A web-based intervention for management of nonalcoholic fatty liver disease – which researchers said may help reach busy or remote patients not able to attend in-person sessions – had a similar number of patients reach a target weight-loss goal of at least 10% of body weight, compared with a group-based intervention.

“The use of web education in the management of noncommunicable diseases has long been suggested, considering the huge number of cases at risk and patients’ needs,” wrote Arianna Mazzotti, MD, of the department of medical and surgical sciences, Alma Mater University, Bologna, Italy, and her colleagues. Their report was published in the Journal of Hepatology.

“The majority of cases are in an age range where job constraints make it difficult to implement a systematic face-to-face or group approach, whereas the eHealth procedures may keep the contact between patients and therapists without disrupting normal daily living.”

Dr. Mazzotti and her colleagues studied 716 patients with nonalcoholic fatty liver disease (NAFLD) at the university between January 2010 and December 2015 who attended either a web-based NAFLD intervention (278 patients) or an in-person, group-based lifestyle modification program (438 patients). Patients in the web-based intervention tended to be younger males with a higher education level, similar mean body mass index (33 kg/m²), and significantly lower blood pressure and rates of type 2 diabetes mellitus. The primary outcome included weight loss of at least 10%; secondary outcomes included changes in weight, changes in lifestyle, surrogate markers of steatosis and fibrosis, and alanine aminotransferase (ALT) within normal limits, researchers said.

The group-based program consisted of five 2-hour weekly sessions counseling patients on diet and physical activity, whereas the web-based intervention reproduced these sessions in addition to questionnaires, “highly interactive” slides, examples, and games as well as a mechanism to ask questions. Regardless of intervention, patients attended a 6-month in-person follow-up where they received treatment and reinforcement for comorbidities such as type 2 diabetes mellitus.

In the web-based intervention, 76% of patients attended the 6-month follow-up, 58% attended the 12-month follow-up, and 43% attended the 24-month follow-up, compared with 87%, 80%, and 69% of patients in the group-based intervention, respectively. Patients in the web-based intervention had a significantly decreased intake of calories after 6 months (273 kcal/day vs. 193 kcal/day; P = .006) compared with the group-based intervention. Physical activity significantly increased at 6 months for both groups, but there were no significant differences between groups.

Body weight decreased for the web-based intervention by 3.4% at 6 months, 4.9% at 12 months, and 5.5% at 24 months, compared with 3.1% at 6 months, 4.0% at 12 months, and 4.2% at 24 months in the group-based intervention. There was a nearly two-point reduction in body mass index for both groups, with 20% of web-based intervention patients and 15% of group-based intervention patients achieving the 10% weight-loss target; and, when the researchers performed a logistic regression analysis, the web-based intervention group was not associated with less short- and long-term 10% weight reduction after attrition rates and confounders were adjusted for.

At 24-month follow-up, the researchers found a decrease in ALT levels by an average of 22 ± 32 mU/mL, with the web-based intervention group having normalized ALT levels in 18% of cases at 6 months, 32% at 12 months, and 35% at 24 months, compared with 16% of cases at 6 months, 22% of cases at 12 months, and 29% of cases at 24 months in the group-based intervention. Compared with the group-based intervention, there was a higher reduction in fatty liver index scores at 12-month follow-up (71.3 vs. 78.0; P less than .001) and 24-month follow-up (68.9 vs. 76.3; P = .002) for the web-based intervention group. The researchers noted NAFLD fibrosis score and Fib-4 scores were reduced in both groups.

“The [web-based intervention] program might be extended to other units and/or general practitioners, increasing its impact in the community in prevention and treatment of progressive NAFLD,” Dr. Mazzotti and her colleagues wrote. “It might also be superimposed to drug treatment in the most severe cases, with possible additive effects.”

This study was supported by a grant from the European Community Seventh Framework Program. The authors report no relevant conflicts of interest.

*This story was updated on 10/4/2018.

SOURCE: Mazzotti A et al. J Hepatol. 2018 Oct 2. doi: 10.1016/j.jhep.2018.07.013.

A web-based intervention for management of nonalcoholic fatty liver disease – which researchers said may help reach busy or remote patients not able to attend in-person sessions – had a similar number of patients reach a target weight-loss goal of at least 10% of body weight, compared with a group-based intervention.

“The use of web education in the management of noncommunicable diseases has long been suggested, considering the huge number of cases at risk and patients’ needs,” wrote Arianna Mazzotti, MD, of the department of medical and surgical sciences, Alma Mater University, Bologna, Italy, and her colleagues. Their report was published in the Journal of Hepatology.

“The majority of cases are in an age range where job constraints make it difficult to implement a systematic face-to-face or group approach, whereas the eHealth procedures may keep the contact between patients and therapists without disrupting normal daily living.”

Dr. Mazzotti and her colleagues studied 716 patients with nonalcoholic fatty liver disease (NAFLD) at the university between January 2010 and December 2015 who attended either a web-based NAFLD intervention (278 patients) or an in-person, group-based lifestyle modification program (438 patients). Patients in the web-based intervention tended to be younger males with a higher education level, similar mean body mass index (33 kg/m²), and significantly lower blood pressure and rates of type 2 diabetes mellitus. The primary outcome included weight loss of at least 10%; secondary outcomes included changes in weight, changes in lifestyle, surrogate markers of steatosis and fibrosis, and alanine aminotransferase (ALT) within normal limits, researchers said.

The group-based program consisted of five 2-hour weekly sessions counseling patients on diet and physical activity, whereas the web-based intervention reproduced these sessions in addition to questionnaires, “highly interactive” slides, examples, and games as well as a mechanism to ask questions. Regardless of intervention, patients attended a 6-month in-person follow-up where they received treatment and reinforcement for comorbidities such as type 2 diabetes mellitus.

In the web-based intervention, 76% of patients attended the 6-month follow-up, 58% attended the 12-month follow-up, and 43% attended the 24-month follow-up, compared with 87%, 80%, and 69% of patients in the group-based intervention, respectively. Patients in the web-based intervention had a significantly decreased intake of calories after 6 months (273 kcal/day vs. 193 kcal/day; P = .006) compared with the group-based intervention. Physical activity significantly increased at 6 months for both groups, but there were no significant differences between groups.

Body weight decreased for the web-based intervention by 3.4% at 6 months, 4.9% at 12 months, and 5.5% at 24 months, compared with 3.1% at 6 months, 4.0% at 12 months, and 4.2% at 24 months in the group-based intervention. There was a nearly two-point reduction in body mass index for both groups, with 20% of web-based intervention patients and 15% of group-based intervention patients achieving the 10% weight-loss target; and, when the researchers performed a logistic regression analysis, the web-based intervention group was not associated with less short- and long-term 10% weight reduction after attrition rates and confounders were adjusted for.

At 24-month follow-up, the researchers found a decrease in ALT levels by an average of 22 ± 32 mU/mL, with the web-based intervention group having normalized ALT levels in 18% of cases at 6 months, 32% at 12 months, and 35% at 24 months, compared with 16% of cases at 6 months, 22% of cases at 12 months, and 29% of cases at 24 months in the group-based intervention. Compared with the group-based intervention, there was a higher reduction in fatty liver index scores at 12-month follow-up (71.3 vs. 78.0; P less than .001) and 24-month follow-up (68.9 vs. 76.3; P = .002) for the web-based intervention group. The researchers noted NAFLD fibrosis score and Fib-4 scores were reduced in both groups.

“The [web-based intervention] program might be extended to other units and/or general practitioners, increasing its impact in the community in prevention and treatment of progressive NAFLD,” Dr. Mazzotti and her colleagues wrote. “It might also be superimposed to drug treatment in the most severe cases, with possible additive effects.”

This study was supported by a grant from the European Community Seventh Framework Program. The authors report no relevant conflicts of interest.

*This story was updated on 10/4/2018.

SOURCE: Mazzotti A et al. J Hepatol. 2018 Oct 2. doi: 10.1016/j.jhep.2018.07.013.

A web-based intervention for management of nonalcoholic fatty liver disease – which researchers said may help reach busy or remote patients not able to attend in-person sessions – had a similar number of patients reach a target weight-loss goal of at least 10% of body weight, compared with a group-based intervention.

“The use of web education in the management of noncommunicable diseases has long been suggested, considering the huge number of cases at risk and patients’ needs,” wrote Arianna Mazzotti, MD, of the department of medical and surgical sciences, Alma Mater University, Bologna, Italy, and her colleagues. Their report was published in the Journal of Hepatology.

“The majority of cases are in an age range where job constraints make it difficult to implement a systematic face-to-face or group approach, whereas the eHealth procedures may keep the contact between patients and therapists without disrupting normal daily living.”

Dr. Mazzotti and her colleagues studied 716 patients with nonalcoholic fatty liver disease (NAFLD) at the university between January 2010 and December 2015 who attended either a web-based NAFLD intervention (278 patients) or an in-person, group-based lifestyle modification program (438 patients). Patients in the web-based intervention tended to be younger males with a higher education level, similar mean body mass index (33 kg/m²), and significantly lower blood pressure and rates of type 2 diabetes mellitus. The primary outcome included weight loss of at least 10%; secondary outcomes included changes in weight, changes in lifestyle, surrogate markers of steatosis and fibrosis, and alanine aminotransferase (ALT) within normal limits, researchers said.

The group-based program consisted of five 2-hour weekly sessions counseling patients on diet and physical activity, whereas the web-based intervention reproduced these sessions in addition to questionnaires, “highly interactive” slides, examples, and games as well as a mechanism to ask questions. Regardless of intervention, patients attended a 6-month in-person follow-up where they received treatment and reinforcement for comorbidities such as type 2 diabetes mellitus.

In the web-based intervention, 76% of patients attended the 6-month follow-up, 58% attended the 12-month follow-up, and 43% attended the 24-month follow-up, compared with 87%, 80%, and 69% of patients in the group-based intervention, respectively. Patients in the web-based intervention had a significantly decreased intake of calories after 6 months (273 kcal/day vs. 193 kcal/day; P = .006) compared with the group-based intervention. Physical activity significantly increased at 6 months for both groups, but there were no significant differences between groups.

Body weight decreased for the web-based intervention by 3.4% at 6 months, 4.9% at 12 months, and 5.5% at 24 months, compared with 3.1% at 6 months, 4.0% at 12 months, and 4.2% at 24 months in the group-based intervention. There was a nearly two-point reduction in body mass index for both groups, with 20% of web-based intervention patients and 15% of group-based intervention patients achieving the 10% weight-loss target; and, when the researchers performed a logistic regression analysis, the web-based intervention group was not associated with less short- and long-term 10% weight reduction after attrition rates and confounders were adjusted for.

At 24-month follow-up, the researchers found a decrease in ALT levels by an average of 22 ± 32 mU/mL, with the web-based intervention group having normalized ALT levels in 18% of cases at 6 months, 32% at 12 months, and 35% at 24 months, compared with 16% of cases at 6 months, 22% of cases at 12 months, and 29% of cases at 24 months in the group-based intervention. Compared with the group-based intervention, there was a higher reduction in fatty liver index scores at 12-month follow-up (71.3 vs. 78.0; P less than .001) and 24-month follow-up (68.9 vs. 76.3; P = .002) for the web-based intervention group. The researchers noted NAFLD fibrosis score and Fib-4 scores were reduced in both groups.

“The [web-based intervention] program might be extended to other units and/or general practitioners, increasing its impact in the community in prevention and treatment of progressive NAFLD,” Dr. Mazzotti and her colleagues wrote. “It might also be superimposed to drug treatment in the most severe cases, with possible additive effects.”

This study was supported by a grant from the European Community Seventh Framework Program. The authors report no relevant conflicts of interest.

*This story was updated on 10/4/2018.

SOURCE: Mazzotti A et al. J Hepatol. 2018 Oct 2. doi: 10.1016/j.jhep.2018.07.013.

Antibiotics are associated with increased large intestinal proteolytic activity and gut barrier disruption, thereby raising the risk of chronic colitis in susceptible individuals, a recent study found.

Although the association between antibiotics and chronic colitis has been previously described, this is the first study to demonstrate the causative role of high proteolytic activity, reported lead author Hongsup Yoon, PhD, chair of nutrition and immunology at Technische Universität München in Freising-Weihenstephan, Germany, and colleagues. The team’s experiments support development of antiproteolytic strategies in susceptible humans.

“In the context of IBD, several clinical studies have already revealed that early and frequent antibiotic therapies, especially metronidazole or fluoroquinolone treatments, are associated with increased risk for Crohn’s disease,” the authors wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, the causal role of antibiotic therapies in the disease development and the mechanisms underlying this [potentially] serious long-term adverse effect of antibiotics on the intestinal immune homeostasis remain unknown.”

Previous studies have shown that antibiotic therapy often causes high luminal proteolytic activity in the large intestine, likely because of the elimination of antiproteolytic bacteria that normally control pancreatic protease levels. Other studies have shown that exposing murine colonic mucosa to fecal supernatants with high proteolytic activity increases gut barrier permeability, which triggers chronic inflammation via translocation of luminal antigens.

“In view of these data,” the authors wrote, “we hypothesized that the antibiotic-increased proteolytic activity in the large intestine is a relevant risk factor for the development of colitis in susceptible organisms.”

The first component of the study used transwell experiments to evaluate the impact of high proteolytic activity on gut barrier integrity. High proteolytic activity was induced by several antibiotics, including fluoroquinolones with or without an imidazole (ciprofloxacin and levofloxacin plus or minus metronidazole), a beta-lactam (amoxicillin + clavulanate), cephalosporins with or without a macrolide (azithromycin and ceftriaxone plus or minus azithromycin), and a rifamycin (rifaximin).

“All tested antibiotic classes mediated a major proteolytic activity increase in some patients but not in others,” the authors wrote, “demonstrating individual-specific vulnerability of the intestinal microbiota toward antibiotic therapies, which is likely caused by the high interindividual variability of human microbial ecosystems.”

One-quarter of patients had a 400% or greater increase in large intestinal proteolytic activity following antibiotic therapy, and several had an increase greater than 900%. Analysis indicated that proteolytic activity was caused by pancreatic proteases such as chymotrypsin and trypsin.

Subsequent cell line testing showed that stool supernatants with high proteolytic activity damaged the epithelial barrier, but samples with low proteolytic activity did not. Of note, the negative impact of high proteolytic activity on epithelial cells could be mitigated by incubating stool supernatants with a serine protease inhibitor.

In analogous experiments, mice were given a combination of vancomycin and metronidazole (V/M). In contrast with the various proteolytic activity levels observed in humans, all mice had high proteolytic activity levels following treatment, suggesting that V/M eliminated almost all antiproteolytic bacteria.

The loss of antiproteolytic bacteria was clarified by cecal microbiota transplantation tests. Transplants from untreated mice were capable of normalizing proteolytic activity levels in germ-free mice (which have high proteolytic activity levels), but transplants from V/M-treated mice were ineffective, suggesting a near-total loss of antiproteolytic bacteria. The identity of these antiproteolytic bacteria remains a mystery.

“Although our data are in line with published literature suggesting specific strains of the order Bacteroidales to play a role in the physiological inactivation of pancreatic proteases,” the authors wrote, “the identity of relevant antiproteolytic species/strains remains to be elucidated.”

The next part of the study involved wild-type and interleukin (IL)-10–/– mice, the latter of which serves as a model of human colitis. Both types of mice were given V/M with or without an oral serine protease inhibitor, a potential therapy intended to limit proteolytic activity and associated intestinal barrier damage.

Although both wild-type and IL-10–/– mice had increased intestinal permeability after V/M treatment, only IL-10–/– mice showed lasting inflammation. Of note, coadministration of an oral serine protease inhibitor with V/M protected against colitis in IL-10–/– mice.

The protective benefit of an oral serine protease inhibitor in IL-10–/– mice prompts the development of antiproteolytic strategies in humans. These would target “large intestinal proteolytic activity [e.g., oral administration of encapsulated serine protease inhibitors, commensal antiproteolytic bacteria, or genetically modified bacteria expressing protease inhibitors] to protect the large intestinal mucosa from adverse effects of antibiotic-induced or diarrhea-induced high proteolytic activity,” the authors wrote.

The study was funded by the Deutscher Akademischer Austauschdienst. No conflicts of interest were reported.

SOURCE: Yoon H-S et al. Cell Mol Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.jcmgh.2018.05.008.

Antibiotics are associated with increased large intestinal proteolytic activity and gut barrier disruption, thereby raising the risk of chronic colitis in susceptible individuals, a recent study found.

Although the association between antibiotics and chronic colitis has been previously described, this is the first study to demonstrate the causative role of high proteolytic activity, reported lead author Hongsup Yoon, PhD, chair of nutrition and immunology at Technische Universität München in Freising-Weihenstephan, Germany, and colleagues. The team’s experiments support development of antiproteolytic strategies in susceptible humans.

“In the context of IBD, several clinical studies have already revealed that early and frequent antibiotic therapies, especially metronidazole or fluoroquinolone treatments, are associated with increased risk for Crohn’s disease,” the authors wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, the causal role of antibiotic therapies in the disease development and the mechanisms underlying this [potentially] serious long-term adverse effect of antibiotics on the intestinal immune homeostasis remain unknown.”

