Melanoma

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

Circulating tumor DNA could be effectively isolated from plasma by focusing on a particular range of fragment sizes, which paves the way for noninvasive genomic analysis of tumor DNA, new research suggests.

In a study of 344 plasma samples from 200 patients with 18 cancer types and 65 samples from healthy controls, DNA fragment length could be used to distinguish circulating tumor DNA (ctDNA) from other cell-free DNA (cfDNA), investigators reported in Science Translational Medicine.

“We hypothesized that we could improve the sensitivity for noninvasive cancer genomics by selective sequencing of ctDNA fragments and by leveraging differences in the biology that determine DNA fragmentation,” wrote Florent Mouliere, PhD, from the Cancer Research UK Cambridge Institute, and coauthors.

Cell-free plasma fragments are often cleaved at around 167 base pairs in length and differences in length between circulating fetal and maternal DNA are already used for noninvasive prenatal diagnosis. However, the authors said that only a few studies, with conflicting results, have looked at the size distribution of tumor-derived cfDNA.

The study used two approaches to determining the size profile of mutant ctDNA. The first looked at tumor and nontumor cfDNA in mice with human ovarian cancer xenografts and the second approach used deep sequencing in 19 cancer patients. This revealed that tumor-derived cfDNA was most commonly found in fragments between 90-150 base pairs or 250-320 base pairs in size.

The researchers also noted that mutant circulating tumor DNA was generally more fragmented than nonmutant cfDNA and that patients with untreated advanced cancer showed consistently shorter lengths of mutant DNA.

The next question was whether size selection and other biological properties – such as somatic alterations – of the cfDNA could be used to enhance detection of ctDNA via machine learning technology.

Two models, designed to distinguish between healthy and cancerous samples, were developed using 153 samples, then validated on two datasets of 94 and 83 samples.

One of these models correctly classified cancerous samples in 94% of samples from patients with cancers known to have high levels of ctDNA – colorectal, cholangiocarcinoma, ovarian, breast, and melanoma – and in 65% of samples from low-ctDNA cancers – pancreatic, renal, and glioma.

Another model focused just on fragmentation patterns and was still able to distinguish cancer samples from those of healthy controls, although with slightly reduced area under the curve.

“Our results indicate that exploiting fundamental properties of cfDNA with fragment-specific analyses can allow more sensitive evaluation of ctDNA,” the authors wrote. “We identified features that could determine the presence and amount of ctDNA in plasma samples, without a prior knowledge of somatic aberrations.”

The authors pointed out that size selection of DNA fragments was relatively simple and cheap, and was also compatible with other genome-wide and targeted genomic analyses, “greatly increasing the potential value and utility of liquid biopsies as well as the cost-effectiveness of cfDNA sequencing.”

However, they cautioned that their catalogue had focused solely on double-stranded DNA and was subject to potential biases from the DNA extraction and sequencing methods they used in the study. They also commented that other biological effects could help refine the analysis of ctDNA.

“Other bodily fluids [urine, cerebrospinal fluid, and saliva], different nucleic acids and structures, altered mechanisms of release into circulation, or sample processing methods could exhibit varying fragment size signatures and could offer additional exploitable biological patterns for selective sequencing,” they wrote.

The study was supported by the University of Cambridge, Cancer Research UK, and the Engineering and Physical Sciences Research Council. Research supporting the study was also funded by the European Research Council, the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre, Hutchison Whampoa, Target Ovarian Cancer, the Medical Research Council, and AstraZeneca. Three authors are cofounders, shareholders, and officers/consultants in a company specializing in ctDNA analysis. One author declared research funding and advisory board fees from private industry. Seven authors are listed on related patents.

SOURCE: Mouliere F et al. Sci Transl Med. 2018 Nov 7. doi: 10.1126/scitranslmed.aat4921.
 

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

MUNICH – Four years on, the combination of the immune checkpoint inhibitors nivolumab and ipilimumab as well as nivolumab alone continue to show benefit as first-line therapies for patients with advanced malignant melanoma, compared with ipilimumab monotherapy, reported investigators in the CheckMate O67 trial.

Among 945 patients with previously untreated and unresectable stage III or IV malignant melanoma, median overall survival at a minimum of 48 months follow-up had not been reached for patients assigned to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), compared with 36.9 months for patients assigned to nivolumab alone, and 19.9 months for patients assigned to ipilimumab alone, reported F. Stephen Hodi Jr., MD, of Dana-Farber Cancer Institute, Boston, and his colleagues.

“There’s a durable, sustained clinical benefit that can be achieved with first-line nivo plus ipi combination or nivo alone in patients with advanced melanoma,” he said at the European Society for Medical Oncology Congress. The study results were published online in The Lancet Oncology to coincide with the presentation.

The benefit of immunotherapy also was seen in patients whose tumors had BRAF mutations, and both the combination and nivolumab alone showed improved efficacy compared with ipilimumab alone regardless of tumor expression of the programmed death ligand-1 (PD-L1), the investigators reported.

