or touching an imaginary zone 2 cm around the proximal bronchial tree,” explained Dr. Lindberg of Karolinska University Hospital and the Karolinska Institutet in Stockholm, who presented the first results of the Nordic HILUS Trial.

“When we designed this study we wanted to look at very centrally located tumors, so we tightened up this definition to look at tumors that occurred within 1 cm around the proximal bronchial tree,” she said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

During the trial, SBRT was to be delivered at a dose of 7 Gray (Gy) in 8 fractions at 65%-75% isodose lines to ultra-centrally-located tumors. Dose constraints were stipulated for tumors situated very close to the spinal cord, contralateral main bronchus, and trachea, with some dosing recommendations on reducing the dose delivered to tumors that were ipsilateral to the main bronchus, or very close to the esophagus or heart.

A total of 74 patients with centrally-located, locally progressive tumors, which were less than 5 cm in size and due to non–small-cell lung cancer (NSCLC) or metastatic lung disease from another solid tumor, were recruited. Patients had to have a good performance status and life expectancy of 3 months.

Patients with brain metastases or tumors that reached through the wall of a main bronchus were excluded as were those who were taking any concomitant systemic therapy.

The mean age of the recruited patients was 71 years; 58 (78%) had NSCLC, of which 20 (27%) had adenomas and 19 (26%) had squamous cell cancers. Of those with secondary lung tumors, eight (11%), had primary renal cell carcinoma and four (5%) had colorectal cancer.

After a follow-up of 18.6 months, 31 (42%) patients had died.

The most common adverse events reported were grade 1-2 dyspnea, cough, and fatigue. However, there was a high rate of grade 3 (dyspnea, fatigue, pain, pneumonitis, and heart rhythm disturbance), 4 (pain, lung infection, fever, heart rhythm disturbance, fistula, and pneumothorax) and 5 toxicities (pneumonitis and bleeding).

Bleeding often occurred without warning and had an acute onset and toll.

Seven patients (six in group A and one in group B) may have suffered grade 5 side effects; six patients experienced lethal hemoptysis after a median of 15.5 months (2.5-21 months) and one patient suffered from a lethal pneumonitis 5 months post study treatment. The reintroduction of TKIs may also have played a role, Dr. Lindberg suggested.

SBRT for early stage NSCLC is very effective and “generates outstanding tumor control”, said Feng-Ming Kong, MD, of Indiana University, Indianapolis, who was invited to comment on the findings.

Most studies of SBRT have looked at peripherally-located tumors, however, so the study by the NORDIC Study Group provides valuable information on a more centrally-located approach. The big question of course is what caused the bleeding.

“What percentage of TKI patients had bleeding and how many of them had a TKI without bleeding?” Dr. Kong asked. Other questions around dosing remain: How much radiation was delivered to the great vessels such as the pulmonary artery, and how much of the dose hit critical structures? And, were tumors invading the pulmonary artery?

“SBRT may be applied for centrally-located tumors safely with other prescription regimens, she suggested, such as 10-11 Gy given in 5 fractions. That is assuming that “the dose limits of normal tissues are strictly controlled and the patients are carefully selected to exclude T4 diseases for adjacent organ invasion.”

The NORDIC SBRT Study Group conducted the study. Dr. Lindberg had no conflicts of interest to disclose. Dr. Kong has received research grants from the National Cancer Institute (part of the National Institutes of Health) and speakers honorarium and travel support from Varian Medical.

VIENNA – Stereotactic body radiotherapy (SBRT) proved too toxic for many of patients recruited into a multinational phase II trial with centrally-located lung tumors.

The majority of patients experienced some type of adverse effect, with 28% experiencing serious (grade 3-5) adverse effects.

“Our major concern now is that we had six cases of grade 5 bleedings,” Karen Lindberg, MD, said at the World Conference on Lung Cancer. “Tumor location seems to be a risk factor for bleeding,” she added, with five of the six cases seen in patients who had tumors close to a main bronchus (group A). The other case was in patient who had tumors close to a lobular bronchus (group B).

“The classical definition of a centrally-located lung tumor is a tumor residing within or touching an imaginary zone 2 cm around the proximal bronchial tree,” explained Dr. Lindberg of Karolinska University Hospital and the Karolinska Institutet in Stockholm, who presented the first results of the Nordic HILUS Trial.

“When we designed this study we wanted to look at very centrally located tumors, so we tightened up this definition to look at tumors that occurred within 1 cm around the proximal bronchial tree,” she said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

During the trial, SBRT was to be delivered at a dose of 7 Gray (Gy) in 8 fractions at 65%-75% isodose lines to ultra-centrally-located tumors. Dose constraints were stipulated for tumors situated very close to the spinal cord, contralateral main bronchus, and trachea, with some dosing recommendations on reducing the dose delivered to tumors that were ipsilateral to the main bronchus, or very close to the esophagus or heart.