Previous studies have shown that antibiotic therapy often causes high luminal proteolytic activity in the large intestine, likely because of the elimination of antiproteolytic bacteria that normally control pancreatic protease levels. Other studies have shown that exposing murine colonic mucosa to fecal supernatants with high proteolytic activity increases gut barrier permeability, which triggers chronic inflammation via translocation of luminal antigens.

“In view of these data,” the authors wrote, “we hypothesized that the antibiotic-increased proteolytic activity in the large intestine is a relevant risk factor for the development of colitis in susceptible organisms.”

The first component of the study used transwell experiments to evaluate the impact of high proteolytic activity on gut barrier integrity. High proteolytic activity was induced by several antibiotics, including fluoroquinolones with or without an imidazole (ciprofloxacin and levofloxacin plus or minus metronidazole), a beta-lactam (amoxicillin + clavulanate), cephalosporins with or without a macrolide (azithromycin and ceftriaxone plus or minus azithromycin), and a rifamycin (rifaximin).

“All tested antibiotic classes mediated a major proteolytic activity increase in some patients but not in others,” the authors wrote, “demonstrating individual-specific vulnerability of the intestinal microbiota toward antibiotic therapies, which is likely caused by the high interindividual variability of human microbial ecosystems.”

One-quarter of patients had a 400% or greater increase in large intestinal proteolytic activity following antibiotic therapy, and several had an increase greater than 900%. Analysis indicated that proteolytic activity was caused by pancreatic proteases such as chymotrypsin and trypsin.

Subsequent cell line testing showed that stool supernatants with high proteolytic activity damaged the epithelial barrier, but samples with low proteolytic activity did not. Of note, the negative impact of high proteolytic activity on epithelial cells could be mitigated by incubating stool supernatants with a serine protease inhibitor.

In analogous experiments, mice were given a combination of vancomycin and metronidazole (V/M). In contrast with the various proteolytic activity levels observed in humans, all mice had high proteolytic activity levels following treatment, suggesting that V/M eliminated almost all antiproteolytic bacteria.

The loss of antiproteolytic bacteria was clarified by cecal microbiota transplantation tests. Transplants from untreated mice were capable of normalizing proteolytic activity levels in germ-free mice (which have high proteolytic activity levels), but transplants from V/M-treated mice were ineffective, suggesting a near-total loss of antiproteolytic bacteria. The identity of these antiproteolytic bacteria remains a mystery.

“Although our data are in line with published literature suggesting specific strains of the order Bacteroidales to play a role in the physiological inactivation of pancreatic proteases,” the authors wrote, “the identity of relevant antiproteolytic species/strains remains to be elucidated.”

The next part of the study involved wild-type and interleukin (IL)-10–/– mice, the latter of which serves as a model of human colitis. Both types of mice were given V/M with or without an oral serine protease inhibitor, a potential therapy intended to limit proteolytic activity and associated intestinal barrier damage.

Although both wild-type and IL-10–/– mice had increased intestinal permeability after V/M treatment, only IL-10–/– mice showed lasting inflammation. Of note, coadministration of an oral serine protease inhibitor with V/M protected against colitis in IL-10–/– mice.

The protective benefit of an oral serine protease inhibitor in IL-10–/– mice prompts the development of antiproteolytic strategies in humans. These would target “large intestinal proteolytic activity [e.g., oral administration of encapsulated serine protease inhibitors, commensal antiproteolytic bacteria, or genetically modified bacteria expressing protease inhibitors] to protect the large intestinal mucosa from adverse effects of antibiotic-induced or diarrhea-induced high proteolytic activity,” the authors wrote.

The study was funded by the Deutscher Akademischer Austauschdienst. No conflicts of interest were reported.

SOURCE: Yoon H-S et al. Cell Mol Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.jcmgh.2018.05.008.

Antibiotics are associated with increased large intestinal proteolytic activity and gut barrier disruption, thereby raising the risk of chronic colitis in susceptible individuals, a recent study found.

Although the association between antibiotics and chronic colitis has been previously described, this is the first study to demonstrate the causative role of high proteolytic activity, reported lead author Hongsup Yoon, PhD, chair of nutrition and immunology at Technische Universität München in Freising-Weihenstephan, Germany, and colleagues. The team’s experiments support development of antiproteolytic strategies in susceptible humans.

“In the context of IBD, several clinical studies have already revealed that early and frequent antibiotic therapies, especially metronidazole or fluoroquinolone treatments, are associated with increased risk for Crohn’s disease,” the authors wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, the causal role of antibiotic therapies in the disease development and the mechanisms underlying this [potentially] serious long-term adverse effect of antibiotics on the intestinal immune homeostasis remain unknown.”

Previous studies have shown that antibiotic therapy often causes high luminal proteolytic activity in the large intestine, likely because of the elimination of antiproteolytic bacteria that normally control pancreatic protease levels. Other studies have shown that exposing murine colonic mucosa to fecal supernatants with high proteolytic activity increases gut barrier permeability, which triggers chronic inflammation via translocation of luminal antigens.

“In view of these data,” the authors wrote, “we hypothesized that the antibiotic-increased proteolytic activity in the large intestine is a relevant risk factor for the development of colitis in susceptible organisms.”

The first component of the study used transwell experiments to evaluate the impact of high proteolytic activity on gut barrier integrity. High proteolytic activity was induced by several antibiotics, including fluoroquinolones with or without an imidazole (ciprofloxacin and levofloxacin plus or minus metronidazole), a beta-lactam (amoxicillin + clavulanate), cephalosporins with or without a macrolide (azithromycin and ceftriaxone plus or minus azithromycin), and a rifamycin (rifaximin).

“All tested antibiotic classes mediated a major proteolytic activity increase in some patients but not in others,” the authors wrote, “demonstrating individual-specific vulnerability of the intestinal microbiota toward antibiotic therapies, which is likely caused by the high interindividual variability of human microbial ecosystems.”

One-quarter of patients had a 400% or greater increase in large intestinal proteolytic activity following antibiotic therapy, and several had an increase greater than 900%. Analysis indicated that proteolytic activity was caused by pancreatic proteases such as chymotrypsin and trypsin.

Subsequent cell line testing showed that stool supernatants with high proteolytic activity damaged the epithelial barrier, but samples with low proteolytic activity did not. Of note, the negative impact of high proteolytic activity on epithelial cells could be mitigated by incubating stool supernatants with a serine protease inhibitor.

In analogous experiments, mice were given a combination of vancomycin and metronidazole (V/M). In contrast with the various proteolytic activity levels observed in humans, all mice had high proteolytic activity levels following treatment, suggesting that V/M eliminated almost all antiproteolytic bacteria.

The loss of antiproteolytic bacteria was clarified by cecal microbiota transplantation tests. Transplants from untreated mice were capable of normalizing proteolytic activity levels in germ-free mice (which have high proteolytic activity levels), but transplants from V/M-treated mice were ineffective, suggesting a near-total loss of antiproteolytic bacteria. The identity of these antiproteolytic bacteria remains a mystery.

“Although our data are in line with published literature suggesting specific strains of the order Bacteroidales to play a role in the physiological inactivation of pancreatic proteases,” the authors wrote, “the identity of relevant antiproteolytic species/strains remains to be elucidated.”

The next part of the study involved wild-type and interleukin (IL)-10–/– mice, the latter of which serves as a model of human colitis. Both types of mice were given V/M with or without an oral serine protease inhibitor, a potential therapy intended to limit proteolytic activity and associated intestinal barrier damage.

Although both wild-type and IL-10–/– mice had increased intestinal permeability after V/M treatment, only IL-10–/– mice showed lasting inflammation. Of note, coadministration of an oral serine protease inhibitor with V/M protected against colitis in IL-10–/– mice.

The protective benefit of an oral serine protease inhibitor in IL-10–/– mice prompts the development of antiproteolytic strategies in humans. These would target “large intestinal proteolytic activity [e.g., oral administration of encapsulated serine protease inhibitors, commensal antiproteolytic bacteria, or genetically modified bacteria expressing protease inhibitors] to protect the large intestinal mucosa from adverse effects of antibiotic-induced or diarrhea-induced high proteolytic activity,” the authors wrote.

The study was funded by the Deutscher Akademischer Austauschdienst. No conflicts of interest were reported.

SOURCE: Yoon H-S et al. Cell Mol Gastroenterol Hepatol. 2018 May 29. doi: 10.1016/j.jcmgh.2018.05.008.

Nevus sebaceus (NS) is a benign hair follicle neoplasm present in approximately 1.3% of the population, typically involving the scalp, neck, or face.¹ These lesions usually are present at birth or identified soon after, during the first year. They present as a yellowish hairless patch or plaque but can develop a more papillomatous appearance, especially after puberty. Historically, the concern with NS was its tendency to transform into basal cell carcinoma (BCC), which prompted surgical excision of the lesion during childhood. This theory has been discounted more recently, as further research has suggested that what was once thought to be BCC may have been confused with the similarly appearing trichoblastoma; however, malignant transformation of NS does still occur, with BCC still being the most common.² We present the case of a long-standing NS with rare transformation to apocrine carcinoma.

Case Report

A 76-year-old woman presented with several new lesions within a previously diagnosed NS. She reported having the large plaque for as long as she could recall but reported that several new growths developed within the plaque over the last 2 months, slowly increasing in size. She reported a prior biopsy within the growth several years prior, which she described as an irritated seborrheic keratosis.

Physical examination demonstrated 4 distinct lesions within the flesh-colored, verrucous plaque located on the left side of the temporal scalp (Figure 1). The first lesion was a 2.5-cm pearly, pink, exophytic tumor (labeled as A in Figure 1). The next 2 lesions were brown, pedunculated, verrucous papules (labeled as B and C in Figure 1). The last lesion was a purple papule (labeled as D in Figure 1). Four shave biopsies were performed for histologic analysis of the lesions. Lesions B, C, and D were consistent with trichoblastomas, as pathology showed basaloid epithelial tumors that displayed primitive follicular structures, areas of stromal induction, and some pigmentation. Lesion A, originally thought to be suspicious for a BCC, was determined to be a primary cutaneous apocrine adenocarcinoma upon pathologic review. The pathology showed a dermal tumor displaying solid and tubular areas with decapitation secretion. Nuclear pleomorphism and mitoses were present (Figure 2), and staining for carcinoembryonic antigen was positive (Figure 3). Immunoreactivity with epithelial membrane antigen and cytokeratin 7 was noted as well as focal positivity for mammaglobin. Primary apocrine carcinoma was favored over metastatic carcinoma due to the location of the lesion within an NS along with a negative history of internal malignancy. Dermatopathology recommended complete removal of all lesions within the NS.

Comment

Presentation
Nevus sebaceus is the most common adnexal tumor and is classified as a benign congenital hair follicle tumor that is located most commonly on the scalp but also occurs on the face and neck.¹ The lesions usually are present at birth but also can develop during the first year of life.² Diagnosis may be later, during adolescence, when patients seek medical attention during the lesion’s rapid growth phase.¹ Nevus sebaceus also is known as an organoid nevus because it may contain all components of the skin. It was originally identified by Jadassohn in 1895.³ It presents as a yellowish, smooth, hairless patch or plaque in prepubertal patients. During adolescence, the lesion typically becomes more yellowish, as well as papillomatous, scaly, or warty. The reported incidence of NS is 0.05% to 1% in dermatology patients.²

Differential
Nevus sebaceus also is a component of several syndromes that should be kept in mind, including Schimmelpenning-Feuerstein-Mims syndrome, which presents with neurologic, skeletal, genitourinary, cardiovascular, and ophthalmic disorders, in addition to cutaneous features. Others include phacomatosis pigmentokeratotica, didmyosis aplasticosebacea, SCALP syndrome (sebaceus nevus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus), and more.^4,5

Etiology
The etiology of NS has not been completely determined. One study that evaluated 44 NS tissue samples suggested the presence of human papillomavirus (HPV) in NS formation, finding that 82% of NS lesions studied contained HPV DNA. From these results, Carlson et al⁶ suggested a possible maternal transmission of HPV and infection of ectodermal cells as a potential cause of NS; however, this hypothesis was soon challenged by a study that showed a complete absence of HPV in 16 samples via histological evaluation and polymerase chain reaction for a broad range of HPV types.⁷ There were investigations into a patched (PTCH) deletion as the cause of NS and thus explained the historically high rate of secondary BCC.⁸ Further studies showed no mutations at the PTCH locus in trichoblastomas or other tumors arising from NS.^9,10

More recent studies have recognized HRAS and KRAS mutations as a causative factor in NS.¹¹ Nevus sebaceus belongs to a group of syndromes resulting from lethal mutations that survive via mosaicism. Nevus sebaceus is caused by postzygotic HRAS or KRAS mutations and is known as a mosaic RASopathy.¹² In fact, there is growing evidence to suggest that other nevoid proliferations including keratinocytic epidermal nevi and melanocytic nevi also fall into the spectrum of mosaic RASopathies.¹³

Staging
There are 3 clinical stages of NS, originally described by Mehregan and Pinkus.¹⁴ In stage I (historically known as the infantile stage), the lesion presents as a yellow to pink, smooth, hairless patch. Histologic features include immature hair follicles and hypoplastic sebaceous glands. In stage II (also known as the puberty stage), the lesion becomes more pronounced. Firmer plaques can develop with hyperkeratosis. Hormonal changes cause sebaceous glands to develop, accompanied by epidermal hyperplasia and maturation of apocrine glands. Stage III (the tumoral stage) is a period that various neoplasms have the highest likelihood of occurring. Nevus sebaceus in an adolescent or adult demonstrates mature adnexal structures and greater epidermal hyperplasia.^2,4,15

Malignancy
By virtue of these stages of NS development, malignant transformation is expected most often during stage III. However, cases have been reported of malignant tumor development in NS in children before puberty. Two case reports described a 7-year-old boy and a 10-year-old boy diagnosed with a BCC arising from an NS.^16,17 However, secondary BCC formation before 16 years of age is rare. Basal cell carcinoma arising from an NS has been commonly reported and is the most common malignant neoplasm in NS (1.1%).^2,3 However, the most common neoplasm overall is trichoblastoma (7.4%). The second most common tumor was syringocystadenoma papilliferum, occurring in approximately 5.2% of NS cases. The neoplasm rate in NS was found to be proportional to the patient age.^2,18 Multiple studies have shown the overall rate of secondary neoplasms in NS to be 13% to 21.4%, with malignant tumors composing 0.8% to 2.5%.^2,15,19 Other neoplasms that have been reported include keratoacanthoma, trichilemmoma, sebaceoma, nevocellular nevus, squamous cell carcinoma, adnexal carcinoma, apocrine adenocarcinoma, and malignant melanoma.^19-21

It is argued that the reported rate of BCC formation is overestimated, as prior studies incorrectly labeled trichoblastomas as BCCs. In fact, the largest studies of NS from the 1990s revealed lower rates of malignant secondary tumors than previously determined.⁴

The identification of apocrine adenocarcinoma tumors arising from NS is exceedingly rare. A study performed by Cribier et al¹⁹ in 2000 retrospectively analyzed 596 cases of excised NS from 1932 to 1998. No apocrine carcinomas were reported in this study.¹⁹ Approximately 12 cases have been previously reported throughout the literature.^20-26 Apocrine carcinomas occur most frequently in apocrine-rich areas such as the axillae, external ears, eyelids, and anogenital area. However, in the cases with apocrine carcinomas that developed from NS, the carcinomas have been located almost exclusively on the scalp.²³

Histopathology
Histopathologic examination reveals considerable variation in morphology, and an underlying pattern has been difficult to recognize. Unfortunately, some authors have concluded that the diagnosis of apocrine carcinoma is relatively subjective.²⁶ Robson et al²⁶ identified 3 general architectural patterns: tubular, tubulopapillary, and solid. Tubular structures consisted of glands and ducts lined by a single or multilayered epithelium. Tubulopapillary architecture was characterized by epithelium forming papillary folds without a fibrovascular core. The solid morphology showed sheets of cells with limited ductal or tubular formation.²⁶ The most specific criteria of these apocrine carcinomas are identification of decapitation secretion, periodic acid–Schiff–positive diastase-resistant material present in the cells or lumen, and positive immunostaining for gross cystic disease fluid protein-15.²⁷

Robson et al²⁶ reported estrogen receptor positivity and androgen receptor positivity in 62% and 64% of 24 primary apocrine carcinoma cases, respectively. However, whether these markers are as common in NS-related apocrine carcinomas has yet to be noted in the literature. One study reports a case of apocrine carcinoma from NS with positive staining for human epidermal growth factor-2, a cell membrane receptor tyrosine kinase commonly investigated in breast cancers and extramammary Paget disease.²²

These apocrine carcinomas do have the potential for lymphatic metastasis, as seen with multiple studies. Domingo and Helwig²¹ identified regional lymph node metastasis in 2 of its 4 apocrine carcinoma patients. Robson et al²⁶ reported lymphovascular invasion in 4 cases and perineural invasion in 2 of 24 patients studied. However, even in the context of recurrence and regional metastasis, the prognosis was good and seldom fatal.²⁶

Treatment
The most effective treatment of NS is excision of dermal and epidermal components. Excision should be completed with a minimum of 2- to 3-mm margins and full thickness down to the underlying supporting fat.²⁸ Historically, the practice of prophylactic excision of NS was supported by the potential for malignant transformation; however, early excision of NS may be less reasonable in light of these more recent studies showing lower incidence of BCC (0.8%), replaced by benign trichoblastomas.¹⁹ In the case of apocrine carcinoma development, excision is undoubtedly recommended, with unclear recommendations regarding further evaluation for metastasis.