As previously reported, investigators in CheckMate 067 randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses then nivolumab 3 mg/kg every 2 weeks, or ipilimumab 3 mg/kg every 3 weeks for four doses. Patients were stratified at baseline by PD-L1 expression, BRAF status, and American Joint Commission on Cancer M stage.

Earlier results from the trial, reported at the 2015 annual meeting of the American Society of Clinical Oncology, showed that after a minimum of 9 months follow-up, the risk of disease progression or death was reduced by 43% with nivolumab versus ipilimumab (hazard ratio, 0.57; P less than .001) and by 58% with nivolumab plus ipilimumab vs. ipilimumab (HR, 0.42; P less than .001).

At ESMO 2018, Dr. Hodi presented 4-year follow-up results from the trial, with the analysis conducted at a minimum of 4 years after randomization of the last patient to be enrolled.

Median follow-up was 46.9 months for the nivolumab-plus-ipilimumab arm, 36 months in the nivolumab arm, and 18.6 months in the ipilimumab arm.

Median overall survival in the intention-to-treat population, a coprimary endpoint with progression-free survival (PFS), was as noted before. The HR for death with the combination compared with ipilimumab was 0.54 (P less than .0001) and for nivolumab versus ipilimumab it was 0.65 (P less than .0001).

The 4-year OS rates were 53% in the combination arm, 46% in the nivolumab-alone arm, and 30% in the ipilimumab-alone arm.

Median PFS was 11.5 months with the checkpoint inhibitor combination, 6.9 months in the nivolumab-alone arm, and 2.9 months in the ipilimumab arm.

The HR for PFS with the combination compared with ipilimumab was 0.42 (P less than .0001), and for nivolumab versus ipilimumab it was 0.53 (P less than .0001).

The safety analysis, conducted in all patients who received at least one dose of study drugs, showed that 59% of patients treated with the nivolumab/ipilimumab combination had treatment-related grade 3 or 4 adverse events, compared with 22% for patients treated with nivolumab alone, and 28% of those who received ipilimumab alone.

The most common treatment-related grade 3 adverse events were diarrhea in the combination and nivolumab-alone arms, and colitis in the ipilimumab group. In all three study arms the most common grade 4 adverse event was increased lipase.

Over the 4 years of follow-up, four patients died from treatment-related causes: one patient from cardiomyopathy and one from liver necrosis in the combination group, one from neutropenia in the nivolumab group, and one from colon perforation in the ipilimumab group. All of the deaths occurred within the first 3 years of the follow-up.

The investigators did not report on serious adverse events in the current analysis.

Invited discussant Reinhard Dummer, MD, of University Hospital Zurich Skin Cancer Center in Switzerland, said that while the study shows improved response rates and duration of response and longer PFS and OS with the combination, it’s premature to state conclusively that the combination is superior, because the study was not powered to compare efficacy between the two nivolumab-containing arms.

“So unfortunately, we have results, but we are not really convinced that the combination is so much better,” he said.

He added that the 4-year overall survival results for each arm show a consistent difference in the curves between the nivolumab and ipilimumab-alone arms. He also pointed to encouraging data showing that among patients alive at 4 years, 71% in the combination group did not require subsequent therapy, compared with 50% in the nivolumab group, and 39% in the ipilimumab group.

Dr. Hodi has received grant/research support from, and is a nonpaid consultant to, Bristol-Myers Squibb, which supported Checkmate 067. Dr. Dummer reported advising/consulting roles with the company.

SOURCE: Hodi FS et al. Lancet Oncol. 2018 Oct 22. doi: 10.1016/S1470-2045(18)30700-9.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.^1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.

Case Report

A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.

The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm² with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.

Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm², and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.

For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.

Comment

Shah et al³ reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.^1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.

In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.⁶ Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.⁷ Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.

The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.

Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.

Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.^1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.

Case Report

A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.

The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm² with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.

Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm², and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.

For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.

Comment

Shah et al³ reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.^1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.

In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.⁶ Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.⁷ Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.

The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.

Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.

Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.^1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.

Case Report

A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.

The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm² with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.

Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm², and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.

For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.

Comment

Shah et al³ reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.^1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.

In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.⁶ Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.⁷ Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.

The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.

Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Checkpoint inhibitors are so new that not enough patients have received them to allow clinicians to predict who will benefit most. But researchers from the National Cancer Institute, Center for Cancer Institute; Harvard University in Cambridge, Massachusetts; University of Pennsylvania in Philadelphia; and University of Maryland in College Park may have found a clue: A gene expression predictor.

They began by looking at neuroblastoma cases where the immune system seemed to mount “an unprompted, successful immune response” to cancer, causing spontaneous tumor regression. The researchers were able to define gene expression features that separated regressing from nonregressing disease.