A total of 74 patients with centrally-located, locally progressive tumors, which were less than 5 cm in size and due to non–small-cell lung cancer (NSCLC) or metastatic lung disease from another solid tumor, were recruited. Patients had to have a good performance status and life expectancy of 3 months.

Patients with brain metastases or tumors that reached through the wall of a main bronchus were excluded as were those who were taking any concomitant systemic therapy.

The mean age of the recruited patients was 71 years; 58 (78%) had NSCLC, of which 20 (27%) had adenomas and 19 (26%) had squamous cell cancers. Of those with secondary lung tumors, eight (11%), had primary renal cell carcinoma and four (5%) had colorectal cancer.

After a follow-up of 18.6 months, 31 (42%) patients had died.

The most common adverse events reported were grade 1-2 dyspnea, cough, and fatigue. However, there was a high rate of grade 3 (dyspnea, fatigue, pain, pneumonitis, and heart rhythm disturbance), 4 (pain, lung infection, fever, heart rhythm disturbance, fistula, and pneumothorax) and 5 toxicities (pneumonitis and bleeding).

Bleeding often occurred without warning and had an acute onset and toll.

Seven patients (six in group A and one in group B) may have suffered grade 5 side effects; six patients experienced lethal hemoptysis after a median of 15.5 months (2.5-21 months) and one patient suffered from a lethal pneumonitis 5 months post study treatment. The reintroduction of TKIs may also have played a role, Dr. Lindberg suggested.

SBRT for early stage NSCLC is very effective and “generates outstanding tumor control”, said Feng-Ming Kong, MD, of Indiana University, Indianapolis, who was invited to comment on the findings.

Most studies of SBRT have looked at peripherally-located tumors, however, so the study by the NORDIC Study Group provides valuable information on a more centrally-located approach. The big question of course is what caused the bleeding.

“What percentage of TKI patients had bleeding and how many of them had a TKI without bleeding?” Dr. Kong asked. Other questions around dosing remain: How much radiation was delivered to the great vessels such as the pulmonary artery, and how much of the dose hit critical structures? And, were tumors invading the pulmonary artery?

“SBRT may be applied for centrally-located tumors safely with other prescription regimens, she suggested, such as 10-11 Gy given in 5 fractions. That is assuming that “the dose limits of normal tissues are strictly controlled and the patients are carefully selected to exclude T4 diseases for adjacent organ invasion.”

The NORDIC SBRT Study Group conducted the study. Dr. Lindberg had no conflicts of interest to disclose. Dr. Kong has received research grants from the National Cancer Institute (part of the National Institutes of Health) and speakers honorarium and travel support from Varian Medical.

Keratoacanthomas (KAs) are rapidly growing tumors most prominently found on sun-exposed areas of the skin. The normal progression of a KA is to show rapid growth followed by spontaneous resolution.¹ Most KAs are solitary; however, there are several variants of multiple KAs including the familial Ferguson-Smith type, Gryzbowski syndrome (generalized eruptive KAs), KA centrifugum marginatum, Muir-Torre syndrome, and xeroderma pigmentosum.^2-4 Keratoacanthomas also may develop in areas of trauma, including burns, laser treatment, radiation, and surgical margins from excisional biopsies or skin grafting.⁵ Treatment of multiple KAs can be difficult due to a potentially large field size and number of lesions.⁶ We present a case of multiple KAs developing both in the surgical margins and de novo that responded dramatically to treatment with intralesional methotrexate (MTX).

Case Report

A 55-year-old man with a history of a surgically treated squamous cell carcinoma (SCC) on the anterior aspect of the right leg developed multiple nodules involving the surgical scar. He previously underwent Mohs micrographic surgery (MMS); within a month after the second surgery the patient noticed increased pruritus along with scaly pink changes at the site of the surgical scar.

One month prior to presentation, biopsies from the anterior aspect of the right leg demonstrated well-differentiated SCC and he was subsequently treated with MMS; however, examination 1 month after MMS revealed an 11×7-cm indurated plaque with multiple nodules ranging from 1 to 2 cm near the periphery of the plaque with central atrophy and scarring, reminiscent of KA centrifugum marginatum (Figure, A). In a similar fashion, an 8×5-cm plaque composed of 7 nodular areas was noted on the posterior aspect of the right leg (Figure, B). The patient denied any history of trauma to this area. There was no palpable regional lymphadenopathy and the remainder of the skin examination was normal, except for signs of venous stasis in both legs.