Excision also may be favored for cosmetic purposes, given the visible regions where NS tends to develop. Chepla and Gosain²⁹ argued that surgical intervention should be based on other factors such as location on the scalp, alopecia, and other issues affecting appearance and monitoring rather than incidence of malignant transformation. Close monitoring and biopsy of suspicious areas is a more conservative option.

Other therapies include CO₂ laser, as demonstrated by Kiedrowicz et al,³⁰ on linear NS in a patient with Schimmelpenning-Feuerstein-Mims syndrome.³¹ However, this approach is palliative and not effective in removing the entire lesion. Electrodesiccation and curettage and dermabrasion also are not good options for the same reason.⁴

Occurrence in Children
Nevus sebaceus in children, accompanied by other findings suggestive of epidermal nevus syndromes, should prompt further investigation. Schimmelpenning-Feuerstein-Mims syndrome includes major neurological abnormalities including hemimegalencephaly and seizures.³²

Conclusion

Apocrine carcinomas are malignant neoplasms that may rarely arise within an NS. Their clinical identification is difficult and requires histopathologic evaluation. Upon recognition, prompt excision with tumor-free margins is recommended. As a rare entity, little data is available regarding its metastatic potential or overall survival rates. Further investigation is clearly necessary as new cases arise.

Nevus sebaceus (NS) is a benign hair follicle neoplasm present in approximately 1.3% of the population, typically involving the scalp, neck, or face.¹ These lesions usually are present at birth or identified soon after, during the first year. They present as a yellowish hairless patch or plaque but can develop a more papillomatous appearance, especially after puberty. Historically, the concern with NS was its tendency to transform into basal cell carcinoma (BCC), which prompted surgical excision of the lesion during childhood. This theory has been discounted more recently, as further research has suggested that what was once thought to be BCC may have been confused with the similarly appearing trichoblastoma; however, malignant transformation of NS does still occur, with BCC still being the most common.² We present the case of a long-standing NS with rare transformation to apocrine carcinoma.

Case Report

A 76-year-old woman presented with several new lesions within a previously diagnosed NS. She reported having the large plaque for as long as she could recall but reported that several new growths developed within the plaque over the last 2 months, slowly increasing in size. She reported a prior biopsy within the growth several years prior, which she described as an irritated seborrheic keratosis.

Physical examination demonstrated 4 distinct lesions within the flesh-colored, verrucous plaque located on the left side of the temporal scalp (Figure 1). The first lesion was a 2.5-cm pearly, pink, exophytic tumor (labeled as A in Figure 1). The next 2 lesions were brown, pedunculated, verrucous papules (labeled as B and C in Figure 1). The last lesion was a purple papule (labeled as D in Figure 1). Four shave biopsies were performed for histologic analysis of the lesions. Lesions B, C, and D were consistent with trichoblastomas, as pathology showed basaloid epithelial tumors that displayed primitive follicular structures, areas of stromal induction, and some pigmentation. Lesion A, originally thought to be suspicious for a BCC, was determined to be a primary cutaneous apocrine adenocarcinoma upon pathologic review. The pathology showed a dermal tumor displaying solid and tubular areas with decapitation secretion. Nuclear pleomorphism and mitoses were present (Figure 2), and staining for carcinoembryonic antigen was positive (Figure 3). Immunoreactivity with epithelial membrane antigen and cytokeratin 7 was noted as well as focal positivity for mammaglobin. Primary apocrine carcinoma was favored over metastatic carcinoma due to the location of the lesion within an NS along with a negative history of internal malignancy. Dermatopathology recommended complete removal of all lesions within the NS.

Comment

Presentation
Nevus sebaceus is the most common adnexal tumor and is classified as a benign congenital hair follicle tumor that is located most commonly on the scalp but also occurs on the face and neck.¹ The lesions usually are present at birth but also can develop during the first year of life.² Diagnosis may be later, during adolescence, when patients seek medical attention during the lesion’s rapid growth phase.¹ Nevus sebaceus also is known as an organoid nevus because it may contain all components of the skin. It was originally identified by Jadassohn in 1895.³ It presents as a yellowish, smooth, hairless patch or plaque in prepubertal patients. During adolescence, the lesion typically becomes more yellowish, as well as papillomatous, scaly, or warty. The reported incidence of NS is 0.05% to 1% in dermatology patients.²

Differential
Nevus sebaceus also is a component of several syndromes that should be kept in mind, including Schimmelpenning-Feuerstein-Mims syndrome, which presents with neurologic, skeletal, genitourinary, cardiovascular, and ophthalmic disorders, in addition to cutaneous features. Others include phacomatosis pigmentokeratotica, didmyosis aplasticosebacea, SCALP syndrome (sebaceus nevus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus), and more.^4,5

Etiology
The etiology of NS has not been completely determined. One study that evaluated 44 NS tissue samples suggested the presence of human papillomavirus (HPV) in NS formation, finding that 82% of NS lesions studied contained HPV DNA. From these results, Carlson et al⁶ suggested a possible maternal transmission of HPV and infection of ectodermal cells as a potential cause of NS; however, this hypothesis was soon challenged by a study that showed a complete absence of HPV in 16 samples via histological evaluation and polymerase chain reaction for a broad range of HPV types.⁷ There were investigations into a patched (PTCH) deletion as the cause of NS and thus explained the historically high rate of secondary BCC.⁸ Further studies showed no mutations at the PTCH locus in trichoblastomas or other tumors arising from NS.^9,10

More recent studies have recognized HRAS and KRAS mutations as a causative factor in NS.¹¹ Nevus sebaceus belongs to a group of syndromes resulting from lethal mutations that survive via mosaicism. Nevus sebaceus is caused by postzygotic HRAS or KRAS mutations and is known as a mosaic RASopathy.¹² In fact, there is growing evidence to suggest that other nevoid proliferations including keratinocytic epidermal nevi and melanocytic nevi also fall into the spectrum of mosaic RASopathies.¹³

Staging
There are 3 clinical stages of NS, originally described by Mehregan and Pinkus.¹⁴ In stage I (historically known as the infantile stage), the lesion presents as a yellow to pink, smooth, hairless patch. Histologic features include immature hair follicles and hypoplastic sebaceous glands. In stage II (also known as the puberty stage), the lesion becomes more pronounced. Firmer plaques can develop with hyperkeratosis. Hormonal changes cause sebaceous glands to develop, accompanied by epidermal hyperplasia and maturation of apocrine glands. Stage III (the tumoral stage) is a period that various neoplasms have the highest likelihood of occurring. Nevus sebaceus in an adolescent or adult demonstrates mature adnexal structures and greater epidermal hyperplasia.^2,4,15

Malignancy
By virtue of these stages of NS development, malignant transformation is expected most often during stage III. However, cases have been reported of malignant tumor development in NS in children before puberty. Two case reports described a 7-year-old boy and a 10-year-old boy diagnosed with a BCC arising from an NS.^16,17 However, secondary BCC formation before 16 years of age is rare. Basal cell carcinoma arising from an NS has been commonly reported and is the most common malignant neoplasm in NS (1.1%).^2,3 However, the most common neoplasm overall is trichoblastoma (7.4%). The second most common tumor was syringocystadenoma papilliferum, occurring in approximately 5.2% of NS cases. The neoplasm rate in NS was found to be proportional to the patient age.^2,18 Multiple studies have shown the overall rate of secondary neoplasms in NS to be 13% to 21.4%, with malignant tumors composing 0.8% to 2.5%.^2,15,19 Other neoplasms that have been reported include keratoacanthoma, trichilemmoma, sebaceoma, nevocellular nevus, squamous cell carcinoma, adnexal carcinoma, apocrine adenocarcinoma, and malignant melanoma.^19-21

It is argued that the reported rate of BCC formation is overestimated, as prior studies incorrectly labeled trichoblastomas as BCCs. In fact, the largest studies of NS from the 1990s revealed lower rates of malignant secondary tumors than previously determined.⁴

The identification of apocrine adenocarcinoma tumors arising from NS is exceedingly rare. A study performed by Cribier et al¹⁹ in 2000 retrospectively analyzed 596 cases of excised NS from 1932 to 1998. No apocrine carcinomas were reported in this study.¹⁹ Approximately 12 cases have been previously reported throughout the literature.^20-26 Apocrine carcinomas occur most frequently in apocrine-rich areas such as the axillae, external ears, eyelids, and anogenital area. However, in the cases with apocrine carcinomas that developed from NS, the carcinomas have been located almost exclusively on the scalp.²³

Histopathology
Histopathologic examination reveals considerable variation in morphology, and an underlying pattern has been difficult to recognize. Unfortunately, some authors have concluded that the diagnosis of apocrine carcinoma is relatively subjective.²⁶ Robson et al²⁶ identified 3 general architectural patterns: tubular, tubulopapillary, and solid. Tubular structures consisted of glands and ducts lined by a single or multilayered epithelium. Tubulopapillary architecture was characterized by epithelium forming papillary folds without a fibrovascular core. The solid morphology showed sheets of cells with limited ductal or tubular formation.²⁶ The most specific criteria of these apocrine carcinomas are identification of decapitation secretion, periodic acid–Schiff–positive diastase-resistant material present in the cells or lumen, and positive immunostaining for gross cystic disease fluid protein-15.²⁷

Robson et al²⁶ reported estrogen receptor positivity and androgen receptor positivity in 62% and 64% of 24 primary apocrine carcinoma cases, respectively. However, whether these markers are as common in NS-related apocrine carcinomas has yet to be noted in the literature. One study reports a case of apocrine carcinoma from NS with positive staining for human epidermal growth factor-2, a cell membrane receptor tyrosine kinase commonly investigated in breast cancers and extramammary Paget disease.²²

These apocrine carcinomas do have the potential for lymphatic metastasis, as seen with multiple studies. Domingo and Helwig²¹ identified regional lymph node metastasis in 2 of its 4 apocrine carcinoma patients. Robson et al²⁶ reported lymphovascular invasion in 4 cases and perineural invasion in 2 of 24 patients studied. However, even in the context of recurrence and regional metastasis, the prognosis was good and seldom fatal.²⁶

Treatment
The most effective treatment of NS is excision of dermal and epidermal components. Excision should be completed with a minimum of 2- to 3-mm margins and full thickness down to the underlying supporting fat.²⁸ Historically, the practice of prophylactic excision of NS was supported by the potential for malignant transformation; however, early excision of NS may be less reasonable in light of these more recent studies showing lower incidence of BCC (0.8%), replaced by benign trichoblastomas.¹⁹ In the case of apocrine carcinoma development, excision is undoubtedly recommended, with unclear recommendations regarding further evaluation for metastasis.

Excision also may be favored for cosmetic purposes, given the visible regions where NS tends to develop. Chepla and Gosain²⁹ argued that surgical intervention should be based on other factors such as location on the scalp, alopecia, and other issues affecting appearance and monitoring rather than incidence of malignant transformation. Close monitoring and biopsy of suspicious areas is a more conservative option.

Other therapies include CO₂ laser, as demonstrated by Kiedrowicz et al,³⁰ on linear NS in a patient with Schimmelpenning-Feuerstein-Mims syndrome.³¹ However, this approach is palliative and not effective in removing the entire lesion. Electrodesiccation and curettage and dermabrasion also are not good options for the same reason.⁴

Occurrence in Children
Nevus sebaceus in children, accompanied by other findings suggestive of epidermal nevus syndromes, should prompt further investigation. Schimmelpenning-Feuerstein-Mims syndrome includes major neurological abnormalities including hemimegalencephaly and seizures.³²

Conclusion

Apocrine carcinomas are malignant neoplasms that may rarely arise within an NS. Their clinical identification is difficult and requires histopathologic evaluation. Upon recognition, prompt excision with tumor-free margins is recommended. As a rare entity, little data is available regarding its metastatic potential or overall survival rates. Further investigation is clearly necessary as new cases arise.

Nevus sebaceus (NS) is a benign hair follicle neoplasm present in approximately 1.3% of the population, typically involving the scalp, neck, or face.¹ These lesions usually are present at birth or identified soon after, during the first year. They present as a yellowish hairless patch or plaque but can develop a more papillomatous appearance, especially after puberty. Historically, the concern with NS was its tendency to transform into basal cell carcinoma (BCC), which prompted surgical excision of the lesion during childhood. This theory has been discounted more recently, as further research has suggested that what was once thought to be BCC may have been confused with the similarly appearing trichoblastoma; however, malignant transformation of NS does still occur, with BCC still being the most common.² We present the case of a long-standing NS with rare transformation to apocrine carcinoma.

Case Report

A 76-year-old woman presented with several new lesions within a previously diagnosed NS. She reported having the large plaque for as long as she could recall but reported that several new growths developed within the plaque over the last 2 months, slowly increasing in size. She reported a prior biopsy within the growth several years prior, which she described as an irritated seborrheic keratosis.

Physical examination demonstrated 4 distinct lesions within the flesh-colored, verrucous plaque located on the left side of the temporal scalp (Figure 1). The first lesion was a 2.5-cm pearly, pink, exophytic tumor (labeled as A in Figure 1). The next 2 lesions were brown, pedunculated, verrucous papules (labeled as B and C in Figure 1). The last lesion was a purple papule (labeled as D in Figure 1). Four shave biopsies were performed for histologic analysis of the lesions. Lesions B, C, and D were consistent with trichoblastomas, as pathology showed basaloid epithelial tumors that displayed primitive follicular structures, areas of stromal induction, and some pigmentation. Lesion A, originally thought to be suspicious for a BCC, was determined to be a primary cutaneous apocrine adenocarcinoma upon pathologic review. The pathology showed a dermal tumor displaying solid and tubular areas with decapitation secretion. Nuclear pleomorphism and mitoses were present (Figure 2), and staining for carcinoembryonic antigen was positive (Figure 3). Immunoreactivity with epithelial membrane antigen and cytokeratin 7 was noted as well as focal positivity for mammaglobin. Primary apocrine carcinoma was favored over metastatic carcinoma due to the location of the lesion within an NS along with a negative history of internal malignancy. Dermatopathology recommended complete removal of all lesions within the NS.

Comment

Presentation
Nevus sebaceus is the most common adnexal tumor and is classified as a benign congenital hair follicle tumor that is located most commonly on the scalp but also occurs on the face and neck.¹ The lesions usually are present at birth but also can develop during the first year of life.² Diagnosis may be later, during adolescence, when patients seek medical attention during the lesion’s rapid growth phase.¹ Nevus sebaceus also is known as an organoid nevus because it may contain all components of the skin. It was originally identified by Jadassohn in 1895.³ It presents as a yellowish, smooth, hairless patch or plaque in prepubertal patients. During adolescence, the lesion typically becomes more yellowish, as well as papillomatous, scaly, or warty. The reported incidence of NS is 0.05% to 1% in dermatology patients.²

Differential
Nevus sebaceus also is a component of several syndromes that should be kept in mind, including Schimmelpenning-Feuerstein-Mims syndrome, which presents with neurologic, skeletal, genitourinary, cardiovascular, and ophthalmic disorders, in addition to cutaneous features. Others include phacomatosis pigmentokeratotica, didmyosis aplasticosebacea, SCALP syndrome (sebaceus nevus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus), and more.^4,5

Etiology
The etiology of NS has not been completely determined. One study that evaluated 44 NS tissue samples suggested the presence of human papillomavirus (HPV) in NS formation, finding that 82% of NS lesions studied contained HPV DNA. From these results, Carlson et al⁶ suggested a possible maternal transmission of HPV and infection of ectodermal cells as a potential cause of NS; however, this hypothesis was soon challenged by a study that showed a complete absence of HPV in 16 samples via histological evaluation and polymerase chain reaction for a broad range of HPV types.⁷ There were investigations into a patched (PTCH) deletion as the cause of NS and thus explained the historically high rate of secondary BCC.⁸ Further studies showed no mutations at the PTCH locus in trichoblastomas or other tumors arising from NS.^9,10

More recent studies have recognized HRAS and KRAS mutations as a causative factor in NS.¹¹ Nevus sebaceus belongs to a group of syndromes resulting from lethal mutations that survive via mosaicism. Nevus sebaceus is caused by postzygotic HRAS or KRAS mutations and is known as a mosaic RASopathy.¹² In fact, there is growing evidence to suggest that other nevoid proliferations including keratinocytic epidermal nevi and melanocytic nevi also fall into the spectrum of mosaic RASopathies.¹³

Staging
There are 3 clinical stages of NS, originally described by Mehregan and Pinkus.¹⁴ In stage I (historically known as the infantile stage), the lesion presents as a yellow to pink, smooth, hairless patch. Histologic features include immature hair follicles and hypoplastic sebaceous glands. In stage II (also known as the puberty stage), the lesion becomes more pronounced. Firmer plaques can develop with hyperkeratosis. Hormonal changes cause sebaceous glands to develop, accompanied by epidermal hyperplasia and maturation of apocrine glands. Stage III (the tumoral stage) is a period that various neoplasms have the highest likelihood of occurring. Nevus sebaceus in an adolescent or adult demonstrates mature adnexal structures and greater epidermal hyperplasia.^2,4,15