The researchers then computed Immuno-PREdictive Scores (IMPRES) for each patient sample. The higher the score, the more likely was spontaneous regression. Analyzing 297 samples from several studies, they found the predictor identified nearly all patients who responded to the inhibitors and more than half of those who did not. “Importantly,” the researchers say, their predictor was accurate across many different melanoma patient datasets.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

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.

As technology continues to advance, so too does its accessibility to the general population. In 2013, 56% of Americans owned a smartphone versus 77% in 2017.¹With the increase in mobile applications (apps) available, it is no surprise that the market has extended into the medical field, with dermatology being no exception.² The majority of dermatology apps can be classified as teledermatology apps, followed by self-surveillance, disease guide, and reference apps. Additional types of dermatology apps include dermoscopy, conference, education, photograph storage and sharing, and journal apps, and others.² In this study, we examined Apple App Store rankings to determine the types of dermatology apps that are most popular among patients and physicians.

METHODS

A popular app rankings analyzer (App Annie) was used to search for dermatology apps along with their App Store rankings.³ Although iOS is not the most popular mobile device operating system, we chose to evaluate app rankings via the App Store because iPhones are the top-selling individual phones of any kind in the United States.⁴

We performed our analysis on a single day (July 14, 2018) given that app rankings can change daily. We incorporated the following keywords, which were commonly used in other dermatology app studies: dermatology, psoriasis, rosacea, acne, skin cancer, melanoma, eczema, and teledermatology. The category ranking was defined as the rank of a free or paid app in the App Store’s top charts for the selected country (United States), market (Apple), and device (iPhone) within their app category (Medical). Inclusion criteria required a ranking in the top 1500 Medical apps and being categorized in the App Store as a Medical app. Exclusion criteria included apps that focused on cosmetics, private practice, direct advertisements, photograph editing, or claims to cure skin disease, as well as non–English-language apps. The App Store descriptions were assessed to determine the type of each app (eg, teledermatology, disease guide) and target audience (patient, physician, or both).

Another search was performed using the same keywords but within the Health and Fitness category to capture potentially more highly ranked apps among patients. We also conducted separate searches within the Medical category using the keywords billing, coding, and ICD (International Classification of Diseases) to evaluate rankings for billing/coding apps, as well as EMR and electronic medical records for electronic medical record (EMR) apps.

RESULTS

The initial search yielded 851 results, which was narrowed down to 29 apps after applying the exclusion criteria. Of note, prior to application of the exclusion criteria, one dermatology app that was considered to be a direct advertisement app claiming to cure acne was ranked fourth of 1500 apps in the Medical category. However, the majority of the search results were excluded because they were not popular enough to be ranked among the top 1500 apps. There were more ranked dermatology apps in the Medical category targeting patients than physicians; 18 of 29 (62%) qualifying apps targeted patients and 11 (38%) targeted physicians (Tables 1 and 2). No apps targeted both groups. The most common type of ranked app targeting patients was self-surveillance (11/18), and the most common type targeting physicians was reference (8/11). The highest ranked app targeting patients was a teledermatology app with a ranking of 184, and the highest ranked app targeting physicians was educational, ranked 353. The least common type of ranked apps targeting patients were “other” (2/18 [11%]; 1 prescription and 1 UV monitor app) and conference (1/18 [6%]). The least common type of ranked apps targeting physicians were education (2/11 [18%]) and dermoscopy (1/11 [9%]).

Our search of the Health and Fitness category yielded 6 apps, all targeting patients; 3 (50%) were self-surveillance apps, and 3 (50%) were classified as other (2 UV monitors and a conferencing app for cancer emotional support)(Table 3).

Our search of the Medical category for billing/coding and EMR apps yielded 232 and 164 apps, respectively; of them, 49 (21%) and 54 (33%) apps were ranked. These apps did not overlap with the dermatology-related search criteria; thus, we were not able to ascertain how many of these apps were used specifically by health care providers in dermatology.

COMMENT

Patient Apps

The most common apps used by patients are fitness and nutrition tracker apps categorized as Health and Fitness^5,6; however, the majority of ranked dermatology apps are categorized as Medical per our findings. In a study of 557 dermatology patients, it was found that among the health-related apps they used, the most common apps after fitness/nutrition were references, followed by patient portals, self-surveillance, and emotional assistance apps.⁶ Our search was consistent with these findings, suggesting that the most desired dermatology apps by patients are those that allow them to be proactive with their health. It is no surprise that the top-ranked app targeting patients was a teledermatology app, followed by multiple self-surveillance apps. The highest ranked self-surveillance app in the Health and Fitness category focused on monitoring the effects of nutrition on symptoms of diseases including skin disorders, while the highest ranked (as well as the majority of) self-surveillance apps in the Medical category encompassed mole monitoring and cancer risk calculators.