Based on the location and morphology of the lesions, the clinical presentation was consistent with multiple KAs. Histologic examination from punch biopsies taken from the plaque's periphery demonstrated well-differentiated SCC (KA type), as well as a lichenoid inflammatory process, epidermal hyperplasia, and cystic and endophytic squamous proliferation suggestive of hypertrophic lichen planus (HLP).

In consideration of the size and number of the lesions as well as the prolonged wound healing with prior surgery, the patient consented to treatment with intralesional MTX (1 mL of 12.5 mg/mL every 2 weeks) rather than undergoing further surgery. The MTX injection was distributed between the lesions on the anterior and posterior aspects of the lower right leg. At each injection session, the size, thickness, and nodularity of the tumor decreased with markedly less pruritus and symptomatic relief was achieved. After 3 injection sessions, resulting in a total of 3 mL of 12.5 mg/mL of MTX, biopsies were taken from the residual atrophic scar on the anterior aspect of the right leg and the remaining 3 papules on the posterior aspect of the right leg to rule out HLP and invasive SCC. The pathology report commented on the presence of prurigo nodules without any evidence of SCC.

At 3-month follow-up, the patient demonstrated no new lesions or recurrence (Figure, C and D). The right leg continued to heal with scarring and postinflammatory pigmentary changes. The patient was monitored for recurrence and to determine the diagnosis of HLP.

Comment

We report the development of multiple KAs arising both from within surgical margins and de novo, and resolution with intralesional MTX. Keratoacanthomas, especially various KA types, have been observed to develop due to various types of trauma, including sites of surgical scars, lichen planus, tattoos, thermal burns, radiation, and discoid lupus erythematosus, and within skin grafts and donor sites.^5-19

Hypertrophic lichen planus is a chronic variant of lichen planus that often is found on the pretibial areas of the lower legs.¹³ Both SCC and reactive KAs have been observed to develop within lesions of HLP.¹⁴ Our pathologist commented on the presence of a lichenoid infiltrate with necrotic keratinocytes and epidermal hyperplasia suspicious for HLP, with a small focus of cystic and endophytic squamous proliferation. The latter lacked notable atypia or an invasive component and could represent an irritated infundibular cyst versus an early evolving KA.

The lichenoid inflammation is suspicious for HLP, which has been associated with eruptive KAs^13-16 and may have contributed to the development of persistent KAs in our patient, both in sites of surgical scars (the anterior aspect of the leg) and in uninvolved skin (the posterior aspect of the leg). Trauma from the prior surgery may have stimulated a local inflammatory response and, if coupled with a preexisting underlying chronic inflammatory condition such as HLP, may have triggered the development of new lesions on the posterior leg. Skin pathergy reactions also are caused by an upregulated inflammatory response, which is reduced with immunosuppressive agents such as MTX.¹²

In our patient, there was both an isotopic and isomorphic response. The term isotopic response refers to the occurrence of a new skin disorder at the site of another unrelated and already healed skin disease. It was first defined by Wolf and Wolf²⁰ in 1985 and hence is also known as Wolf isotopic response. The isotopic response in our patient occurred in the setting of lichen planus. The isomorphic response indicates the appearance of typical skin lesions of an existing dermatosis at sites of other skin injuries.

Initially, we thought the patient had recurrence of SCC, but with the rapid development of multiple lesions, the diagnosis of multiple KAs was more likely. Kimyai-Asadi et al⁸ demonstrated that surgical trauma can precede the development of KAs, as they reported a patient who developed a KA at an excision site. Tamir et al⁷ reported the simultaneous appearance of KAs in burn scars and skin graft donor sites 4 months after a 40% total body surface area burn. Hamilton et al¹¹ described surgical trauma from a split-skin graft donor site as a trigger for the onset of a KA.

Multiple treatment alternatives exist for KAs, with the standard of care for large or high-risk KAs being excisional surgery^21,22; however, other approaches may need to be considered in certain cases, such as with multiple KAs in which lesions may be large and extensive, thereby yielding poor cosmetic outcomes, or with increased surgical risk.²³ Furthermore, multiple KAs that develop in the setting of surgical scars require special consideration. Topical 5-fluorouracil, various systemic and intralesional agents (eg, retinoids, interferon, bleomycin, MTX), laser therapy, electrodesiccation and curettage, radiotherapy, and photodynamic therapy all have been reported as methods employed for the treatment of KA.^23-27 Goldberg et al⁵ reported cases of resolution of eruptive KAs arising in both surgical and nonsurgical sites with a combination of deep shave excision, MMS, curettage and desiccation, and oral isotretinoin.