Malignancy
By virtue of these stages of NS development, malignant transformation is expected most often during stage III. However, cases have been reported of malignant tumor development in NS in children before puberty. Two case reports described a 7-year-old boy and a 10-year-old boy diagnosed with a BCC arising from an NS.^16,17 However, secondary BCC formation before 16 years of age is rare. Basal cell carcinoma arising from an NS has been commonly reported and is the most common malignant neoplasm in NS (1.1%).^2,3 However, the most common neoplasm overall is trichoblastoma (7.4%). The second most common tumor was syringocystadenoma papilliferum, occurring in approximately 5.2% of NS cases. The neoplasm rate in NS was found to be proportional to the patient age.^2,18 Multiple studies have shown the overall rate of secondary neoplasms in NS to be 13% to 21.4%, with malignant tumors composing 0.8% to 2.5%.^2,15,19 Other neoplasms that have been reported include keratoacanthoma, trichilemmoma, sebaceoma, nevocellular nevus, squamous cell carcinoma, adnexal carcinoma, apocrine adenocarcinoma, and malignant melanoma.^19-21

It is argued that the reported rate of BCC formation is overestimated, as prior studies incorrectly labeled trichoblastomas as BCCs. In fact, the largest studies of NS from the 1990s revealed lower rates of malignant secondary tumors than previously determined.⁴

The identification of apocrine adenocarcinoma tumors arising from NS is exceedingly rare. A study performed by Cribier et al¹⁹ in 2000 retrospectively analyzed 596 cases of excised NS from 1932 to 1998. No apocrine carcinomas were reported in this study.¹⁹ Approximately 12 cases have been previously reported throughout the literature.^20-26 Apocrine carcinomas occur most frequently in apocrine-rich areas such as the axillae, external ears, eyelids, and anogenital area. However, in the cases with apocrine carcinomas that developed from NS, the carcinomas have been located almost exclusively on the scalp.²³

Histopathology
Histopathologic examination reveals considerable variation in morphology, and an underlying pattern has been difficult to recognize. Unfortunately, some authors have concluded that the diagnosis of apocrine carcinoma is relatively subjective.²⁶ Robson et al²⁶ identified 3 general architectural patterns: tubular, tubulopapillary, and solid. Tubular structures consisted of glands and ducts lined by a single or multilayered epithelium. Tubulopapillary architecture was characterized by epithelium forming papillary folds without a fibrovascular core. The solid morphology showed sheets of cells with limited ductal or tubular formation.²⁶ The most specific criteria of these apocrine carcinomas are identification of decapitation secretion, periodic acid–Schiff–positive diastase-resistant material present in the cells or lumen, and positive immunostaining for gross cystic disease fluid protein-15.²⁷

Robson et al²⁶ reported estrogen receptor positivity and androgen receptor positivity in 62% and 64% of 24 primary apocrine carcinoma cases, respectively. However, whether these markers are as common in NS-related apocrine carcinomas has yet to be noted in the literature. One study reports a case of apocrine carcinoma from NS with positive staining for human epidermal growth factor-2, a cell membrane receptor tyrosine kinase commonly investigated in breast cancers and extramammary Paget disease.²²

These apocrine carcinomas do have the potential for lymphatic metastasis, as seen with multiple studies. Domingo and Helwig²¹ identified regional lymph node metastasis in 2 of its 4 apocrine carcinoma patients. Robson et al²⁶ reported lymphovascular invasion in 4 cases and perineural invasion in 2 of 24 patients studied. However, even in the context of recurrence and regional metastasis, the prognosis was good and seldom fatal.²⁶

Treatment
The most effective treatment of NS is excision of dermal and epidermal components. Excision should be completed with a minimum of 2- to 3-mm margins and full thickness down to the underlying supporting fat.²⁸ Historically, the practice of prophylactic excision of NS was supported by the potential for malignant transformation; however, early excision of NS may be less reasonable in light of these more recent studies showing lower incidence of BCC (0.8%), replaced by benign trichoblastomas.¹⁹ In the case of apocrine carcinoma development, excision is undoubtedly recommended, with unclear recommendations regarding further evaluation for metastasis.

Excision also may be favored for cosmetic purposes, given the visible regions where NS tends to develop. Chepla and Gosain²⁹ argued that surgical intervention should be based on other factors such as location on the scalp, alopecia, and other issues affecting appearance and monitoring rather than incidence of malignant transformation. Close monitoring and biopsy of suspicious areas is a more conservative option.

Other therapies include CO₂ laser, as demonstrated by Kiedrowicz et al,³⁰ on linear NS in a patient with Schimmelpenning-Feuerstein-Mims syndrome.³¹ However, this approach is palliative and not effective in removing the entire lesion. Electrodesiccation and curettage and dermabrasion also are not good options for the same reason.⁴

Occurrence in Children
Nevus sebaceus in children, accompanied by other findings suggestive of epidermal nevus syndromes, should prompt further investigation. Schimmelpenning-Feuerstein-Mims syndrome includes major neurological abnormalities including hemimegalencephaly and seizures.³²

Conclusion

Apocrine carcinomas are malignant neoplasms that may rarely arise within an NS. Their clinical identification is difficult and requires histopathologic evaluation. Upon recognition, prompt excision with tumor-free margins is recommended. As a rare entity, little data is available regarding its metastatic potential or overall survival rates. Further investigation is clearly necessary as new cases arise.

The safety profile for adalimumab in children is similar to that of adults, according to findings published in the Journal of Pediatrics.

Lori Farmer/MDedge News

In an analysis of data from seven clinical trials from 2002-2015, the most common adverse events across indications were upper respiratory tract infection (24 events per 100 patient-years), nasopharyngitis (17 events per 100 PY), and headache (20 events per 100 PY). Serious infections were the most frequent adverse events across indications (8% of all patients; 4 events per 100 PY), reported Gerd Horneff, MD, of the department of general pediatrics at Asklepios Klinik Sankt Augustin (Germany), and his coauthors.

All of the clinical trials were funded by AbbVie, and included 577 pediatric patients with juvenile idiopathic arthritis (JIA), psoriasis, or Crohn’s disease. Patients received subcutaneous injection of adalimumab at a dosage of either 40 mg/0.8 mL or 20 mg/0.4 mL.

Adverse events that occurred after the first adalimumab dose and up to 70 days after the last dose were included. Serious adverse events were defined as “events that were fatal or immediately life-threatening; required inpatient or prolonged hospitalization; resulted in persistent or significant disability/incapacity, congenital anomaly, or spontaneous or elective abortion; or required medical or surgical intervention to prevent a serious outcome,” the authors said.

Infections occurred in 82% of JIA patients (151 events per 100 PY), 74% of patients with psoriasis (169 events per 100 PY), and 76% of patients with CD (132 events per 100 PY). The most common events for JIA, psoriasis, and Crohn’s were injection-site pain (22% of patients; 75 events per 100 PY), headache (30% of patients; 47 events per 100 PY), and worsening of Crohn’s disease (55% of patients; 37 events per 100 PY), respectively.

Serious adverse events occurred in 29% of patients. Rates for JIA, psoriasis, and Crohn’s were 14, 7, and 32 events per 100 PY, respectively. Serious infections were the most common serious adverse event, with rates of 3, 1, and 7 events per 100 PY for JIA, psoriasis, and Crohn’s disease, respectively. Pneumonia was the most commonly reported serious infection (1% of patients; 1 event per 100 PY). One death, due to an accidental fall, occurred in an adolescent patient with psoriasis.

The study findings add to “a more complete understanding of the established safety profile of adalimumab,” and suggest that in pediatric patients, “the overall safety profile was comparable and consistent with that in adults,” Dr. Horneff and his associates added.

AbbVie funded the study. Dr. Horneff has received grants from AbbVie, Chugai, Novartis, Pfizer, and Roche. Seven of the investigators are or were employees of AbbVie and may own AbbVie stock and stock options. Two of the investigators disclosed ties with a number of pharmaceutical companies.

SOURCE: Horneff G et al. J Pediatr. 2018 Oct. doi: 10.1016/j.jpeds.2018.05.042.

The safety profile for adalimumab in children is similar to that of adults, according to findings published in the Journal of Pediatrics.

Lori Farmer/MDedge News

In an analysis of data from seven clinical trials from 2002-2015, the most common adverse events across indications were upper respiratory tract infection (24 events per 100 patient-years), nasopharyngitis (17 events per 100 PY), and headache (20 events per 100 PY). Serious infections were the most frequent adverse events across indications (8% of all patients; 4 events per 100 PY), reported Gerd Horneff, MD, of the department of general pediatrics at Asklepios Klinik Sankt Augustin (Germany), and his coauthors.

All of the clinical trials were funded by AbbVie, and included 577 pediatric patients with juvenile idiopathic arthritis (JIA), psoriasis, or Crohn’s disease. Patients received subcutaneous injection of adalimumab at a dosage of either 40 mg/0.8 mL or 20 mg/0.4 mL.

Adverse events that occurred after the first adalimumab dose and up to 70 days after the last dose were included. Serious adverse events were defined as “events that were fatal or immediately life-threatening; required inpatient or prolonged hospitalization; resulted in persistent or significant disability/incapacity, congenital anomaly, or spontaneous or elective abortion; or required medical or surgical intervention to prevent a serious outcome,” the authors said.

Infections occurred in 82% of JIA patients (151 events per 100 PY), 74% of patients with psoriasis (169 events per 100 PY), and 76% of patients with CD (132 events per 100 PY). The most common events for JIA, psoriasis, and Crohn’s were injection-site pain (22% of patients; 75 events per 100 PY), headache (30% of patients; 47 events per 100 PY), and worsening of Crohn’s disease (55% of patients; 37 events per 100 PY), respectively.

Serious adverse events occurred in 29% of patients. Rates for JIA, psoriasis, and Crohn’s were 14, 7, and 32 events per 100 PY, respectively. Serious infections were the most common serious adverse event, with rates of 3, 1, and 7 events per 100 PY for JIA, psoriasis, and Crohn’s disease, respectively. Pneumonia was the most commonly reported serious infection (1% of patients; 1 event per 100 PY). One death, due to an accidental fall, occurred in an adolescent patient with psoriasis.

The study findings add to “a more complete understanding of the established safety profile of adalimumab,” and suggest that in pediatric patients, “the overall safety profile was comparable and consistent with that in adults,” Dr. Horneff and his associates added.

AbbVie funded the study. Dr. Horneff has received grants from AbbVie, Chugai, Novartis, Pfizer, and Roche. Seven of the investigators are or were employees of AbbVie and may own AbbVie stock and stock options. Two of the investigators disclosed ties with a number of pharmaceutical companies.

SOURCE: Horneff G et al. J Pediatr. 2018 Oct. doi: 10.1016/j.jpeds.2018.05.042.

The safety profile for adalimumab in children is similar to that of adults, according to findings published in the Journal of Pediatrics.

Lori Farmer/MDedge News

In an analysis of data from seven clinical trials from 2002-2015, the most common adverse events across indications were upper respiratory tract infection (24 events per 100 patient-years), nasopharyngitis (17 events per 100 PY), and headache (20 events per 100 PY). Serious infections were the most frequent adverse events across indications (8% of all patients; 4 events per 100 PY), reported Gerd Horneff, MD, of the department of general pediatrics at Asklepios Klinik Sankt Augustin (Germany), and his coauthors.

All of the clinical trials were funded by AbbVie, and included 577 pediatric patients with juvenile idiopathic arthritis (JIA), psoriasis, or Crohn’s disease. Patients received subcutaneous injection of adalimumab at a dosage of either 40 mg/0.8 mL or 20 mg/0.4 mL.

Adverse events that occurred after the first adalimumab dose and up to 70 days after the last dose were included. Serious adverse events were defined as “events that were fatal or immediately life-threatening; required inpatient or prolonged hospitalization; resulted in persistent or significant disability/incapacity, congenital anomaly, or spontaneous or elective abortion; or required medical or surgical intervention to prevent a serious outcome,” the authors said.

Infections occurred in 82% of JIA patients (151 events per 100 PY), 74% of patients with psoriasis (169 events per 100 PY), and 76% of patients with CD (132 events per 100 PY). The most common events for JIA, psoriasis, and Crohn’s were injection-site pain (22% of patients; 75 events per 100 PY), headache (30% of patients; 47 events per 100 PY), and worsening of Crohn’s disease (55% of patients; 37 events per 100 PY), respectively.

Serious adverse events occurred in 29% of patients. Rates for JIA, psoriasis, and Crohn’s were 14, 7, and 32 events per 100 PY, respectively. Serious infections were the most common serious adverse event, with rates of 3, 1, and 7 events per 100 PY for JIA, psoriasis, and Crohn’s disease, respectively. Pneumonia was the most commonly reported serious infection (1% of patients; 1 event per 100 PY). One death, due to an accidental fall, occurred in an adolescent patient with psoriasis.

The study findings add to “a more complete understanding of the established safety profile of adalimumab,” and suggest that in pediatric patients, “the overall safety profile was comparable and consistent with that in adults,” Dr. Horneff and his associates added.

AbbVie funded the study. Dr. Horneff has received grants from AbbVie, Chugai, Novartis, Pfizer, and Roche. Seven of the investigators are or were employees of AbbVie and may own AbbVie stock and stock options. Two of the investigators disclosed ties with a number of pharmaceutical companies.

SOURCE: Horneff G et al. J Pediatr. 2018 Oct. doi: 10.1016/j.jpeds.2018.05.042.

SAN DIEGO – Following in the wake of a previous prospective comparison of ketamine and haloperidol for control of severe prehospital agitation, a new prospective study by the same group and presented at the annual meeting of the American College of Emergency Physicians found ketamine superior to midazolam for the same indication.

“The difference between the two drugs was larger when agitation was more profound,” reported Jon B. Cole, MD, an emergency medicine physician at Hennepin Healthcare and associate professor of emergency medicine at the University of Minnesota, Minneapolis.

Relative to ketamine (Ketalar), midazolam (Versed) was associated with fewer side effects, “so for less agitated patients, midazolam may still be the preferred therapy,” he added in his late-breaker presentation.

In recent years, ketamine has become a popular drug in emergency medical services for control of agitation, according to Dr. Cole, but he said that this approach has been adopted with relatively limited support from objective evidence. In his literature search, only 2 of 11 original studies that addressed ketamine for agitation involved prospective comparative studies.

One of those prior prospective studies was one Dr. Cole led and published 2 years ago (Clin Toxicol. 2016;54:556-62). In that study, comparing 5 mg/kg of intramuscular (IM) ketamine to 10 mg IM haloperidol, ketamine had a faster onset (median 5 vs. 17 minutes) but produced more side effects, including higher rates of intubation (39% vs. 4%).

In the new prospective study, ketamine and midazolam were compared over separate consecutive 6-month periods in which ketamine and then midazolam were employed as the dominant strategy for agitation control. This was the same open-label, nonrandomized design used for the comparison of ketamine and haloperidol, but with one difference. When the Altered Mental Status Score was +2 or +3, considered severe agitation, patients received 3 mg/kg of IM ketamine or 5 mg of IM midazolam. When the AMS score was +4, called profound agitation, the doses were 5 mg/kg and 15 mg, respectively.

The primary result was that adequate sedation overall was achieved in a median 4.3 minutes on ketamine but 8.8 minutes on midazolam, producing a more than 3-minute advantage for ketamine, which translated into an odds ratio (OR) of 1.8 for adequate agitation control favoring ketamine, according to Dr. Cole. In those with severe agitation, the median advantage was less than 2 minutes, but the OR of 1.6 remained significant. In those with profound agitation, the mean difference climbed above 5 minutes with an OR of 2.5.

Unlike the comparison with haloperidol, ketamine was not associated with a significantly higher risk of intubation or other airway related events, but Dr. Cole did report that midazolam was better tolerated. On the lower doses of the two drugs, for example, adverse events that were more common on ketamine than midazolam included vomiting (7% vs. 1%) and hypersalivation (20% vs. 0%).

In addition to the nonrandomized design, one limitation was unequal numbers of patients in the comparative groups. Only 113 were treated with midazolam while 202 patients were treated with ketamine. The reason was that the study of these drugs, which had been in widespread use at Dr. Cole’s institution, was conducted without asking patients to agree to participate. When negative stories in local papers framed this as a study conducted without consent, the institution asked the investigators to halt the study, and they complied.

“Subsequently, we have been assured after multiple evaluations that the rights and safety of our patient population were never violated,” Dr. Cole said, but he acknowledged that closing the study was an appropriate step in order to preserve patient confidence. “What we learned from this experience is that we may need to reconsider how we do waive of consent research at our institution,” he added.

In the meantime, the comparisons of ketamine with haloperidol and midazolam have provided objective evidence of their relative efficacy and safety in the management of prehospital agitation.

Dr. Cole reported no conflicts of interest.
 

SOURCE: Ann Emerg Med. 2018 Oct. doi. org/10.1016/j.annemergmed.2018.08.007.