Benefits of the ranked dermatology apps in the Medical and Health and Fitness categories targeting patients include more immediate access to health care and education. Despite this popularity among patients, Masud et al⁷ demonstrated that only 20.5% (9/44) of dermatology apps targeting patients may be reliable resources based on a rubric created by the investigators. Overall, there remains a research gap for a standardized scientific approach to evaluating app validity and reliability.

Teledermatology
Teledermatology apps are the most common dermatology apps,² allowing for remote evaluation of patients through either live consultations or transmittance of medical information for later review by board-certified physicians.⁸ Features common to many teledermatology apps include accessibility on Android (Google Inc) and iOS as well as a web version. Security and Health Insurance Portability and Accountability Act compliance is especially important and is enforced through user authentications, data encryption, and automatic logout features. Data is not stored locally and is secured on a private server with backup. Referring providers and consultants often can communicate within the app. Insurance providers also may cover teledermatology services, and if not, the out-of-pocket costs often are affordable.

The highest-ranked patient app (ranked 184 in the Medical category) was a teledermatology app that did not meet the American Telemedicine Association standards for teledermatology apps.⁹ The popularity of this app among patients may have been attributable to multiple ease-of-use and turnaround time features. The user interface was simplistic, and the design was appealing to the eye. The entry field options were minimal to avoid confusion. The turnaround time to receive a diagnosis depended on 1 of 3 options, including a more rapid response for an increased cost. Ease of use was the highlight of this app at the cost of accuracy, as the limited amount of information that users were required to provide physicians compromised diagnostic accuracy in this app.

For comparison, we chose a nonranked (and thus less frequently used) teledermatology app that had previously undergone scientific evaluation using 13 evaluation criteria specific to teledermatology.¹⁰ The app also met the American Telemedicine Association standard for teledermatology apps.⁹ The app was originally a broader telemedicine app but featured a section specific to teledermatology. The user interface was simple but professional, almost resembling an EMR. The input fields included a comprehensive history that permitted a better evaluation of a lesion but might be tedious for users. This app boasted professionalism and accuracy, but from a user standpoint, it may have been too time-consuming.

Striking a balance between ensuring proper care versus appealing to patients is a difficult but important task. Based on this study, it appears that popular patient apps may in fact have less scientific rationale and therefore potentially less accuracy.

Self-surveillance
Although self-surveillance apps did not account for the highest-ranked app, they were the most frequently ranked app type in our study. Most of the ranked self-surveillance apps in the Medical category were for monitoring lesions over time to assess for changes. These apps help users take photographs that are well organized in a single, easy-to-find location. Some apps were risk calculators that assessed the risk for malignancies using a questionnaire. The majority of these self-surveillance apps were specific to skin cancer detection. Of note, one of the ranked self-surveillance apps assessed drug effectiveness by monitoring clinical appearance and symptoms. The lowest ranked self-surveillance app in the top 1500 ranked Medical apps in our search monitored cancer symptoms not specific to dermatology. Although this app had a low ranking (1380/1500), it received a high number of reviews and was well rated at 4.8 out of 5 stars; therefore, it seemed more helpful than the other higher-ranked apps targeting patients, which had higher rankings but minimal to no reviews or ratings. A comparison of the ease-of-use features of all the ranked patient-targeted self-surveillance apps in the Medical category is provided in Table 4.

Physician Apps

After examining the results of apps targeting physicians, we realized that the data may be accurate but may not be as representative of all currently practicing dermatology providers. Given the increased usage of apps among younger age groups,¹¹ our data may be skewed toward medical students and residents, supported by the fact that the top-ranked physician app in our study was an education app and the majority were reference apps. Future studies are needed to reexamine app ranking as this age group transitions from entry-level health care providers in the next 5 to 10 years. These findings also suggest less frequent app use among more veteran health care providers within our specific search parameters. Therefore, we decided to do subsequent searches for available billing/coding and EMR apps, which were many, but as mentioned above, none were specific to dermatology.

General Dermatology References
Most of the dermatology reference apps were formatted as e-books; however, other apps such as the Amazon Kindle app (categorized under Books) providing access to multiple e-books within one app were not included. Some apps included study aid features (eg, flash cards, quizzes), and topics spanned both dermatology and dermatopathology. Apps provide a unique way for on-the-go studying for dermatologists in training, and if the usage continues to grow, there may be a need for increased formal integration in dermatology education in the future.

Journals
Journal apps were not among those listed in the top-ranked apps we evaluated, which we suspect may be because journals were categorized differently from one journal to the next; for example, the Journal of the American Academy of Dermatology was ranked 1168 in the Magazines and Newspapers category. On the other hand, Dermatology World was ranked 1363 in the Reference category. An article’s citation affects the publishing journal’s impact factor, which is one of the most important variables in measuring a journal’s influence. In the future, there may be other variables that could aid in understanding journal impact as it relates to the journal’s accessibility.