For our patient, we opted for treatment with intralesional MTX, both due to its effectiveness for solitary KAs and reasonably decreased risk of morbidity compared to surgical excision of regions of the pretibial calves. Treatment with MTX would not have been attempted if there was any clinical doubt that the lesions were not the well-differentiated KA type. Also, we had a low threshold for discontinuing therapy and reverting to MMS treatment if any of the lesions displayed a paradoxical growth post-MTX treatment or failed to respond after 3 treatments. Intralesional MTX is less invasive, relatively inexpensive, and a treatment modality with decreased morbidity for KAs, especially for multiple KAs. It should be considered as a potential alternative to surgery in such cases.^23-27

Keratoacanthomas (KAs) are rapidly growing tumors most prominently found on sun-exposed areas of the skin. The normal progression of a KA is to show rapid growth followed by spontaneous resolution.¹ Most KAs are solitary; however, there are several variants of multiple KAs including the familial Ferguson-Smith type, Gryzbowski syndrome (generalized eruptive KAs), KA centrifugum marginatum, Muir-Torre syndrome, and xeroderma pigmentosum.^2-4 Keratoacanthomas also may develop in areas of trauma, including burns, laser treatment, radiation, and surgical margins from excisional biopsies or skin grafting.⁵ Treatment of multiple KAs can be difficult due to a potentially large field size and number of lesions.⁶ We present a case of multiple KAs developing both in the surgical margins and de novo that responded dramatically to treatment with intralesional methotrexate (MTX).

Case Report

A 55-year-old man with a history of a surgically treated squamous cell carcinoma (SCC) on the anterior aspect of the right leg developed multiple nodules involving the surgical scar. He previously underwent Mohs micrographic surgery (MMS); within a month after the second surgery the patient noticed increased pruritus along with scaly pink changes at the site of the surgical scar.

One month prior to presentation, biopsies from the anterior aspect of the right leg demonstrated well-differentiated SCC and he was subsequently treated with MMS; however, examination 1 month after MMS revealed an 11×7-cm indurated plaque with multiple nodules ranging from 1 to 2 cm near the periphery of the plaque with central atrophy and scarring, reminiscent of KA centrifugum marginatum (Figure, A). In a similar fashion, an 8×5-cm plaque composed of 7 nodular areas was noted on the posterior aspect of the right leg (Figure, B). The patient denied any history of trauma to this area. There was no palpable regional lymphadenopathy and the remainder of the skin examination was normal, except for signs of venous stasis in both legs.

Based on the location and morphology of the lesions, the clinical presentation was consistent with multiple KAs. Histologic examination from punch biopsies taken from the plaque's periphery demonstrated well-differentiated SCC (KA type), as well as a lichenoid inflammatory process, epidermal hyperplasia, and cystic and endophytic squamous proliferation suggestive of hypertrophic lichen planus (HLP).

In consideration of the size and number of the lesions as well as the prolonged wound healing with prior surgery, the patient consented to treatment with intralesional MTX (1 mL of 12.5 mg/mL every 2 weeks) rather than undergoing further surgery. The MTX injection was distributed between the lesions on the anterior and posterior aspects of the lower right leg. At each injection session, the size, thickness, and nodularity of the tumor decreased with markedly less pruritus and symptomatic relief was achieved. After 3 injection sessions, resulting in a total of 3 mL of 12.5 mg/mL of MTX, biopsies were taken from the residual atrophic scar on the anterior aspect of the right leg and the remaining 3 papules on the posterior aspect of the right leg to rule out HLP and invasive SCC. The pathology report commented on the presence of prurigo nodules without any evidence of SCC.

At 3-month follow-up, the patient demonstrated no new lesions or recurrence (Figure, C and D). The right leg continued to heal with scarring and postinflammatory pigmentary changes. The patient was monitored for recurrence and to determine the diagnosis of HLP.

Comment

We report the development of multiple KAs arising both from within surgical margins and de novo, and resolution with intralesional MTX. Keratoacanthomas, especially various KA types, have been observed to develop due to various types of trauma, including sites of surgical scars, lichen planus, tattoos, thermal burns, radiation, and discoid lupus erythematosus, and within skin grafts and donor sites.^5-19

Hypertrophic lichen planus is a chronic variant of lichen planus that often is found on the pretibial areas of the lower legs.¹³ Both SCC and reactive KAs have been observed to develop within lesions of HLP.¹⁴ Our pathologist commented on the presence of a lichenoid infiltrate with necrotic keratinocytes and epidermal hyperplasia suspicious for HLP, with a small focus of cystic and endophytic squamous proliferation. The latter lacked notable atypia or an invasive component and could represent an irritated infundibular cyst versus an early evolving KA.