SAN DIEGO – Following in the wake of a previous prospective comparison of ketamine and haloperidol for control of severe prehospital agitation, a new prospective study by the same group and presented at the annual meeting of the American College of Emergency Physicians found ketamine superior to midazolam for the same indication.

“The difference between the two drugs was larger when agitation was more profound,” reported Jon B. Cole, MD, an emergency medicine physician at Hennepin Healthcare and associate professor of emergency medicine at the University of Minnesota, Minneapolis.

Relative to ketamine (Ketalar), midazolam (Versed) was associated with fewer side effects, “so for less agitated patients, midazolam may still be the preferred therapy,” he added in his late-breaker presentation.

In recent years, ketamine has become a popular drug in emergency medical services for control of agitation, according to Dr. Cole, but he said that this approach has been adopted with relatively limited support from objective evidence. In his literature search, only 2 of 11 original studies that addressed ketamine for agitation involved prospective comparative studies.

One of those prior prospective studies was one Dr. Cole led and published 2 years ago (Clin Toxicol. 2016;54:556-62). In that study, comparing 5 mg/kg of intramuscular (IM) ketamine to 10 mg IM haloperidol, ketamine had a faster onset (median 5 vs. 17 minutes) but produced more side effects, including higher rates of intubation (39% vs. 4%).

In the new prospective study, ketamine and midazolam were compared over separate consecutive 6-month periods in which ketamine and then midazolam were employed as the dominant strategy for agitation control. This was the same open-label, nonrandomized design used for the comparison of ketamine and haloperidol, but with one difference. When the Altered Mental Status Score was +2 or +3, considered severe agitation, patients received 3 mg/kg of IM ketamine or 5 mg of IM midazolam. When the AMS score was +4, called profound agitation, the doses were 5 mg/kg and 15 mg, respectively.

The primary result was that adequate sedation overall was achieved in a median 4.3 minutes on ketamine but 8.8 minutes on midazolam, producing a more than 3-minute advantage for ketamine, which translated into an odds ratio (OR) of 1.8 for adequate agitation control favoring ketamine, according to Dr. Cole. In those with severe agitation, the median advantage was less than 2 minutes, but the OR of 1.6 remained significant. In those with profound agitation, the mean difference climbed above 5 minutes with an OR of 2.5.

Unlike the comparison with haloperidol, ketamine was not associated with a significantly higher risk of intubation or other airway related events, but Dr. Cole did report that midazolam was better tolerated. On the lower doses of the two drugs, for example, adverse events that were more common on ketamine than midazolam included vomiting (7% vs. 1%) and hypersalivation (20% vs. 0%).

In addition to the nonrandomized design, one limitation was unequal numbers of patients in the comparative groups. Only 113 were treated with midazolam while 202 patients were treated with ketamine. The reason was that the study of these drugs, which had been in widespread use at Dr. Cole’s institution, was conducted without asking patients to agree to participate. When negative stories in local papers framed this as a study conducted without consent, the institution asked the investigators to halt the study, and they complied.

“Subsequently, we have been assured after multiple evaluations that the rights and safety of our patient population were never violated,” Dr. Cole said, but he acknowledged that closing the study was an appropriate step in order to preserve patient confidence. “What we learned from this experience is that we may need to reconsider how we do waive of consent research at our institution,” he added.

In the meantime, the comparisons of ketamine with haloperidol and midazolam have provided objective evidence of their relative efficacy and safety in the management of prehospital agitation.

Dr. Cole reported no conflicts of interest.
 

SOURCE: Ann Emerg Med. 2018 Oct. doi. org/10.1016/j.annemergmed.2018.08.007.

SAN DIEGO – Following in the wake of a previous prospective comparison of ketamine and haloperidol for control of severe prehospital agitation, a new prospective study by the same group and presented at the annual meeting of the American College of Emergency Physicians found ketamine superior to midazolam for the same indication.

“The difference between the two drugs was larger when agitation was more profound,” reported Jon B. Cole, MD, an emergency medicine physician at Hennepin Healthcare and associate professor of emergency medicine at the University of Minnesota, Minneapolis.

Relative to ketamine (Ketalar), midazolam (Versed) was associated with fewer side effects, “so for less agitated patients, midazolam may still be the preferred therapy,” he added in his late-breaker presentation.

In recent years, ketamine has become a popular drug in emergency medical services for control of agitation, according to Dr. Cole, but he said that this approach has been adopted with relatively limited support from objective evidence. In his literature search, only 2 of 11 original studies that addressed ketamine for agitation involved prospective comparative studies.

One of those prior prospective studies was one Dr. Cole led and published 2 years ago (Clin Toxicol. 2016;54:556-62). In that study, comparing 5 mg/kg of intramuscular (IM) ketamine to 10 mg IM haloperidol, ketamine had a faster onset (median 5 vs. 17 minutes) but produced more side effects, including higher rates of intubation (39% vs. 4%).

In the new prospective study, ketamine and midazolam were compared over separate consecutive 6-month periods in which ketamine and then midazolam were employed as the dominant strategy for agitation control. This was the same open-label, nonrandomized design used for the comparison of ketamine and haloperidol, but with one difference. When the Altered Mental Status Score was +2 or +3, considered severe agitation, patients received 3 mg/kg of IM ketamine or 5 mg of IM midazolam. When the AMS score was +4, called profound agitation, the doses were 5 mg/kg and 15 mg, respectively.

The primary result was that adequate sedation overall was achieved in a median 4.3 minutes on ketamine but 8.8 minutes on midazolam, producing a more than 3-minute advantage for ketamine, which translated into an odds ratio (OR) of 1.8 for adequate agitation control favoring ketamine, according to Dr. Cole. In those with severe agitation, the median advantage was less than 2 minutes, but the OR of 1.6 remained significant. In those with profound agitation, the mean difference climbed above 5 minutes with an OR of 2.5.

Unlike the comparison with haloperidol, ketamine was not associated with a significantly higher risk of intubation or other airway related events, but Dr. Cole did report that midazolam was better tolerated. On the lower doses of the two drugs, for example, adverse events that were more common on ketamine than midazolam included vomiting (7% vs. 1%) and hypersalivation (20% vs. 0%).

In addition to the nonrandomized design, one limitation was unequal numbers of patients in the comparative groups. Only 113 were treated with midazolam while 202 patients were treated with ketamine. The reason was that the study of these drugs, which had been in widespread use at Dr. Cole’s institution, was conducted without asking patients to agree to participate. When negative stories in local papers framed this as a study conducted without consent, the institution asked the investigators to halt the study, and they complied.

“Subsequently, we have been assured after multiple evaluations that the rights and safety of our patient population were never violated,” Dr. Cole said, but he acknowledged that closing the study was an appropriate step in order to preserve patient confidence. “What we learned from this experience is that we may need to reconsider how we do waive of consent research at our institution,” he added.

In the meantime, the comparisons of ketamine with haloperidol and midazolam have provided objective evidence of their relative efficacy and safety in the management of prehospital agitation.

Dr. Cole reported no conflicts of interest.
 

SOURCE: Ann Emerg Med. 2018 Oct. doi. org/10.1016/j.annemergmed.2018.08.007.

A decade ago, the few agents approved by the US Food and Drug Administration for treatment of metastatic melanoma demonstrated low therapeutic success rates (ie, <15%–20%).¹ Since then, advances in molecular biology have identified oncogenes that contribute to melanoma progression.² Inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting mutant BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) has created promising pharmacologic treatment opportunities.³ Due to the recent US Food and Drug Administration approval of these therapies for treatment of melanoma, it is important to better characterize these adverse events (AEs) so that we can manage them. We present the development of an unusual cutaneous reaction to trametinib, a MEK inhibitor, in a man with stage IV M1b malignant melanoma.

Case Report

A 66-year-old man with stage IV M1b malignant melanoma with metastases to the brain and lungs presented with recurring pruritic erythematous papules on the face and bilateral forearms that began shortly after initiating therapy with trametinib. The cutaneous eruption had initially presented on the face, forearms, and dorsal hands when trametinib was used in combination with vemurafenib, a BRAF inhibitor, and ipilimumab, a human cytotoxic T-lymphocyte antigen 4–blocking antibody; however, lesions initially were minimal and self-resolving. When trametinib was reintroduced as monotherapy due to fever attributed to the combination treatment regimen, the cutaneous eruption recurred more severely. Physical examination revealed erythematous scaly papules limited to the face and bilateral upper extremities, including the flexural surfaces.

A biopsy from the flexural surface of the right forearm revealed a dense perivascular lymphoid and xanthomatous infiltrate in the dermis (Figure 1). Poorly formed granulomas within the mid reticular dermis demonstrated focal palisading of histiocytes with prominent giant cells at the periphery. Histiocytes and giant cells showed foamy or xanthomatous cytoplasm. Within the reaction, degenerative and swollen collagen fibers were noted with no mucin deposition, which was confirmed with negative colloidal iron staining.

Brief cessation of trametinib along with application of clobetasol propionate ointment 0.05% resulted in resolution of the cutaneous eruption. Later, trametinib was reintroduced in combination with vemurafenib, though therapy was intermittently discontinued due to various side effects. Skin lesions continued to recur (Figure 2) while the patient was on trametinib but remained minimal and continued to respond to topical clobetasol propionate. One year later, the patient continues to tolerate combination therapy with trametinib and vemurafenib.

Comment

BRAF Inhibitors
Normally, activated BRAF phosphorylates and stimulates MEK proteins, ultimately influencing cell proliferation, survival, and differentiation.^3-5 BRAF mutations that constitutively activate this pathway have been detected in several malignancies, including papillary thyroid cancer, colorectal cancer, and brain tumors, but they are particularly prevalent in melanoma.^4,6 The majority of BRAF-positive malignant melanomas are associated with V600E, in which valine is substituted for glutamic acid at codon 600. The next most common BRAF mutation is V600K, in which valine is substituted for lysine.^2,7 Together these constitute approximately 95% of BRAF mutations in melanoma patients.⁵

MEK Inhibitors
Initially, BRAF inhibitors (BRAFi) were introduced to the market for treating melanoma with great success; however, resistance to BRAFi therapy quickly was identified within months of initiating therapy, leading to investigations for combination therapy with MEK inhibitors (MEKi).^2,5 MEK inhibition decreases cellular proliferation and also leads to apoptosis of melanoma cells in patients with BRAF V600E or V600K mutations.^2,8 Trametinib, in particular, is a reversible, highly selective allosteric inhibitor of both MEK1 and MEK2. While on trametinib, patients with metastatic melanoma have experienced 3 times as long progression-free survival as well as 81% overall survival compared to 67% overall survival at 6 months in patients on chemotherapy, dacarbazine, or paclitaxel.⁵ However, AEs are quite common with trametinib, with cutaneous AEs being a leading side effect. Several large trials have reported that 57% to 92% of patients on trametinib report cutaneous AEs, with the majority of cases being described as papulopustular or acneform (Table).^5,9

Combination Therapy
Fortunately, combination treatment with a BRAFi may alleviate MEKi-induced cutaneous drug reactions. In one study, acneform eruptions were identified in only 10% of those on combination therapy—trametinib with the BRAFi dabrafenib—compared to 77% of patients on trametinib monotherapy.¹⁰ Strikingly, cutaneous AEs occurred in 100% of trametinib-treated mice compared to 30% of combination-treated mice in another study, while the benefits of MEKi remained similar in both groups.¹¹ Because BRAFi and MEKi combination therapy improves progression-free survival while minimizing AEs, we support the use of combination therapy instead of BRAFi or MEKi monotherapy.⁵

Histologic Evidence of AEs
Histology of trametinib-associated cutaneous reactions is not well characterized, which is in contrast to our understanding of cutaneous AEs associated with BRAFi in which transient acantholytic dermatosis (seen in 45% of patients) and verrucal keratosis (seen in 18% of patients) have been well characterized on histology.¹² Interestingly, cutaneous granulomatous eruptions have been attributed to BRAFi therapy in 4 patients.^13,14 One patient was on monotherapy with vemurafenib and granulomatous dermatitis with focal necrosis was seen on histology.¹³ The other 3 patients were on combination therapy with trametinib; 2 had histology-proven sarcoidal granulomatous inflammation, and 1 demonstrated perifollicular granulomatous inflammation and granulomatous inflammation surrounding a focus of melanoma cells.^13,14 Although these granulomatous reactions were attributed to BRAFi or combination therapy, the association with trametinib remains unclear. On the other hand, our patient’s granulomatous reaction was exacerbated on trametinib monotherapy, suggesting a relationship to trametinib itself rather than BRAFi.

Conclusion

With the discovery of molecular targeting in melanoma, BRAFi and MEKi therapies provide major milestones in metastatic melanoma management. As more patients are treated with these agents, it is important that we better characterize their associated side effects. Our case of an unusual xanthogranulomatous reaction to trametinib adds to the knowledge base of possible cutaneous reactions caused by this drug. We hope that prospective studies will further investigate and differentiate the cutaneous AEs described so that we can better manage these patients.

A decade ago, the few agents approved by the US Food and Drug Administration for treatment of metastatic melanoma demonstrated low therapeutic success rates (ie, <15%–20%).¹ Since then, advances in molecular biology have identified oncogenes that contribute to melanoma progression.² Inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting mutant BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) has created promising pharmacologic treatment opportunities.³ Due to the recent US Food and Drug Administration approval of these therapies for treatment of melanoma, it is important to better characterize these adverse events (AEs) so that we can manage them. We present the development of an unusual cutaneous reaction to trametinib, a MEK inhibitor, in a man with stage IV M1b malignant melanoma.

Case Report

A 66-year-old man with stage IV M1b malignant melanoma with metastases to the brain and lungs presented with recurring pruritic erythematous papules on the face and bilateral forearms that began shortly after initiating therapy with trametinib. The cutaneous eruption had initially presented on the face, forearms, and dorsal hands when trametinib was used in combination with vemurafenib, a BRAF inhibitor, and ipilimumab, a human cytotoxic T-lymphocyte antigen 4–blocking antibody; however, lesions initially were minimal and self-resolving. When trametinib was reintroduced as monotherapy due to fever attributed to the combination treatment regimen, the cutaneous eruption recurred more severely. Physical examination revealed erythematous scaly papules limited to the face and bilateral upper extremities, including the flexural surfaces.

A biopsy from the flexural surface of the right forearm revealed a dense perivascular lymphoid and xanthomatous infiltrate in the dermis (Figure 1). Poorly formed granulomas within the mid reticular dermis demonstrated focal palisading of histiocytes with prominent giant cells at the periphery. Histiocytes and giant cells showed foamy or xanthomatous cytoplasm. Within the reaction, degenerative and swollen collagen fibers were noted with no mucin deposition, which was confirmed with negative colloidal iron staining.

Brief cessation of trametinib along with application of clobetasol propionate ointment 0.05% resulted in resolution of the cutaneous eruption. Later, trametinib was reintroduced in combination with vemurafenib, though therapy was intermittently discontinued due to various side effects. Skin lesions continued to recur (Figure 2) while the patient was on trametinib but remained minimal and continued to respond to topical clobetasol propionate. One year later, the patient continues to tolerate combination therapy with trametinib and vemurafenib.

Comment

BRAF Inhibitors
Normally, activated BRAF phosphorylates and stimulates MEK proteins, ultimately influencing cell proliferation, survival, and differentiation.^3-5 BRAF mutations that constitutively activate this pathway have been detected in several malignancies, including papillary thyroid cancer, colorectal cancer, and brain tumors, but they are particularly prevalent in melanoma.^4,6 The majority of BRAF-positive malignant melanomas are associated with V600E, in which valine is substituted for glutamic acid at codon 600. The next most common BRAF mutation is V600K, in which valine is substituted for lysine.^2,7 Together these constitute approximately 95% of BRAF mutations in melanoma patients.⁵

MEK Inhibitors
Initially, BRAF inhibitors (BRAFi) were introduced to the market for treating melanoma with great success; however, resistance to BRAFi therapy quickly was identified within months of initiating therapy, leading to investigations for combination therapy with MEK inhibitors (MEKi).^2,5 MEK inhibition decreases cellular proliferation and also leads to apoptosis of melanoma cells in patients with BRAF V600E or V600K mutations.^2,8 Trametinib, in particular, is a reversible, highly selective allosteric inhibitor of both MEK1 and MEK2. While on trametinib, patients with metastatic melanoma have experienced 3 times as long progression-free survival as well as 81% overall survival compared to 67% overall survival at 6 months in patients on chemotherapy, dacarbazine, or paclitaxel.⁵ However, AEs are quite common with trametinib, with cutaneous AEs being a leading side effect. Several large trials have reported that 57% to 92% of patients on trametinib report cutaneous AEs, with the majority of cases being described as papulopustular or acneform (Table).^5,9

Combination Therapy
Fortunately, combination treatment with a BRAFi may alleviate MEKi-induced cutaneous drug reactions. In one study, acneform eruptions were identified in only 10% of those on combination therapy—trametinib with the BRAFi dabrafenib—compared to 77% of patients on trametinib monotherapy.¹⁰ Strikingly, cutaneous AEs occurred in 100% of trametinib-treated mice compared to 30% of combination-treated mice in another study, while the benefits of MEKi remained similar in both groups.¹¹ Because BRAFi and MEKi combination therapy improves progression-free survival while minimizing AEs, we support the use of combination therapy instead of BRAFi or MEKi monotherapy.⁵

Histologic Evidence of AEs
Histology of trametinib-associated cutaneous reactions is not well characterized, which is in contrast to our understanding of cutaneous AEs associated with BRAFi in which transient acantholytic dermatosis (seen in 45% of patients) and verrucal keratosis (seen in 18% of patients) have been well characterized on histology.¹² Interestingly, cutaneous granulomatous eruptions have been attributed to BRAFi therapy in 4 patients.^13,14 One patient was on monotherapy with vemurafenib and granulomatous dermatitis with focal necrosis was seen on histology.¹³ The other 3 patients were on combination therapy with trametinib; 2 had histology-proven sarcoidal granulomatous inflammation, and 1 demonstrated perifollicular granulomatous inflammation and granulomatous inflammation surrounding a focus of melanoma cells.^13,14 Although these granulomatous reactions were attributed to BRAFi or combination therapy, the association with trametinib remains unclear. On the other hand, our patient’s granulomatous reaction was exacerbated on trametinib monotherapy, suggesting a relationship to trametinib itself rather than BRAFi.