Limitations

Our study did not look at Android apps. The top chart apps in the Android and Apple App Stores use undisclosed algorithms likely involving different characteristics such as number of downloads, frequency of updates, number of reviews, ratings, and more. Thus, the rankings across these different markets would not be comparable. Although our choice of keywords stemmed from the majority of prior studies looking at dermatology apps, our search was limited due to the use of these specific keywords. To avoid skewing data by cross-comparison of noncomparable categories, we could not compare apps in the Medical category versus those in other categories.

CONCLUSION

There seems to be a disconnect between the apps that are popular among patients and the scientific validity of the apps. As app usage increases among dermatology providers, whose demographic is shifting younger and younger, apps may become more incorporated in our education, and as such, it will become more critical to develop formal scientific standards. Given these future trends, we may need to increase our current literature and understanding of apps in dermatology with regard to their impact on both patients and health care providers.

As technology continues to advance, so too does its accessibility to the general population. In 2013, 56% of Americans owned a smartphone versus 77% in 2017.¹With the increase in mobile applications (apps) available, it is no surprise that the market has extended into the medical field, with dermatology being no exception.² The majority of dermatology apps can be classified as teledermatology apps, followed by self-surveillance, disease guide, and reference apps. Additional types of dermatology apps include dermoscopy, conference, education, photograph storage and sharing, and journal apps, and others.² In this study, we examined Apple App Store rankings to determine the types of dermatology apps that are most popular among patients and physicians.

METHODS

A popular app rankings analyzer (App Annie) was used to search for dermatology apps along with their App Store rankings.³ Although iOS is not the most popular mobile device operating system, we chose to evaluate app rankings via the App Store because iPhones are the top-selling individual phones of any kind in the United States.⁴

We performed our analysis on a single day (July 14, 2018) given that app rankings can change daily. We incorporated the following keywords, which were commonly used in other dermatology app studies: dermatology, psoriasis, rosacea, acne, skin cancer, melanoma, eczema, and teledermatology. The category ranking was defined as the rank of a free or paid app in the App Store’s top charts for the selected country (United States), market (Apple), and device (iPhone) within their app category (Medical). Inclusion criteria required a ranking in the top 1500 Medical apps and being categorized in the App Store as a Medical app. Exclusion criteria included apps that focused on cosmetics, private practice, direct advertisements, photograph editing, or claims to cure skin disease, as well as non–English-language apps. The App Store descriptions were assessed to determine the type of each app (eg, teledermatology, disease guide) and target audience (patient, physician, or both).

Another search was performed using the same keywords but within the Health and Fitness category to capture potentially more highly ranked apps among patients. We also conducted separate searches within the Medical category using the keywords billing, coding, and ICD (International Classification of Diseases) to evaluate rankings for billing/coding apps, as well as EMR and electronic medical records for electronic medical record (EMR) apps.

RESULTS

The initial search yielded 851 results, which was narrowed down to 29 apps after applying the exclusion criteria. Of note, prior to application of the exclusion criteria, one dermatology app that was considered to be a direct advertisement app claiming to cure acne was ranked fourth of 1500 apps in the Medical category. However, the majority of the search results were excluded because they were not popular enough to be ranked among the top 1500 apps. There were more ranked dermatology apps in the Medical category targeting patients than physicians; 18 of 29 (62%) qualifying apps targeted patients and 11 (38%) targeted physicians (Tables 1 and 2). No apps targeted both groups. The most common type of ranked app targeting patients was self-surveillance (11/18), and the most common type targeting physicians was reference (8/11). The highest ranked app targeting patients was a teledermatology app with a ranking of 184, and the highest ranked app targeting physicians was educational, ranked 353. The least common type of ranked apps targeting patients were “other” (2/18 [11%]; 1 prescription and 1 UV monitor app) and conference (1/18 [6%]). The least common type of ranked apps targeting physicians were education (2/11 [18%]) and dermoscopy (1/11 [9%]).

Our search of the Health and Fitness category yielded 6 apps, all targeting patients; 3 (50%) were self-surveillance apps, and 3 (50%) were classified as other (2 UV monitors and a conferencing app for cancer emotional support)(Table 3).

Our search of the Medical category for billing/coding and EMR apps yielded 232 and 164 apps, respectively; of them, 49 (21%) and 54 (33%) apps were ranked. These apps did not overlap with the dermatology-related search criteria; thus, we were not able to ascertain how many of these apps were used specifically by health care providers in dermatology.

COMMENT

Patient Apps

The most common apps used by patients are fitness and nutrition tracker apps categorized as Health and Fitness^5,6; however, the majority of ranked dermatology apps are categorized as Medical per our findings. In a study of 557 dermatology patients, it was found that among the health-related apps they used, the most common apps after fitness/nutrition were references, followed by patient portals, self-surveillance, and emotional assistance apps.⁶ Our search was consistent with these findings, suggesting that the most desired dermatology apps by patients are those that allow them to be proactive with their health. It is no surprise that the top-ranked app targeting patients was a teledermatology app, followed by multiple self-surveillance apps. The highest ranked self-surveillance app in the Health and Fitness category focused on monitoring the effects of nutrition on symptoms of diseases including skin disorders, while the highest ranked (as well as the majority of) self-surveillance apps in the Medical category encompassed mole monitoring and cancer risk calculators.