The lichenoid inflammation is suspicious for HLP, which has been associated with eruptive KAs^13-16 and may have contributed to the development of persistent KAs in our patient, both in sites of surgical scars (the anterior aspect of the leg) and in uninvolved skin (the posterior aspect of the leg). Trauma from the prior surgery may have stimulated a local inflammatory response and, if coupled with a preexisting underlying chronic inflammatory condition such as HLP, may have triggered the development of new lesions on the posterior leg. Skin pathergy reactions also are caused by an upregulated inflammatory response, which is reduced with immunosuppressive agents such as MTX.¹²

In our patient, there was both an isotopic and isomorphic response. The term isotopic response refers to the occurrence of a new skin disorder at the site of another unrelated and already healed skin disease. It was first defined by Wolf and Wolf²⁰ in 1985 and hence is also known as Wolf isotopic response. The isotopic response in our patient occurred in the setting of lichen planus. The isomorphic response indicates the appearance of typical skin lesions of an existing dermatosis at sites of other skin injuries.

Initially, we thought the patient had recurrence of SCC, but with the rapid development of multiple lesions, the diagnosis of multiple KAs was more likely. Kimyai-Asadi et al⁸ demonstrated that surgical trauma can precede the development of KAs, as they reported a patient who developed a KA at an excision site. Tamir et al⁷ reported the simultaneous appearance of KAs in burn scars and skin graft donor sites 4 months after a 40% total body surface area burn. Hamilton et al¹¹ described surgical trauma from a split-skin graft donor site as a trigger for the onset of a KA.

Multiple treatment alternatives exist for KAs, with the standard of care for large or high-risk KAs being excisional surgery^21,22; however, other approaches may need to be considered in certain cases, such as with multiple KAs in which lesions may be large and extensive, thereby yielding poor cosmetic outcomes, or with increased surgical risk.²³ Furthermore, multiple KAs that develop in the setting of surgical scars require special consideration. Topical 5-fluorouracil, various systemic and intralesional agents (eg, retinoids, interferon, bleomycin, MTX), laser therapy, electrodesiccation and curettage, radiotherapy, and photodynamic therapy all have been reported as methods employed for the treatment of KA.^23-27 Goldberg et al⁵ reported cases of resolution of eruptive KAs arising in both surgical and nonsurgical sites with a combination of deep shave excision, MMS, curettage and desiccation, and oral isotretinoin.

For our patient, we opted for treatment with intralesional MTX, both due to its effectiveness for solitary KAs and reasonably decreased risk of morbidity compared to surgical excision of regions of the pretibial calves. Treatment with MTX would not have been attempted if there was any clinical doubt that the lesions were not the well-differentiated KA type. Also, we had a low threshold for discontinuing therapy and reverting to MMS treatment if any of the lesions displayed a paradoxical growth post-MTX treatment or failed to respond after 3 treatments. Intralesional MTX is less invasive, relatively inexpensive, and a treatment modality with decreased morbidity for KAs, especially for multiple KAs. It should be considered as a potential alternative to surgery in such cases.^23-27

Keratoacanthomas (KAs) are rapidly growing tumors most prominently found on sun-exposed areas of the skin. The normal progression of a KA is to show rapid growth followed by spontaneous resolution.¹ Most KAs are solitary; however, there are several variants of multiple KAs including the familial Ferguson-Smith type, Gryzbowski syndrome (generalized eruptive KAs), KA centrifugum marginatum, Muir-Torre syndrome, and xeroderma pigmentosum.^2-4 Keratoacanthomas also may develop in areas of trauma, including burns, laser treatment, radiation, and surgical margins from excisional biopsies or skin grafting.⁵ Treatment of multiple KAs can be difficult due to a potentially large field size and number of lesions.⁶ We present a case of multiple KAs developing both in the surgical margins and de novo that responded dramatically to treatment with intralesional methotrexate (MTX).

Case Report

A 55-year-old man with a history of a surgically treated squamous cell carcinoma (SCC) on the anterior aspect of the right leg developed multiple nodules involving the surgical scar. He previously underwent Mohs micrographic surgery (MMS); within a month after the second surgery the patient noticed increased pruritus along with scaly pink changes at the site of the surgical scar.

One month prior to presentation, biopsies from the anterior aspect of the right leg demonstrated well-differentiated SCC and he was subsequently treated with MMS; however, examination 1 month after MMS revealed an 11×7-cm indurated plaque with multiple nodules ranging from 1 to 2 cm near the periphery of the plaque with central atrophy and scarring, reminiscent of KA centrifugum marginatum (Figure, A). In a similar fashion, an 8×5-cm plaque composed of 7 nodular areas was noted on the posterior aspect of the right leg (Figure, B). The patient denied any history of trauma to this area. There was no palpable regional lymphadenopathy and the remainder of the skin examination was normal, except for signs of venous stasis in both legs.