Conclusion

With the discovery of molecular targeting in melanoma, BRAFi and MEKi therapies provide major milestones in metastatic melanoma management. As more patients are treated with these agents, it is important that we better characterize their associated side effects. Our case of an unusual xanthogranulomatous reaction to trametinib adds to the knowledge base of possible cutaneous reactions caused by this drug. We hope that prospective studies will further investigate and differentiate the cutaneous AEs described so that we can better manage these patients.

A decade ago, the few agents approved by the US Food and Drug Administration for treatment of metastatic melanoma demonstrated low therapeutic success rates (ie, <15%–20%).¹ Since then, advances in molecular biology have identified oncogenes that contribute to melanoma progression.² Inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting mutant BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) has created promising pharmacologic treatment opportunities.³ Due to the recent US Food and Drug Administration approval of these therapies for treatment of melanoma, it is important to better characterize these adverse events (AEs) so that we can manage them. We present the development of an unusual cutaneous reaction to trametinib, a MEK inhibitor, in a man with stage IV M1b malignant melanoma.

Case Report

A 66-year-old man with stage IV M1b malignant melanoma with metastases to the brain and lungs presented with recurring pruritic erythematous papules on the face and bilateral forearms that began shortly after initiating therapy with trametinib. The cutaneous eruption had initially presented on the face, forearms, and dorsal hands when trametinib was used in combination with vemurafenib, a BRAF inhibitor, and ipilimumab, a human cytotoxic T-lymphocyte antigen 4–blocking antibody; however, lesions initially were minimal and self-resolving. When trametinib was reintroduced as monotherapy due to fever attributed to the combination treatment regimen, the cutaneous eruption recurred more severely. Physical examination revealed erythematous scaly papules limited to the face and bilateral upper extremities, including the flexural surfaces.

A biopsy from the flexural surface of the right forearm revealed a dense perivascular lymphoid and xanthomatous infiltrate in the dermis (Figure 1). Poorly formed granulomas within the mid reticular dermis demonstrated focal palisading of histiocytes with prominent giant cells at the periphery. Histiocytes and giant cells showed foamy or xanthomatous cytoplasm. Within the reaction, degenerative and swollen collagen fibers were noted with no mucin deposition, which was confirmed with negative colloidal iron staining.

Brief cessation of trametinib along with application of clobetasol propionate ointment 0.05% resulted in resolution of the cutaneous eruption. Later, trametinib was reintroduced in combination with vemurafenib, though therapy was intermittently discontinued due to various side effects. Skin lesions continued to recur (Figure 2) while the patient was on trametinib but remained minimal and continued to respond to topical clobetasol propionate. One year later, the patient continues to tolerate combination therapy with trametinib and vemurafenib.

Comment

BRAF Inhibitors
Normally, activated BRAF phosphorylates and stimulates MEK proteins, ultimately influencing cell proliferation, survival, and differentiation.^3-5 BRAF mutations that constitutively activate this pathway have been detected in several malignancies, including papillary thyroid cancer, colorectal cancer, and brain tumors, but they are particularly prevalent in melanoma.^4,6 The majority of BRAF-positive malignant melanomas are associated with V600E, in which valine is substituted for glutamic acid at codon 600. The next most common BRAF mutation is V600K, in which valine is substituted for lysine.^2,7 Together these constitute approximately 95% of BRAF mutations in melanoma patients.⁵

MEK Inhibitors
Initially, BRAF inhibitors (BRAFi) were introduced to the market for treating melanoma with great success; however, resistance to BRAFi therapy quickly was identified within months of initiating therapy, leading to investigations for combination therapy with MEK inhibitors (MEKi).^2,5 MEK inhibition decreases cellular proliferation and also leads to apoptosis of melanoma cells in patients with BRAF V600E or V600K mutations.^2,8 Trametinib, in particular, is a reversible, highly selective allosteric inhibitor of both MEK1 and MEK2. While on trametinib, patients with metastatic melanoma have experienced 3 times as long progression-free survival as well as 81% overall survival compared to 67% overall survival at 6 months in patients on chemotherapy, dacarbazine, or paclitaxel.⁵ However, AEs are quite common with trametinib, with cutaneous AEs being a leading side effect. Several large trials have reported that 57% to 92% of patients on trametinib report cutaneous AEs, with the majority of cases being described as papulopustular or acneform (Table).^5,9

Combination Therapy
Fortunately, combination treatment with a BRAFi may alleviate MEKi-induced cutaneous drug reactions. In one study, acneform eruptions were identified in only 10% of those on combination therapy—trametinib with the BRAFi dabrafenib—compared to 77% of patients on trametinib monotherapy.¹⁰ Strikingly, cutaneous AEs occurred in 100% of trametinib-treated mice compared to 30% of combination-treated mice in another study, while the benefits of MEKi remained similar in both groups.¹¹ Because BRAFi and MEKi combination therapy improves progression-free survival while minimizing AEs, we support the use of combination therapy instead of BRAFi or MEKi monotherapy.⁵

Histologic Evidence of AEs
Histology of trametinib-associated cutaneous reactions is not well characterized, which is in contrast to our understanding of cutaneous AEs associated with BRAFi in which transient acantholytic dermatosis (seen in 45% of patients) and verrucal keratosis (seen in 18% of patients) have been well characterized on histology.¹² Interestingly, cutaneous granulomatous eruptions have been attributed to BRAFi therapy in 4 patients.^13,14 One patient was on monotherapy with vemurafenib and granulomatous dermatitis with focal necrosis was seen on histology.¹³ The other 3 patients were on combination therapy with trametinib; 2 had histology-proven sarcoidal granulomatous inflammation, and 1 demonstrated perifollicular granulomatous inflammation and granulomatous inflammation surrounding a focus of melanoma cells.^13,14 Although these granulomatous reactions were attributed to BRAFi or combination therapy, the association with trametinib remains unclear. On the other hand, our patient’s granulomatous reaction was exacerbated on trametinib monotherapy, suggesting a relationship to trametinib itself rather than BRAFi.

Conclusion

With the discovery of molecular targeting in melanoma, BRAFi and MEKi therapies provide major milestones in metastatic melanoma management. As more patients are treated with these agents, it is important that we better characterize their associated side effects. Our case of an unusual xanthogranulomatous reaction to trametinib adds to the knowledge base of possible cutaneous reactions caused by this drug. We hope that prospective studies will further investigate and differentiate the cutaneous AEs described so that we can better manage these patients.

Case Report

A 57-year-old black woman with a history of dialysis-dependent end-stage renal disease, diabetes mellitus (DM), hypertension, diastolic congestive heart failure, and chronic bronchitis was admitted to Howard University Hospital (Washington, DC) for acute chest pain and shortness of breath. During her hospital stay the dermatology team was consulted for evaluation of two 1.6-cm teardrop-shaped, yellow-white-chalky plaques noted in the center of an atrophic, hyperpigmented, shiny, contracted split-thickness skin graft (STSG) on the right posterior forearm (Figure 1). Twenty years prior, the patient received STSGs on the right and left forearm secondary to caustic burns. Two months before the current admission she noticed 2 adjacent teardrop-shaped white plaques within the center of the STSG on the right forearm. At a 3-month follow-up, she had developed more lesions within both graft sites of the bilateral forearm. There was no notable pruritus associated with the lesions.

A 4-mm punch biopsy showed an orthokeratotic plug with basophilic inflammatory debris adjacent to acanthotic epidermis, necrotic basophilic debris at the superficial dermis with epidermal canals extending from the base of the lesion superiorly, and transepidermal elimination of elastic fibers (Figure 2A). A Verhoeff-van Gieson stain revealed the necrotic basophilic debris located in the superficial dermis admixed with a cluster of black wavy elastic fibers establishing the identity of the perforating substance (Figure 2B). Masson trichrome stain revealed loss of collagen structure within the aggregate of elastic fibers adjacent to the epidermis and no collagen within epidermal canals (Figure 2C). These histopathologic findings together with the clinical presentation were consistent with a diagnosis of acquired perforating dermatosis (APD).

Comment

Presentation
Acquired perforating dermatosis is a dermatologic condition characterized by multiple pruritic, dome-shaped papules and plaques with central keratotic plugs giving a craterlike appearance.^1-4 A green-brown or black crust with an erythematous border typically surrounds the primary lesions.⁴ Acquired perforating dermatosis favors a distribution over the trunk, gluteal region, and the extensor surfaces of the upper and lower extremities. Palmoplantar, intertriginous, and mucous membrane regions typically are spared.⁴ Occasionally, APD may present as generalized nodules and papules. Our case consisting of lesions that were localized to STSGs on the forearms supports the typical distribution; however, the presentation of APD occurring within a skin graft is unique.

From an epidemiologic standpoint, APD is more likely to affect men than women (1.5:1 ratio). Additionally, APD’s affected age range is 29 to 96 years (mean, 56.8 years),⁵ which is consistent with our patient’s age. Acquired perforating dermatosis has no racial predilection, though there is a predominance among black patients with concomitant chronic renal failure, as seen in our patient.³

Pathogenesis
The etiology of APD remains unknown.⁶ Some believe that the uremic or calcium deposits on the skin of patients with chronic kidney disease may trigger chronic pruritus, leading to epithelial hyperplasia and the development of perforating lesions.^1,3 A prominent theory in the literature is that superficial trauma, such as scratching, induces necrosis of tissue, facilitating transepidermal elimination of connective tissue components.⁷ The Köbner phenomenon, which can easily be induced by scratching the skin, supports this idea.⁸ Fujimoto et al⁹ suggested that scratching exposes keratinocytes to advanced glycation end product–modified extracellular matrix proteins, particularly types I and III collagen. This exposure leads to the terminal differentiation of keratinocytes with the advanced glycation end receptor (CD36) followed by the upward movement of keratinocytes with glycated collagen. Others postulate fibronectin, involved in epidermal cell signaling, locomotion, and differentiation, is an antigenic trigger because patients with DM and uremia have increased levels of fibronectin in the serum and at sites of perforating skin lesions.¹⁰

Diseases Associated With APD
Acquired perforating dermatosis is an umbrella term for perforating disease found in adults. It is associated with systemic diseases, such as DM and pruritus of renal failure.¹¹ Our patient had both dialysis-dependent end-stage renal disease and DM. Acquired perforating dermatosis is observed in 4.5% to 11% of patients on hemodialysis^12,13; however, APD may occur prior to or in the absence of dialysis.³ Other examples of systemic conditions associated with APD include obstructive uropathy, chronic nephritis, anuria, and hypertensive nephrosclerosis. Koebnerization also may trigger lesions to manifest in a linear pattern after localized trauma to the skin.⁷ Acquired perforating dermatosis is associated with other types of trauma, such as healing herpes zoster, or following exposure to drugs, such as tumor necrosis factor α inhibitors, bevacizumab, telaprevir, sorafenib, sirolimus, and indinavir.^14-16 Rarely, there have been associations with a history of insect bites, scabies, lymphoma, and hepatobiliary disease.^1-3

Histopathology
Acquired perforating dermatosis is classified as a perforating disease, along with reactive perforating collagenosis, elastosis perforans serpiginosa (EPS), perforating folliculitis, and perforating calcific elastosis. Perforating diseases are histologically characterized by the transepidermal penetration and elimination of altered connective tissue and inflammatory cells.⁵ Each disease differs based on their clinical and histological characteristics.

Histologic sections of APD show a plug of crusting or hyperkeratosis with variable parakeratosis, acanthosis, and occasional dyskeratotic keratinocytes. In the dermis, aggregates of neutrophils, lymphocytes, macrophages, or multinucleated giant cells may be found.¹⁷ The histologic findings vary depending on the stage of evolution of the individual lesion. Early lesions show a concave depression with acanthosis, vacuolation of basal keratinocytes, and dermal inflammation.⁴ Additionally, transepidermal channels filled with keratin, pyknotic nuclear debris, inflammatory cells, elastin, or collagen can be noted.³ Over time, the elastic fibers, as detected by the Verhoeff-van Gieson stain, dissipate and the collagen acquires a basophilic staining. Adjacent to the channels, the basement membrane remains intact in early lesions but later shows discontinuities and electron-dense fibrinlike material.³ Occasionally, amorphous degenerated material within the perforations is the major histologic finding.¹¹ Usually, the material cannot be clearly identified as collagen or elastin, but sometimes both are present.

In our case, we identified elastin as the perforating substance, which is less common than collagen, the typical perforating substance in APD. Elastin has occasionally been seen to serve as the only perforating substance from APD lesions among patients. Abe et al¹⁸ reported that the biopsy of a Japanese patient with keratotic follicular papules and serpiginous-arranged papules demonstrated elimination of atypical elastin fibers from the transepidermal channels. This patient was diagnosed with APD as well as EPS and perforating folliculitis based on the clinical presentation.¹⁸ Kim et al¹⁹ studied 30 Korean patients with APD. One had serpiginous hyperkeratotic plaques along the upper extremity and trunk that revealed transepidermal channels containing coarse elastic fibers and basophilic debris; however, due to the serpiginous morphology of lesions, both Abe et al¹⁸ and Kim et al¹⁹ favored a diagnosis of acquired EPS. Saray et al²⁰ conducted a retrospective study of 22 Turkish patients with APD; 1 patient had a painful hyperkeratotic papule on the auricle that on histopathology showed degenerated elastin perforating through the keratotic plug, features similar to our case.

Differential Diagnosis
The differential diagnoses include perforating diseases^14,19 as well as other disorders that exhibit the Köbner phenomenon, such as psoriasis, lichen planus, and verruca vulgaris.^21,22 Also, it is not uncommon for patients with APD to have coexisting folliculitis or prurigo nodularis.²²

Treatment
Management is focused on treating the symptoms. For pruritus, sedating antihistamines and other antipruritic agents are efficacious.²³ Topical, intra-lesional, or systemic corticosteroids and topical retinoids have shown variable resolution in APD lesions.²⁴ Some case reports describe topical menthol, salicylic acid, sulfur, benzoyl peroxide, systemic antibiotics (eg, clindamycin, doxycycline), and allopurinol for elevated uric acid levels as effective treatment methods.⁶ Narrowband UVB phototherapy is beneficial for APD and renal disease.^25,26 Renal transplantation has been curative for some patients with APD.²⁷ Given that our patient’s lesions were asymptomatic, no treatment was offered at the time.

Conclusion

Our patient presented with APD localized exclusively to the site of a skin graft, and histologic examination identified elastin as the primary perforating substance. A medical history of DM and chronic kidney disease predisposes patients to APD. This case suggests that skin graft sites may be predisposed to the development of APD.

Case Report

A 57-year-old black woman with a history of dialysis-dependent end-stage renal disease, diabetes mellitus (DM), hypertension, diastolic congestive heart failure, and chronic bronchitis was admitted to Howard University Hospital (Washington, DC) for acute chest pain and shortness of breath. During her hospital stay the dermatology team was consulted for evaluation of two 1.6-cm teardrop-shaped, yellow-white-chalky plaques noted in the center of an atrophic, hyperpigmented, shiny, contracted split-thickness skin graft (STSG) on the right posterior forearm (Figure 1). Twenty years prior, the patient received STSGs on the right and left forearm secondary to caustic burns. Two months before the current admission she noticed 2 adjacent teardrop-shaped white plaques within the center of the STSG on the right forearm. At a 3-month follow-up, she had developed more lesions within both graft sites of the bilateral forearm. There was no notable pruritus associated with the lesions.

A 4-mm punch biopsy showed an orthokeratotic plug with basophilic inflammatory debris adjacent to acanthotic epidermis, necrotic basophilic debris at the superficial dermis with epidermal canals extending from the base of the lesion superiorly, and transepidermal elimination of elastic fibers (Figure 2A). A Verhoeff-van Gieson stain revealed the necrotic basophilic debris located in the superficial dermis admixed with a cluster of black wavy elastic fibers establishing the identity of the perforating substance (Figure 2B). Masson trichrome stain revealed loss of collagen structure within the aggregate of elastic fibers adjacent to the epidermis and no collagen within epidermal canals (Figure 2C). These histopathologic findings together with the clinical presentation were consistent with a diagnosis of acquired perforating dermatosis (APD).