Benefits of the ranked dermatology apps in the Medical and Health and Fitness categories targeting patients include more immediate access to health care and education. Despite this popularity among patients, Masud et al⁷ demonstrated that only 20.5% (9/44) of dermatology apps targeting patients may be reliable resources based on a rubric created by the investigators. Overall, there remains a research gap for a standardized scientific approach to evaluating app validity and reliability.

Teledermatology
Teledermatology apps are the most common dermatology apps,² allowing for remote evaluation of patients through either live consultations or transmittance of medical information for later review by board-certified physicians.⁸ Features common to many teledermatology apps include accessibility on Android (Google Inc) and iOS as well as a web version. Security and Health Insurance Portability and Accountability Act compliance is especially important and is enforced through user authentications, data encryption, and automatic logout features. Data is not stored locally and is secured on a private server with backup. Referring providers and consultants often can communicate within the app. Insurance providers also may cover teledermatology services, and if not, the out-of-pocket costs often are affordable.

The highest-ranked patient app (ranked 184 in the Medical category) was a teledermatology app that did not meet the American Telemedicine Association standards for teledermatology apps.⁹ The popularity of this app among patients may have been attributable to multiple ease-of-use and turnaround time features. The user interface was simplistic, and the design was appealing to the eye. The entry field options were minimal to avoid confusion. The turnaround time to receive a diagnosis depended on 1 of 3 options, including a more rapid response for an increased cost. Ease of use was the highlight of this app at the cost of accuracy, as the limited amount of information that users were required to provide physicians compromised diagnostic accuracy in this app.

For comparison, we chose a nonranked (and thus less frequently used) teledermatology app that had previously undergone scientific evaluation using 13 evaluation criteria specific to teledermatology.¹⁰ The app also met the American Telemedicine Association standard for teledermatology apps.⁹ The app was originally a broader telemedicine app but featured a section specific to teledermatology. The user interface was simple but professional, almost resembling an EMR. The input fields included a comprehensive history that permitted a better evaluation of a lesion but might be tedious for users. This app boasted professionalism and accuracy, but from a user standpoint, it may have been too time-consuming.

Striking a balance between ensuring proper care versus appealing to patients is a difficult but important task. Based on this study, it appears that popular patient apps may in fact have less scientific rationale and therefore potentially less accuracy.

Self-surveillance
Although self-surveillance apps did not account for the highest-ranked app, they were the most frequently ranked app type in our study. Most of the ranked self-surveillance apps in the Medical category were for monitoring lesions over time to assess for changes. These apps help users take photographs that are well organized in a single, easy-to-find location. Some apps were risk calculators that assessed the risk for malignancies using a questionnaire. The majority of these self-surveillance apps were specific to skin cancer detection. Of note, one of the ranked self-surveillance apps assessed drug effectiveness by monitoring clinical appearance and symptoms. The lowest ranked self-surveillance app in the top 1500 ranked Medical apps in our search monitored cancer symptoms not specific to dermatology. Although this app had a low ranking (1380/1500), it received a high number of reviews and was well rated at 4.8 out of 5 stars; therefore, it seemed more helpful than the other higher-ranked apps targeting patients, which had higher rankings but minimal to no reviews or ratings. A comparison of the ease-of-use features of all the ranked patient-targeted self-surveillance apps in the Medical category is provided in Table 4.

Physician Apps

After examining the results of apps targeting physicians, we realized that the data may be accurate but may not be as representative of all currently practicing dermatology providers. Given the increased usage of apps among younger age groups,¹¹ our data may be skewed toward medical students and residents, supported by the fact that the top-ranked physician app in our study was an education app and the majority were reference apps. Future studies are needed to reexamine app ranking as this age group transitions from entry-level health care providers in the next 5 to 10 years. These findings also suggest less frequent app use among more veteran health care providers within our specific search parameters. Therefore, we decided to do subsequent searches for available billing/coding and EMR apps, which were many, but as mentioned above, none were specific to dermatology.

General Dermatology References
Most of the dermatology reference apps were formatted as e-books; however, other apps such as the Amazon Kindle app (categorized under Books) providing access to multiple e-books within one app were not included. Some apps included study aid features (eg, flash cards, quizzes), and topics spanned both dermatology and dermatopathology. Apps provide a unique way for on-the-go studying for dermatologists in training, and if the usage continues to grow, there may be a need for increased formal integration in dermatology education in the future.