Based on the location and morphology of the lesions, the clinical presentation was consistent with multiple KAs. Histologic examination from punch biopsies taken from the plaque's periphery demonstrated well-differentiated SCC (KA type), as well as a lichenoid inflammatory process, epidermal hyperplasia, and cystic and endophytic squamous proliferation suggestive of hypertrophic lichen planus (HLP).

In consideration of the size and number of the lesions as well as the prolonged wound healing with prior surgery, the patient consented to treatment with intralesional MTX (1 mL of 12.5 mg/mL every 2 weeks) rather than undergoing further surgery. The MTX injection was distributed between the lesions on the anterior and posterior aspects of the lower right leg. At each injection session, the size, thickness, and nodularity of the tumor decreased with markedly less pruritus and symptomatic relief was achieved. After 3 injection sessions, resulting in a total of 3 mL of 12.5 mg/mL of MTX, biopsies were taken from the residual atrophic scar on the anterior aspect of the right leg and the remaining 3 papules on the posterior aspect of the right leg to rule out HLP and invasive SCC. The pathology report commented on the presence of prurigo nodules without any evidence of SCC.

At 3-month follow-up, the patient demonstrated no new lesions or recurrence (Figure, C and D). The right leg continued to heal with scarring and postinflammatory pigmentary changes. The patient was monitored for recurrence and to determine the diagnosis of HLP.

Comment

We report the development of multiple KAs arising both from within surgical margins and de novo, and resolution with intralesional MTX. Keratoacanthomas, especially various KA types, have been observed to develop due to various types of trauma, including sites of surgical scars, lichen planus, tattoos, thermal burns, radiation, and discoid lupus erythematosus, and within skin grafts and donor sites.^5-19

Hypertrophic lichen planus is a chronic variant of lichen planus that often is found on the pretibial areas of the lower legs.¹³ Both SCC and reactive KAs have been observed to develop within lesions of HLP.¹⁴ Our pathologist commented on the presence of a lichenoid infiltrate with necrotic keratinocytes and epidermal hyperplasia suspicious for HLP, with a small focus of cystic and endophytic squamous proliferation. The latter lacked notable atypia or an invasive component and could represent an irritated infundibular cyst versus an early evolving KA.

The lichenoid inflammation is suspicious for HLP, which has been associated with eruptive KAs^13-16 and may have contributed to the development of persistent KAs in our patient, both in sites of surgical scars (the anterior aspect of the leg) and in uninvolved skin (the posterior aspect of the leg). Trauma from the prior surgery may have stimulated a local inflammatory response and, if coupled with a preexisting underlying chronic inflammatory condition such as HLP, may have triggered the development of new lesions on the posterior leg. Skin pathergy reactions also are caused by an upregulated inflammatory response, which is reduced with immunosuppressive agents such as MTX.¹²

In our patient, there was both an isotopic and isomorphic response. The term isotopic response refers to the occurrence of a new skin disorder at the site of another unrelated and already healed skin disease. It was first defined by Wolf and Wolf²⁰ in 1985 and hence is also known as Wolf isotopic response. The isotopic response in our patient occurred in the setting of lichen planus. The isomorphic response indicates the appearance of typical skin lesions of an existing dermatosis at sites of other skin injuries.

Initially, we thought the patient had recurrence of SCC, but with the rapid development of multiple lesions, the diagnosis of multiple KAs was more likely. Kimyai-Asadi et al⁸ demonstrated that surgical trauma can precede the development of KAs, as they reported a patient who developed a KA at an excision site. Tamir et al⁷ reported the simultaneous appearance of KAs in burn scars and skin graft donor sites 4 months after a 40% total body surface area burn. Hamilton et al¹¹ described surgical trauma from a split-skin graft donor site as a trigger for the onset of a KA.

Multiple treatment alternatives exist for KAs, with the standard of care for large or high-risk KAs being excisional surgery^21,22; however, other approaches may need to be considered in certain cases, such as with multiple KAs in which lesions may be large and extensive, thereby yielding poor cosmetic outcomes, or with increased surgical risk.²³ Furthermore, multiple KAs that develop in the setting of surgical scars require special consideration. Topical 5-fluorouracil, various systemic and intralesional agents (eg, retinoids, interferon, bleomycin, MTX), laser therapy, electrodesiccation and curettage, radiotherapy, and photodynamic therapy all have been reported as methods employed for the treatment of KA.^23-27 Goldberg et al⁵ reported cases of resolution of eruptive KAs arising in both surgical and nonsurgical sites with a combination of deep shave excision, MMS, curettage and desiccation, and oral isotretinoin.