Comment

Presentation
Acquired perforating dermatosis is a dermatologic condition characterized by multiple pruritic, dome-shaped papules and plaques with central keratotic plugs giving a craterlike appearance.^1-4 A green-brown or black crust with an erythematous border typically surrounds the primary lesions.⁴ Acquired perforating dermatosis favors a distribution over the trunk, gluteal region, and the extensor surfaces of the upper and lower extremities. Palmoplantar, intertriginous, and mucous membrane regions typically are spared.⁴ Occasionally, APD may present as generalized nodules and papules. Our case consisting of lesions that were localized to STSGs on the forearms supports the typical distribution; however, the presentation of APD occurring within a skin graft is unique.

From an epidemiologic standpoint, APD is more likely to affect men than women (1.5:1 ratio). Additionally, APD’s affected age range is 29 to 96 years (mean, 56.8 years),⁵ which is consistent with our patient’s age. Acquired perforating dermatosis has no racial predilection, though there is a predominance among black patients with concomitant chronic renal failure, as seen in our patient.³

Pathogenesis
The etiology of APD remains unknown.⁶ Some believe that the uremic or calcium deposits on the skin of patients with chronic kidney disease may trigger chronic pruritus, leading to epithelial hyperplasia and the development of perforating lesions.^1,3 A prominent theory in the literature is that superficial trauma, such as scratching, induces necrosis of tissue, facilitating transepidermal elimination of connective tissue components.⁷ The Köbner phenomenon, which can easily be induced by scratching the skin, supports this idea.⁸ Fujimoto et al⁹ suggested that scratching exposes keratinocytes to advanced glycation end product–modified extracellular matrix proteins, particularly types I and III collagen. This exposure leads to the terminal differentiation of keratinocytes with the advanced glycation end receptor (CD36) followed by the upward movement of keratinocytes with glycated collagen. Others postulate fibronectin, involved in epidermal cell signaling, locomotion, and differentiation, is an antigenic trigger because patients with DM and uremia have increased levels of fibronectin in the serum and at sites of perforating skin lesions.¹⁰

Diseases Associated With APD
Acquired perforating dermatosis is an umbrella term for perforating disease found in adults. It is associated with systemic diseases, such as DM and pruritus of renal failure.¹¹ Our patient had both dialysis-dependent end-stage renal disease and DM. Acquired perforating dermatosis is observed in 4.5% to 11% of patients on hemodialysis^12,13; however, APD may occur prior to or in the absence of dialysis.³ Other examples of systemic conditions associated with APD include obstructive uropathy, chronic nephritis, anuria, and hypertensive nephrosclerosis. Koebnerization also may trigger lesions to manifest in a linear pattern after localized trauma to the skin.⁷ Acquired perforating dermatosis is associated with other types of trauma, such as healing herpes zoster, or following exposure to drugs, such as tumor necrosis factor α inhibitors, bevacizumab, telaprevir, sorafenib, sirolimus, and indinavir.^14-16 Rarely, there have been associations with a history of insect bites, scabies, lymphoma, and hepatobiliary disease.^1-3

Histopathology
Acquired perforating dermatosis is classified as a perforating disease, along with reactive perforating collagenosis, elastosis perforans serpiginosa (EPS), perforating folliculitis, and perforating calcific elastosis. Perforating diseases are histologically characterized by the transepidermal penetration and elimination of altered connective tissue and inflammatory cells.⁵ Each disease differs based on their clinical and histological characteristics.

Histologic sections of APD show a plug of crusting or hyperkeratosis with variable parakeratosis, acanthosis, and occasional dyskeratotic keratinocytes. In the dermis, aggregates of neutrophils, lymphocytes, macrophages, or multinucleated giant cells may be found.¹⁷ The histologic findings vary depending on the stage of evolution of the individual lesion. Early lesions show a concave depression with acanthosis, vacuolation of basal keratinocytes, and dermal inflammation.⁴ Additionally, transepidermal channels filled with keratin, pyknotic nuclear debris, inflammatory cells, elastin, or collagen can be noted.³ Over time, the elastic fibers, as detected by the Verhoeff-van Gieson stain, dissipate and the collagen acquires a basophilic staining. Adjacent to the channels, the basement membrane remains intact in early lesions but later shows discontinuities and electron-dense fibrinlike material.³ Occasionally, amorphous degenerated material within the perforations is the major histologic finding.¹¹ Usually, the material cannot be clearly identified as collagen or elastin, but sometimes both are present.

In our case, we identified elastin as the perforating substance, which is less common than collagen, the typical perforating substance in APD. Elastin has occasionally been seen to serve as the only perforating substance from APD lesions among patients. Abe et al¹⁸ reported that the biopsy of a Japanese patient with keratotic follicular papules and serpiginous-arranged papules demonstrated elimination of atypical elastin fibers from the transepidermal channels. This patient was diagnosed with APD as well as EPS and perforating folliculitis based on the clinical presentation.¹⁸ Kim et al¹⁹ studied 30 Korean patients with APD. One had serpiginous hyperkeratotic plaques along the upper extremity and trunk that revealed transepidermal channels containing coarse elastic fibers and basophilic debris; however, due to the serpiginous morphology of lesions, both Abe et al¹⁸ and Kim et al¹⁹ favored a diagnosis of acquired EPS. Saray et al²⁰ conducted a retrospective study of 22 Turkish patients with APD; 1 patient had a painful hyperkeratotic papule on the auricle that on histopathology showed degenerated elastin perforating through the keratotic plug, features similar to our case.

Differential Diagnosis
The differential diagnoses include perforating diseases^14,19 as well as other disorders that exhibit the Köbner phenomenon, such as psoriasis, lichen planus, and verruca vulgaris.^21,22 Also, it is not uncommon for patients with APD to have coexisting folliculitis or prurigo nodularis.²²

Treatment
Management is focused on treating the symptoms. For pruritus, sedating antihistamines and other antipruritic agents are efficacious.²³ Topical, intra-lesional, or systemic corticosteroids and topical retinoids have shown variable resolution in APD lesions.²⁴ Some case reports describe topical menthol, salicylic acid, sulfur, benzoyl peroxide, systemic antibiotics (eg, clindamycin, doxycycline), and allopurinol for elevated uric acid levels as effective treatment methods.⁶ Narrowband UVB phototherapy is beneficial for APD and renal disease.^25,26 Renal transplantation has been curative for some patients with APD.²⁷ Given that our patient’s lesions were asymptomatic, no treatment was offered at the time.

Conclusion

Our patient presented with APD localized exclusively to the site of a skin graft, and histologic examination identified elastin as the primary perforating substance. A medical history of DM and chronic kidney disease predisposes patients to APD. This case suggests that skin graft sites may be predisposed to the development of APD.

Case Report

A 57-year-old black woman with a history of dialysis-dependent end-stage renal disease, diabetes mellitus (DM), hypertension, diastolic congestive heart failure, and chronic bronchitis was admitted to Howard University Hospital (Washington, DC) for acute chest pain and shortness of breath. During her hospital stay the dermatology team was consulted for evaluation of two 1.6-cm teardrop-shaped, yellow-white-chalky plaques noted in the center of an atrophic, hyperpigmented, shiny, contracted split-thickness skin graft (STSG) on the right posterior forearm (Figure 1). Twenty years prior, the patient received STSGs on the right and left forearm secondary to caustic burns. Two months before the current admission she noticed 2 adjacent teardrop-shaped white plaques within the center of the STSG on the right forearm. At a 3-month follow-up, she had developed more lesions within both graft sites of the bilateral forearm. There was no notable pruritus associated with the lesions.

A 4-mm punch biopsy showed an orthokeratotic plug with basophilic inflammatory debris adjacent to acanthotic epidermis, necrotic basophilic debris at the superficial dermis with epidermal canals extending from the base of the lesion superiorly, and transepidermal elimination of elastic fibers (Figure 2A). A Verhoeff-van Gieson stain revealed the necrotic basophilic debris located in the superficial dermis admixed with a cluster of black wavy elastic fibers establishing the identity of the perforating substance (Figure 2B). Masson trichrome stain revealed loss of collagen structure within the aggregate of elastic fibers adjacent to the epidermis and no collagen within epidermal canals (Figure 2C). These histopathologic findings together with the clinical presentation were consistent with a diagnosis of acquired perforating dermatosis (APD).

Comment

Presentation
Acquired perforating dermatosis is a dermatologic condition characterized by multiple pruritic, dome-shaped papules and plaques with central keratotic plugs giving a craterlike appearance.^1-4 A green-brown or black crust with an erythematous border typically surrounds the primary lesions.⁴ Acquired perforating dermatosis favors a distribution over the trunk, gluteal region, and the extensor surfaces of the upper and lower extremities. Palmoplantar, intertriginous, and mucous membrane regions typically are spared.⁴ Occasionally, APD may present as generalized nodules and papules. Our case consisting of lesions that were localized to STSGs on the forearms supports the typical distribution; however, the presentation of APD occurring within a skin graft is unique.

From an epidemiologic standpoint, APD is more likely to affect men than women (1.5:1 ratio). Additionally, APD’s affected age range is 29 to 96 years (mean, 56.8 years),⁵ which is consistent with our patient’s age. Acquired perforating dermatosis has no racial predilection, though there is a predominance among black patients with concomitant chronic renal failure, as seen in our patient.³

Pathogenesis
The etiology of APD remains unknown.⁶ Some believe that the uremic or calcium deposits on the skin of patients with chronic kidney disease may trigger chronic pruritus, leading to epithelial hyperplasia and the development of perforating lesions.^1,3 A prominent theory in the literature is that superficial trauma, such as scratching, induces necrosis of tissue, facilitating transepidermal elimination of connective tissue components.⁷ The Köbner phenomenon, which can easily be induced by scratching the skin, supports this idea.⁸ Fujimoto et al⁹ suggested that scratching exposes keratinocytes to advanced glycation end product–modified extracellular matrix proteins, particularly types I and III collagen. This exposure leads to the terminal differentiation of keratinocytes with the advanced glycation end receptor (CD36) followed by the upward movement of keratinocytes with glycated collagen. Others postulate fibronectin, involved in epidermal cell signaling, locomotion, and differentiation, is an antigenic trigger because patients with DM and uremia have increased levels of fibronectin in the serum and at sites of perforating skin lesions.¹⁰

Diseases Associated With APD
Acquired perforating dermatosis is an umbrella term for perforating disease found in adults. It is associated with systemic diseases, such as DM and pruritus of renal failure.¹¹ Our patient had both dialysis-dependent end-stage renal disease and DM. Acquired perforating dermatosis is observed in 4.5% to 11% of patients on hemodialysis^12,13; however, APD may occur prior to or in the absence of dialysis.³ Other examples of systemic conditions associated with APD include obstructive uropathy, chronic nephritis, anuria, and hypertensive nephrosclerosis. Koebnerization also may trigger lesions to manifest in a linear pattern after localized trauma to the skin.⁷ Acquired perforating dermatosis is associated with other types of trauma, such as healing herpes zoster, or following exposure to drugs, such as tumor necrosis factor α inhibitors, bevacizumab, telaprevir, sorafenib, sirolimus, and indinavir.^14-16 Rarely, there have been associations with a history of insect bites, scabies, lymphoma, and hepatobiliary disease.^1-3

Histopathology
Acquired perforating dermatosis is classified as a perforating disease, along with reactive perforating collagenosis, elastosis perforans serpiginosa (EPS), perforating folliculitis, and perforating calcific elastosis. Perforating diseases are histologically characterized by the transepidermal penetration and elimination of altered connective tissue and inflammatory cells.⁵ Each disease differs based on their clinical and histological characteristics.

Histologic sections of APD show a plug of crusting or hyperkeratosis with variable parakeratosis, acanthosis, and occasional dyskeratotic keratinocytes. In the dermis, aggregates of neutrophils, lymphocytes, macrophages, or multinucleated giant cells may be found.¹⁷ The histologic findings vary depending on the stage of evolution of the individual lesion. Early lesions show a concave depression with acanthosis, vacuolation of basal keratinocytes, and dermal inflammation.⁴ Additionally, transepidermal channels filled with keratin, pyknotic nuclear debris, inflammatory cells, elastin, or collagen can be noted.³ Over time, the elastic fibers, as detected by the Verhoeff-van Gieson stain, dissipate and the collagen acquires a basophilic staining. Adjacent to the channels, the basement membrane remains intact in early lesions but later shows discontinuities and electron-dense fibrinlike material.³ Occasionally, amorphous degenerated material within the perforations is the major histologic finding.¹¹ Usually, the material cannot be clearly identified as collagen or elastin, but sometimes both are present.

In our case, we identified elastin as the perforating substance, which is less common than collagen, the typical perforating substance in APD. Elastin has occasionally been seen to serve as the only perforating substance from APD lesions among patients. Abe et al¹⁸ reported that the biopsy of a Japanese patient with keratotic follicular papules and serpiginous-arranged papules demonstrated elimination of atypical elastin fibers from the transepidermal channels. This patient was diagnosed with APD as well as EPS and perforating folliculitis based on the clinical presentation.¹⁸ Kim et al¹⁹ studied 30 Korean patients with APD. One had serpiginous hyperkeratotic plaques along the upper extremity and trunk that revealed transepidermal channels containing coarse elastic fibers and basophilic debris; however, due to the serpiginous morphology of lesions, both Abe et al¹⁸ and Kim et al¹⁹ favored a diagnosis of acquired EPS. Saray et al²⁰ conducted a retrospective study of 22 Turkish patients with APD; 1 patient had a painful hyperkeratotic papule on the auricle that on histopathology showed degenerated elastin perforating through the keratotic plug, features similar to our case.

Differential Diagnosis
The differential diagnoses include perforating diseases^14,19 as well as other disorders that exhibit the Köbner phenomenon, such as psoriasis, lichen planus, and verruca vulgaris.^21,22 Also, it is not uncommon for patients with APD to have coexisting folliculitis or prurigo nodularis.²²

Treatment
Management is focused on treating the symptoms. For pruritus, sedating antihistamines and other antipruritic agents are efficacious.²³ Topical, intra-lesional, or systemic corticosteroids and topical retinoids have shown variable resolution in APD lesions.²⁴ Some case reports describe topical menthol, salicylic acid, sulfur, benzoyl peroxide, systemic antibiotics (eg, clindamycin, doxycycline), and allopurinol for elevated uric acid levels as effective treatment methods.⁶ Narrowband UVB phototherapy is beneficial for APD and renal disease.^25,26 Renal transplantation has been curative for some patients with APD.²⁷ Given that our patient’s lesions were asymptomatic, no treatment was offered at the time.

Conclusion

Our patient presented with APD localized exclusively to the site of a skin graft, and histologic examination identified elastin as the primary perforating substance. A medical history of DM and chronic kidney disease predisposes patients to APD. This case suggests that skin graft sites may be predisposed to the development of APD.

NEW YORK – Despite initial concerns that stopping tyrosine kinase inhibitor treatment would be ill-advised in patients with chronic myeloid leukemia (CML), clinical trial data suggest it is a safe and reasonable strategy, according to a leading expert.

“About 95% of people in all of these trials will regain their original response when they start off on therapy again,” said Jerald P. Radich, MD, of Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance.

“There’s been a few that don’t, but blast crisis has been very, very rare, thank goodness, so it looks to be fairly safe for now,” Dr. Radich said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

That being said, careful follow up is still required, Dr. Radich cautioned, noting that there was still an excess of CML in Hiroshima and Nagasaki atomic bomb survivors evident decades after radiation exposure.

“CML is a very strange disease,” he said. “You can’t eliminate the possibility of some slow-growing clone that, once you take [a patient] off tyrosine kinase therapy, is going into an accelerated phase and might take years to manifest itself.”

In one of the latest reports to shed light on what happens after discontinuation, investigators for the ENESTop study reported that treatment-free remission “seems achievable” in patients who have sustained, deep remissions after discontinuing nilotinib second-line therapy (Ann Intern Med. 2018 Apr 3;168[7]:461-70).

In ENESTop, chronic phase CML patients on tyrosine kinase inhibitors for at least 3 years were eligible to discontinue therapy if they achieved MR^4.5 (BCR-ABL1IS of 0.0032% or less) and maintained that response level during a 1-year consolidation phase.

Out of 163 patients in the study, 126 met the criteria to enter the treatment-free remission phase; of that subset, 58% maintained treatment-free remission at 48 weeks, while 53% maintained it at 96 weeks, investigators said.

For 56 patients who restarted nilotinib, 55 regained at least major molecular response (MMR), and 52 regained MR^4.5, while none had progression to accelerated phase or blast crisis, according to the report.

Similarly, earlier reported results from the ENESTfreedom trial showed that, of 190 patients entering the treatment-free remission phase after a median duration of 43.5 months on nilotinib, more than half remained in MMR or better at 48 weeks (Leukemia. 2017 Jul;31[7]:1525-31).

Of 86 patients who started nilotinib again after losing MMR, 98.8% regained MMR and 88.4% regained MR^4.5 by the data cutoff date for the trial.

Duration and depth of response may make a “little bit of difference” in likelihood of relapse, Dr. Radich added.