Journals
Journal apps were not among those listed in the top-ranked apps we evaluated, which we suspect may be because journals were categorized differently from one journal to the next; for example, the Journal of the American Academy of Dermatology was ranked 1168 in the Magazines and Newspapers category. On the other hand, Dermatology World was ranked 1363 in the Reference category. An article’s citation affects the publishing journal’s impact factor, which is one of the most important variables in measuring a journal’s influence. In the future, there may be other variables that could aid in understanding journal impact as it relates to the journal’s accessibility.

Limitations

Our study did not look at Android apps. The top chart apps in the Android and Apple App Stores use undisclosed algorithms likely involving different characteristics such as number of downloads, frequency of updates, number of reviews, ratings, and more. Thus, the rankings across these different markets would not be comparable. Although our choice of keywords stemmed from the majority of prior studies looking at dermatology apps, our search was limited due to the use of these specific keywords. To avoid skewing data by cross-comparison of noncomparable categories, we could not compare apps in the Medical category versus those in other categories.

CONCLUSION

There seems to be a disconnect between the apps that are popular among patients and the scientific validity of the apps. As app usage increases among dermatology providers, whose demographic is shifting younger and younger, apps may become more incorporated in our education, and as such, it will become more critical to develop formal scientific standards. Given these future trends, we may need to increase our current literature and understanding of apps in dermatology with regard to their impact on both patients and health care providers.

As technology continues to advance, so too does its accessibility to the general population. In 2013, 56% of Americans owned a smartphone versus 77% in 2017.¹With the increase in mobile applications (apps) available, it is no surprise that the market has extended into the medical field, with dermatology being no exception.² The majority of dermatology apps can be classified as teledermatology apps, followed by self-surveillance, disease guide, and reference apps. Additional types of dermatology apps include dermoscopy, conference, education, photograph storage and sharing, and journal apps, and others.² In this study, we examined Apple App Store rankings to determine the types of dermatology apps that are most popular among patients and physicians.

METHODS

A popular app rankings analyzer (App Annie) was used to search for dermatology apps along with their App Store rankings.³ Although iOS is not the most popular mobile device operating system, we chose to evaluate app rankings via the App Store because iPhones are the top-selling individual phones of any kind in the United States.⁴

We performed our analysis on a single day (July 14, 2018) given that app rankings can change daily. We incorporated the following keywords, which were commonly used in other dermatology app studies: dermatology, psoriasis, rosacea, acne, skin cancer, melanoma, eczema, and teledermatology. The category ranking was defined as the rank of a free or paid app in the App Store’s top charts for the selected country (United States), market (Apple), and device (iPhone) within their app category (Medical). Inclusion criteria required a ranking in the top 1500 Medical apps and being categorized in the App Store as a Medical app. Exclusion criteria included apps that focused on cosmetics, private practice, direct advertisements, photograph editing, or claims to cure skin disease, as well as non–English-language apps. The App Store descriptions were assessed to determine the type of each app (eg, teledermatology, disease guide) and target audience (patient, physician, or both).

Another search was performed using the same keywords but within the Health and Fitness category to capture potentially more highly ranked apps among patients. We also conducted separate searches within the Medical category using the keywords billing, coding, and ICD (International Classification of Diseases) to evaluate rankings for billing/coding apps, as well as EMR and electronic medical records for electronic medical record (EMR) apps.

RESULTS

The initial search yielded 851 results, which was narrowed down to 29 apps after applying the exclusion criteria. Of note, prior to application of the exclusion criteria, one dermatology app that was considered to be a direct advertisement app claiming to cure acne was ranked fourth of 1500 apps in the Medical category. However, the majority of the search results were excluded because they were not popular enough to be ranked among the top 1500 apps. There were more ranked dermatology apps in the Medical category targeting patients than physicians; 18 of 29 (62%) qualifying apps targeted patients and 11 (38%) targeted physicians (Tables 1 and 2). No apps targeted both groups. The most common type of ranked app targeting patients was self-surveillance (11/18), and the most common type targeting physicians was reference (8/11). The highest ranked app targeting patients was a teledermatology app with a ranking of 184, and the highest ranked app targeting physicians was educational, ranked 353. The least common type of ranked apps targeting patients were “other” (2/18 [11%]; 1 prescription and 1 UV monitor app) and conference (1/18 [6%]). The least common type of ranked apps targeting physicians were education (2/11 [18%]) and dermoscopy (1/11 [9%]).

Our search of the Health and Fitness category yielded 6 apps, all targeting patients; 3 (50%) were self-surveillance apps, and 3 (50%) were classified as other (2 UV monitors and a conferencing app for cancer emotional support)(Table 3).

Our search of the Medical category for billing/coding and EMR apps yielded 232 and 164 apps, respectively; of them, 49 (21%) and 54 (33%) apps were ranked. These apps did not overlap with the dermatology-related search criteria; thus, we were not able to ascertain how many of these apps were used specifically by health care providers in dermatology.