For our patient, we opted for treatment with intralesional MTX, both due to its effectiveness for solitary KAs and reasonably decreased risk of morbidity compared to surgical excision of regions of the pretibial calves. Treatment with MTX would not have been attempted if there was any clinical doubt that the lesions were not the well-differentiated KA type. Also, we had a low threshold for discontinuing therapy and reverting to MMS treatment if any of the lesions displayed a paradoxical growth post-MTX treatment or failed to respond after 3 treatments. Intralesional MTX is less invasive, relatively inexpensive, and a treatment modality with decreased morbidity for KAs, especially for multiple KAs. It should be considered as a potential alternative to surgery in such cases.^23-27

To improve patient care and outcomes, leading dermatologists offered their recommendations on self-tanners. Consideration must be given to:

• Anthelios 50 Mineral Tinted
  La Roche-Posay Laboratoire Dermatologique
  Recommended by Gary Goldenberg, MD, New York, New York

• St. Tropez Self Tan products
  PZ Cussons Beauty LLP
  “It helps to produce an even and natural-looking skin tone.”—Anthony M. Rossi, MD, New York, New York

• Sun-Free Self-Tanning Formula
  Kiehl’s
  Recommended by Gary Goldenberg, MD, New York, New York

• Sunless Tanning Towelette
  Sun Bum
  “This product is easy to use. Make sure to use it in conjunction with a broad-spectrum sunscreen.”—Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Cleansing devices, skin-lightening products, and athlete’s foot treatments will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on self-tanners. Consideration must be given to:

• Anthelios 50 Mineral Tinted
  La Roche-Posay Laboratoire Dermatologique
  Recommended by Gary Goldenberg, MD, New York, New York

• St. Tropez Self Tan products
  PZ Cussons Beauty LLP
  “It helps to produce an even and natural-looking skin tone.”—Anthony M. Rossi, MD, New York, New York

• Sun-Free Self-Tanning Formula
  Kiehl’s
  Recommended by Gary Goldenberg, MD, New York, New York

• Sunless Tanning Towelette
  Sun Bum
  “This product is easy to use. Make sure to use it in conjunction with a broad-spectrum sunscreen.”—Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Cleansing devices, skin-lightening products, and athlete’s foot treatments will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on self-tanners. Consideration must be given to:

• Anthelios 50 Mineral Tinted
  La Roche-Posay Laboratoire Dermatologique
  Recommended by Gary Goldenberg, MD, New York, New York

• St. Tropez Self Tan products
  PZ Cussons Beauty LLP
  “It helps to produce an even and natural-looking skin tone.”—Anthony M. Rossi, MD, New York, New York

• Sun-Free Self-Tanning Formula
  Kiehl’s
  Recommended by Gary Goldenberg, MD, New York, New York

• Sunless Tanning Towelette
  Sun Bum
  “This product is easy to use. Make sure to use it in conjunction with a broad-spectrum sunscreen.”—Shari Lipner, MD, PhD, New York, New York

Cutis invites readers to send us their recommendations. Cleansing devices, skin-lightening products, and athlete’s foot treatments will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

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ORLANDO – Direct visualization with sonovaginography had greater success in predicting rectal/rectosigmoid deep infiltrating endometriosis than did negative transvaginal ultrasound uterine “sliding sign,” according to the findings of a prospective study of 189 women.

“Both performed quite well,” but sonovaginography was superior for predicting rectal deep infiltrating endometriosis on all measures, including accuracy – 92% vs. 88%, said Bassem Gerges, MBBS, an ob.gyn. at the University of Sydney, Kingswood.

Dr. Gerges and his colleagues evaluated 189 women of reproductive age who were scheduled for operative laparoscopy at a tertiary referral center for women. The patients had a history of chronic pelvic pain and/or endometriosis and presented between 2009 and 2013.

The women first had transvaginal ultrasound to determine if their uterine sliding sign was positive or negative, followed by sonovaginography to assess the posterior pelvic compartment for rectal or rectosigmoid deep infiltrating endometriosis. All patients then underwent laparoscopic surgery for endometriosis.

Laparoscopy revealed pouch of Douglas obliteration in 47 of the 189 women and rectal and/or rectosigmoid deep infiltrating endometriosis in 43 women.

The sensitivity of sonovaginography to predict deep infiltrating endometriosis was 88%, compared with 74% for the sliding-sign approach. Specificity was the same with the two methods at 93%. The positive predictive value was 79% vs. 74%, respectively, and the negative predictive value was 97% vs. 93%.

“These findings can help clinicians with preoperative planning,” Dr. Gerges said at the meeting, which was sponsored by AAGL.

Dr. Gerges and his colleagues also identified 11 false-negative cases in which the sliding sign was positive but laparoscopy confirmed rectal deep infiltrating endometriosis.

Previous research suggests that, in women with suspected endometriosis, a negative transvaginal ultrasound uterine sliding sign can predict rectal or rectosigmoid deep infiltrating endometriosis (Ultrasound Obstet Gynecol. 2013;41[6]:692-5, J Ultrasound Med. 2014;33:315-21). A negative sliding sign indicates the presence of uterorectal adhesions and whether the pouch of Douglas might be obliterated. The current study, however, suggested that sonovaginography might be the better method.