In an interim analysis of a prospective multicenter, nonrandomized European discontinuation trial (EURO-SKI), investigators found that patients achieving deep molecular responses had good molecular relapse-free survival (Lancet Oncol. 2018 Jun;19[6]:747-57).

Based on that, investigators suggested that patients with deep molecular responses should be considered for discontinuation to spare them from side effects and to reduce health expenditures.

Results of these and other trials are “pretty much unbelievable,” Dr. Radich said. That’s in part because mathematical modeling – extrapolated from early trials – had suggested it could take nearly 50 years to completely eradicate minimal residual disease with tyrosine kinase inhibitors, and that the cumulative cure rate after 30 years of treatment could be as low as 31%.

Dr. Radich reported financial disclosures related to Amgen, Novartis, and Seattle Genetics.

NEW YORK – Despite initial concerns that stopping tyrosine kinase inhibitor treatment would be ill-advised in patients with chronic myeloid leukemia (CML), clinical trial data suggest it is a safe and reasonable strategy, according to a leading expert.

“About 95% of people in all of these trials will regain their original response when they start off on therapy again,” said Jerald P. Radich, MD, of Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance.

“There’s been a few that don’t, but blast crisis has been very, very rare, thank goodness, so it looks to be fairly safe for now,” Dr. Radich said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

That being said, careful follow up is still required, Dr. Radich cautioned, noting that there was still an excess of CML in Hiroshima and Nagasaki atomic bomb survivors evident decades after radiation exposure.

“CML is a very strange disease,” he said. “You can’t eliminate the possibility of some slow-growing clone that, once you take [a patient] off tyrosine kinase therapy, is going into an accelerated phase and might take years to manifest itself.”

In one of the latest reports to shed light on what happens after discontinuation, investigators for the ENESTop study reported that treatment-free remission “seems achievable” in patients who have sustained, deep remissions after discontinuing nilotinib second-line therapy (Ann Intern Med. 2018 Apr 3;168[7]:461-70).

In ENESTop, chronic phase CML patients on tyrosine kinase inhibitors for at least 3 years were eligible to discontinue therapy if they achieved MR^4.5 (BCR-ABL1IS of 0.0032% or less) and maintained that response level during a 1-year consolidation phase.

Out of 163 patients in the study, 126 met the criteria to enter the treatment-free remission phase; of that subset, 58% maintained treatment-free remission at 48 weeks, while 53% maintained it at 96 weeks, investigators said.

For 56 patients who restarted nilotinib, 55 regained at least major molecular response (MMR), and 52 regained MR^4.5, while none had progression to accelerated phase or blast crisis, according to the report.

Similarly, earlier reported results from the ENESTfreedom trial showed that, of 190 patients entering the treatment-free remission phase after a median duration of 43.5 months on nilotinib, more than half remained in MMR or better at 48 weeks (Leukemia. 2017 Jul;31[7]:1525-31).

Of 86 patients who started nilotinib again after losing MMR, 98.8% regained MMR and 88.4% regained MR^4.5 by the data cutoff date for the trial.

Duration and depth of response may make a “little bit of difference” in likelihood of relapse, Dr. Radich added.

In an interim analysis of a prospective multicenter, nonrandomized European discontinuation trial (EURO-SKI), investigators found that patients achieving deep molecular responses had good molecular relapse-free survival (Lancet Oncol. 2018 Jun;19[6]:747-57).

Based on that, investigators suggested that patients with deep molecular responses should be considered for discontinuation to spare them from side effects and to reduce health expenditures.

Results of these and other trials are “pretty much unbelievable,” Dr. Radich said. That’s in part because mathematical modeling – extrapolated from early trials – had suggested it could take nearly 50 years to completely eradicate minimal residual disease with tyrosine kinase inhibitors, and that the cumulative cure rate after 30 years of treatment could be as low as 31%.

Dr. Radich reported financial disclosures related to Amgen, Novartis, and Seattle Genetics.

NEW YORK – Despite initial concerns that stopping tyrosine kinase inhibitor treatment would be ill-advised in patients with chronic myeloid leukemia (CML), clinical trial data suggest it is a safe and reasonable strategy, according to a leading expert.

“About 95% of people in all of these trials will regain their original response when they start off on therapy again,” said Jerald P. Radich, MD, of Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance.

“There’s been a few that don’t, but blast crisis has been very, very rare, thank goodness, so it looks to be fairly safe for now,” Dr. Radich said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

That being said, careful follow up is still required, Dr. Radich cautioned, noting that there was still an excess of CML in Hiroshima and Nagasaki atomic bomb survivors evident decades after radiation exposure.

“CML is a very strange disease,” he said. “You can’t eliminate the possibility of some slow-growing clone that, once you take [a patient] off tyrosine kinase therapy, is going into an accelerated phase and might take years to manifest itself.”

In one of the latest reports to shed light on what happens after discontinuation, investigators for the ENESTop study reported that treatment-free remission “seems achievable” in patients who have sustained, deep remissions after discontinuing nilotinib second-line therapy (Ann Intern Med. 2018 Apr 3;168[7]:461-70).

In ENESTop, chronic phase CML patients on tyrosine kinase inhibitors for at least 3 years were eligible to discontinue therapy if they achieved MR^4.5 (BCR-ABL1IS of 0.0032% or less) and maintained that response level during a 1-year consolidation phase.

Out of 163 patients in the study, 126 met the criteria to enter the treatment-free remission phase; of that subset, 58% maintained treatment-free remission at 48 weeks, while 53% maintained it at 96 weeks, investigators said.

For 56 patients who restarted nilotinib, 55 regained at least major molecular response (MMR), and 52 regained MR^4.5, while none had progression to accelerated phase or blast crisis, according to the report.

Similarly, earlier reported results from the ENESTfreedom trial showed that, of 190 patients entering the treatment-free remission phase after a median duration of 43.5 months on nilotinib, more than half remained in MMR or better at 48 weeks (Leukemia. 2017 Jul;31[7]:1525-31).

Of 86 patients who started nilotinib again after losing MMR, 98.8% regained MMR and 88.4% regained MR^4.5 by the data cutoff date for the trial.

Duration and depth of response may make a “little bit of difference” in likelihood of relapse, Dr. Radich added.

In an interim analysis of a prospective multicenter, nonrandomized European discontinuation trial (EURO-SKI), investigators found that patients achieving deep molecular responses had good molecular relapse-free survival (Lancet Oncol. 2018 Jun;19[6]:747-57).

Based on that, investigators suggested that patients with deep molecular responses should be considered for discontinuation to spare them from side effects and to reduce health expenditures.

Results of these and other trials are “pretty much unbelievable,” Dr. Radich said. That’s in part because mathematical modeling – extrapolated from early trials – had suggested it could take nearly 50 years to completely eradicate minimal residual disease with tyrosine kinase inhibitors, and that the cumulative cure rate after 30 years of treatment could be as low as 31%.

Dr. Radich reported financial disclosures related to Amgen, Novartis, and Seattle Genetics.

Takeda Pharmaceuticals and Seattle Genetics announced top-line results in the ECHELON-2 phase 3 trial of brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, prednisone) in the frontline treatment of CD-30 expressing peripheral T-cell lymphoma (PTCL).

The combination achieved statistically significant improvement in progression-free survival (PFS), compared with the control arm of standard chemotherapy alone using cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The PFS was assessed by an Independent Review Facility (hazard ratio, 0.71; P = .0110).

The combination of brentuximab vedotin plus CHP also outperformed CHOP in overall survival, a secondary endpoint of the trial (hazard ratio, 0.66, P = .0244), according to the drug sponsors.

Full results of ECHELON-2 will be presented in December 2018 at the annual meeting of the American Society of Hematology, according to the announcement from Seattle Genetics and Takeda.
 

Takeda Pharmaceuticals and Seattle Genetics announced top-line results in the ECHELON-2 phase 3 trial of brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, prednisone) in the frontline treatment of CD-30 expressing peripheral T-cell lymphoma (PTCL).

The combination achieved statistically significant improvement in progression-free survival (PFS), compared with the control arm of standard chemotherapy alone using cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The PFS was assessed by an Independent Review Facility (hazard ratio, 0.71; P = .0110).

The combination of brentuximab vedotin plus CHP also outperformed CHOP in overall survival, a secondary endpoint of the trial (hazard ratio, 0.66, P = .0244), according to the drug sponsors.

Full results of ECHELON-2 will be presented in December 2018 at the annual meeting of the American Society of Hematology, according to the announcement from Seattle Genetics and Takeda.
 

Takeda Pharmaceuticals and Seattle Genetics announced top-line results in the ECHELON-2 phase 3 trial of brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, prednisone) in the frontline treatment of CD-30 expressing peripheral T-cell lymphoma (PTCL).

The combination achieved statistically significant improvement in progression-free survival (PFS), compared with the control arm of standard chemotherapy alone using cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The PFS was assessed by an Independent Review Facility (hazard ratio, 0.71; P = .0110).

The combination of brentuximab vedotin plus CHP also outperformed CHOP in overall survival, a secondary endpoint of the trial (hazard ratio, 0.66, P = .0244), according to the drug sponsors.

Full results of ECHELON-2 will be presented in December 2018 at the annual meeting of the American Society of Hematology, according to the announcement from Seattle Genetics and Takeda.
 

I’m not sure why I read the “Letter from the President” in the American Academy of Pediatrics’ AAP News every month. I guess it is out of curiosity about how far the guild to which I belong is drifting from where I think it should be going.

Getty Images

In her August 2018 letter, Colleen A. Kraft, MD, lays out the challenges pediatricians will be facing in the next several decades as the “era of health care consumerism” engulfs us, a change that she suggests will mean “redefining the patient/provider relationship.” As an example, she observes that millennial parents who want “personalized care when and where they want it” have become our “new target market.” Dr. Kraft goes on to suggest that telemedicine may provide a way to reconcile the millennials’ two seemingly incompatible demands. However, she notes that only “15% of pediatricians report using telehealth technologies to provide patient care.” Dr. Kraft recommends that to survive the rising waters of health consumerism more of us should consider climbing onto the telemedicine ship.

There is no question that millennials are aging into the childbearing and child-rearing phases of their lives. They have become the major consumers of pediatric services. Is Dr. Kraft correct that we must change how we practice pediatrics to accommodate the I-want-it-now-delivered-to-my-inbox mentality of the millennials? If we fail to adjust, will we be committing financial suicide?

She makes a valid point. If your practice isn’t providing evening and weekend hours, if your patients’ calls aren’t being answered in a timely manner, and if your receptionists are more about deflecting calls than helping patients get their questions answered, you are running the risk of choking off your income stream to an unsustainable trickle.

But how far should we chase that “target market” made up of people who believe that they can receive personalized care without putting a wrinkle in their device-driven lives? It may be that they have never experienced the benefits of real personalized service from the same person encounter after encounter. I’m convinced that if you provide quality care that is reasonably available, enough patients will stick with you to make your practice sustainable. You will lose some impatient patients to walk-in-quick-care operations, but if you are giving good personalized care, many will return to the quality you are offering. But if you aren’t willing to consider improving your availability, even being the most personable provider in town isn’t going to keep you afloat.

Now to the claim that telemedicine may hold the answer to surviving consumerism. I think we must move cautiously. The fact that only 15% of us aren’t climbing on board doesn’t mean we are all Luddites. It is very likely that many of us are still feeling the sting of investing large amounts of money and time to computerize our health records and seeing little benefit. Telemedicine means lots of things to lots of people. It won’t hurt to keep an open mind and listen as technology evolves. But if you had it to do all over again, wouldn’t you have taken more time and given more thought into signing on for your electronic medical records system?

Finally, let’s remember millennials will be followed by another generation. Although some “experts” suggest that the post-millennials will be just more of the same, I’m not so sure. Millennials and their expectations have become fodder for comedians, even from within their own cohort. The post-millennials may surprise us and provide a refreshing breath of retro and a market that is much easier to reconcile with the realities of good patient care.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

I’m not sure why I read the “Letter from the President” in the American Academy of Pediatrics’ AAP News every month. I guess it is out of curiosity about how far the guild to which I belong is drifting from where I think it should be going.

Getty Images

In her August 2018 letter, Colleen A. Kraft, MD, lays out the challenges pediatricians will be facing in the next several decades as the “era of health care consumerism” engulfs us, a change that she suggests will mean “redefining the patient/provider relationship.” As an example, she observes that millennial parents who want “personalized care when and where they want it” have become our “new target market.” Dr. Kraft goes on to suggest that telemedicine may provide a way to reconcile the millennials’ two seemingly incompatible demands. However, she notes that only “15% of pediatricians report using telehealth technologies to provide patient care.” Dr. Kraft recommends that to survive the rising waters of health consumerism more of us should consider climbing onto the telemedicine ship.

There is no question that millennials are aging into the childbearing and child-rearing phases of their lives. They have become the major consumers of pediatric services. Is Dr. Kraft correct that we must change how we practice pediatrics to accommodate the I-want-it-now-delivered-to-my-inbox mentality of the millennials? If we fail to adjust, will we be committing financial suicide?

She makes a valid point. If your practice isn’t providing evening and weekend hours, if your patients’ calls aren’t being answered in a timely manner, and if your receptionists are more about deflecting calls than helping patients get their questions answered, you are running the risk of choking off your income stream to an unsustainable trickle.

But how far should we chase that “target market” made up of people who believe that they can receive personalized care without putting a wrinkle in their device-driven lives? It may be that they have never experienced the benefits of real personalized service from the same person encounter after encounter. I’m convinced that if you provide quality care that is reasonably available, enough patients will stick with you to make your practice sustainable. You will lose some impatient patients to walk-in-quick-care operations, but if you are giving good personalized care, many will return to the quality you are offering. But if you aren’t willing to consider improving your availability, even being the most personable provider in town isn’t going to keep you afloat.

Now to the claim that telemedicine may hold the answer to surviving consumerism. I think we must move cautiously. The fact that only 15% of us aren’t climbing on board doesn’t mean we are all Luddites. It is very likely that many of us are still feeling the sting of investing large amounts of money and time to computerize our health records and seeing little benefit. Telemedicine means lots of things to lots of people. It won’t hurt to keep an open mind and listen as technology evolves. But if you had it to do all over again, wouldn’t you have taken more time and given more thought into signing on for your electronic medical records system?

Finally, let’s remember millennials will be followed by another generation. Although some “experts” suggest that the post-millennials will be just more of the same, I’m not so sure. Millennials and their expectations have become fodder for comedians, even from within their own cohort. The post-millennials may surprise us and provide a refreshing breath of retro and a market that is much easier to reconcile with the realities of good patient care.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

I’m not sure why I read the “Letter from the President” in the American Academy of Pediatrics’ AAP News every month. I guess it is out of curiosity about how far the guild to which I belong is drifting from where I think it should be going.

Getty Images

In her August 2018 letter, Colleen A. Kraft, MD, lays out the challenges pediatricians will be facing in the next several decades as the “era of health care consumerism” engulfs us, a change that she suggests will mean “redefining the patient/provider relationship.” As an example, she observes that millennial parents who want “personalized care when and where they want it” have become our “new target market.” Dr. Kraft goes on to suggest that telemedicine may provide a way to reconcile the millennials’ two seemingly incompatible demands. However, she notes that only “15% of pediatricians report using telehealth technologies to provide patient care.” Dr. Kraft recommends that to survive the rising waters of health consumerism more of us should consider climbing onto the telemedicine ship.

There is no question that millennials are aging into the childbearing and child-rearing phases of their lives. They have become the major consumers of pediatric services. Is Dr. Kraft correct that we must change how we practice pediatrics to accommodate the I-want-it-now-delivered-to-my-inbox mentality of the millennials? If we fail to adjust, will we be committing financial suicide?

She makes a valid point. If your practice isn’t providing evening and weekend hours, if your patients’ calls aren’t being answered in a timely manner, and if your receptionists are more about deflecting calls than helping patients get their questions answered, you are running the risk of choking off your income stream to an unsustainable trickle.

But how far should we chase that “target market” made up of people who believe that they can receive personalized care without putting a wrinkle in their device-driven lives? It may be that they have never experienced the benefits of real personalized service from the same person encounter after encounter. I’m convinced that if you provide quality care that is reasonably available, enough patients will stick with you to make your practice sustainable. You will lose some impatient patients to walk-in-quick-care operations, but if you are giving good personalized care, many will return to the quality you are offering. But if you aren’t willing to consider improving your availability, even being the most personable provider in town isn’t going to keep you afloat.

Now to the claim that telemedicine may hold the answer to surviving consumerism. I think we must move cautiously. The fact that only 15% of us aren’t climbing on board doesn’t mean we are all Luddites. It is very likely that many of us are still feeling the sting of investing large amounts of money and time to computerize our health records and seeing little benefit. Telemedicine means lots of things to lots of people. It won’t hurt to keep an open mind and listen as technology evolves. But if you had it to do all over again, wouldn’t you have taken more time and given more thought into signing on for your electronic medical records system?

Finally, let’s remember millennials will be followed by another generation. Although some “experts” suggest that the post-millennials will be just more of the same, I’m not so sure. Millennials and their expectations have become fodder for comedians, even from within their own cohort. The post-millennials may surprise us and provide a refreshing breath of retro and a market that is much easier to reconcile with the realities of good patient care.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].