Dr. Gerges reported having no relevant financial disclosures.

ORLANDO – Direct visualization with sonovaginography had greater success in predicting rectal/rectosigmoid deep infiltrating endometriosis than did negative transvaginal ultrasound uterine “sliding sign,” according to the findings of a prospective study of 189 women.

“Both performed quite well,” but sonovaginography was superior for predicting rectal deep infiltrating endometriosis on all measures, including accuracy – 92% vs. 88%, said Bassem Gerges, MBBS, an ob.gyn. at the University of Sydney, Kingswood.

Dr. Gerges and his colleagues evaluated 189 women of reproductive age who were scheduled for operative laparoscopy at a tertiary referral center for women. The patients had a history of chronic pelvic pain and/or endometriosis and presented between 2009 and 2013.

The women first had transvaginal ultrasound to determine if their uterine sliding sign was positive or negative, followed by sonovaginography to assess the posterior pelvic compartment for rectal or rectosigmoid deep infiltrating endometriosis. All patients then underwent laparoscopic surgery for endometriosis.

Laparoscopy revealed pouch of Douglas obliteration in 47 of the 189 women and rectal and/or rectosigmoid deep infiltrating endometriosis in 43 women.

The sensitivity of sonovaginography to predict deep infiltrating endometriosis was 88%, compared with 74% for the sliding-sign approach. Specificity was the same with the two methods at 93%. The positive predictive value was 79% vs. 74%, respectively, and the negative predictive value was 97% vs. 93%.

“These findings can help clinicians with preoperative planning,” Dr. Gerges said at the meeting, which was sponsored by AAGL.

Dr. Gerges and his colleagues also identified 11 false-negative cases in which the sliding sign was positive but laparoscopy confirmed rectal deep infiltrating endometriosis.

Previous research suggests that, in women with suspected endometriosis, a negative transvaginal ultrasound uterine sliding sign can predict rectal or rectosigmoid deep infiltrating endometriosis (Ultrasound Obstet Gynecol. 2013;41[6]:692-5, J Ultrasound Med. 2014;33:315-21). A negative sliding sign indicates the presence of uterorectal adhesions and whether the pouch of Douglas might be obliterated. The current study, however, suggested that sonovaginography might be the better method.

Dr. Gerges reported having no relevant financial disclosures.

ORLANDO – Direct visualization with sonovaginography had greater success in predicting rectal/rectosigmoid deep infiltrating endometriosis than did negative transvaginal ultrasound uterine “sliding sign,” according to the findings of a prospective study of 189 women.

“Both performed quite well,” but sonovaginography was superior for predicting rectal deep infiltrating endometriosis on all measures, including accuracy – 92% vs. 88%, said Bassem Gerges, MBBS, an ob.gyn. at the University of Sydney, Kingswood.

Dr. Gerges and his colleagues evaluated 189 women of reproductive age who were scheduled for operative laparoscopy at a tertiary referral center for women. The patients had a history of chronic pelvic pain and/or endometriosis and presented between 2009 and 2013.

The women first had transvaginal ultrasound to determine if their uterine sliding sign was positive or negative, followed by sonovaginography to assess the posterior pelvic compartment for rectal or rectosigmoid deep infiltrating endometriosis. All patients then underwent laparoscopic surgery for endometriosis.

Laparoscopy revealed pouch of Douglas obliteration in 47 of the 189 women and rectal and/or rectosigmoid deep infiltrating endometriosis in 43 women.

The sensitivity of sonovaginography to predict deep infiltrating endometriosis was 88%, compared with 74% for the sliding-sign approach. Specificity was the same with the two methods at 93%. The positive predictive value was 79% vs. 74%, respectively, and the negative predictive value was 97% vs. 93%.

“These findings can help clinicians with preoperative planning,” Dr. Gerges said at the meeting, which was sponsored by AAGL.

Dr. Gerges and his colleagues also identified 11 false-negative cases in which the sliding sign was positive but laparoscopy confirmed rectal deep infiltrating endometriosis.

Previous research suggests that, in women with suspected endometriosis, a negative transvaginal ultrasound uterine sliding sign can predict rectal or rectosigmoid deep infiltrating endometriosis (Ultrasound Obstet Gynecol. 2013;41[6]:692-5, J Ultrasound Med. 2014;33:315-21). A negative sliding sign indicates the presence of uterorectal adhesions and whether the pouch of Douglas might be obliterated. The current study, however, suggested that sonovaginography might be the better method.

Dr. Gerges reported having no relevant financial disclosures.