COMMENT

Patient Apps

The most common apps used by patients are fitness and nutrition tracker apps categorized as Health and Fitness^5,6; however, the majority of ranked dermatology apps are categorized as Medical per our findings. In a study of 557 dermatology patients, it was found that among the health-related apps they used, the most common apps after fitness/nutrition were references, followed by patient portals, self-surveillance, and emotional assistance apps.⁶ Our search was consistent with these findings, suggesting that the most desired dermatology apps by patients are those that allow them to be proactive with their health. It is no surprise that the top-ranked app targeting patients was a teledermatology app, followed by multiple self-surveillance apps. The highest ranked self-surveillance app in the Health and Fitness category focused on monitoring the effects of nutrition on symptoms of diseases including skin disorders, while the highest ranked (as well as the majority of) self-surveillance apps in the Medical category encompassed mole monitoring and cancer risk calculators.

Benefits of the ranked dermatology apps in the Medical and Health and Fitness categories targeting patients include more immediate access to health care and education. Despite this popularity among patients, Masud et al⁷ demonstrated that only 20.5% (9/44) of dermatology apps targeting patients may be reliable resources based on a rubric created by the investigators. Overall, there remains a research gap for a standardized scientific approach to evaluating app validity and reliability.

Teledermatology
Teledermatology apps are the most common dermatology apps,² allowing for remote evaluation of patients through either live consultations or transmittance of medical information for later review by board-certified physicians.⁸ Features common to many teledermatology apps include accessibility on Android (Google Inc) and iOS as well as a web version. Security and Health Insurance Portability and Accountability Act compliance is especially important and is enforced through user authentications, data encryption, and automatic logout features. Data is not stored locally and is secured on a private server with backup. Referring providers and consultants often can communicate within the app. Insurance providers also may cover teledermatology services, and if not, the out-of-pocket costs often are affordable.

The highest-ranked patient app (ranked 184 in the Medical category) was a teledermatology app that did not meet the American Telemedicine Association standards for teledermatology apps.⁹ The popularity of this app among patients may have been attributable to multiple ease-of-use and turnaround time features. The user interface was simplistic, and the design was appealing to the eye. The entry field options were minimal to avoid confusion. The turnaround time to receive a diagnosis depended on 1 of 3 options, including a more rapid response for an increased cost. Ease of use was the highlight of this app at the cost of accuracy, as the limited amount of information that users were required to provide physicians compromised diagnostic accuracy in this app.

For comparison, we chose a nonranked (and thus less frequently used) teledermatology app that had previously undergone scientific evaluation using 13 evaluation criteria specific to teledermatology.¹⁰ The app also met the American Telemedicine Association standard for teledermatology apps.⁹ The app was originally a broader telemedicine app but featured a section specific to teledermatology. The user interface was simple but professional, almost resembling an EMR. The input fields included a comprehensive history that permitted a better evaluation of a lesion but might be tedious for users. This app boasted professionalism and accuracy, but from a user standpoint, it may have been too time-consuming.

Striking a balance between ensuring proper care versus appealing to patients is a difficult but important task. Based on this study, it appears that popular patient apps may in fact have less scientific rationale and therefore potentially less accuracy.

Self-surveillance
Although self-surveillance apps did not account for the highest-ranked app, they were the most frequently ranked app type in our study. Most of the ranked self-surveillance apps in the Medical category were for monitoring lesions over time to assess for changes. These apps help users take photographs that are well organized in a single, easy-to-find location. Some apps were risk calculators that assessed the risk for malignancies using a questionnaire. The majority of these self-surveillance apps were specific to skin cancer detection. Of note, one of the ranked self-surveillance apps assessed drug effectiveness by monitoring clinical appearance and symptoms. The lowest ranked self-surveillance app in the top 1500 ranked Medical apps in our search monitored cancer symptoms not specific to dermatology. Although this app had a low ranking (1380/1500), it received a high number of reviews and was well rated at 4.8 out of 5 stars; therefore, it seemed more helpful than the other higher-ranked apps targeting patients, which had higher rankings but minimal to no reviews or ratings. A comparison of the ease-of-use features of all the ranked patient-targeted self-surveillance apps in the Medical category is provided in Table 4.

Physician Apps

After examining the results of apps targeting physicians, we realized that the data may be accurate but may not be as representative of all currently practicing dermatology providers. Given the increased usage of apps among younger age groups,¹¹ our data may be skewed toward medical students and residents, supported by the fact that the top-ranked physician app in our study was an education app and the majority were reference apps. Future studies are needed to reexamine app ranking as this age group transitions from entry-level health care providers in the next 5 to 10 years. These findings also suggest less frequent app use among more veteran health care providers within our specific search parameters. Therefore, we decided to do subsequent searches for available billing/coding and EMR apps, which were many, but as mentioned above, none were specific to dermatology.

General Dermatology References
Most of the dermatology reference apps were formatted as e-books; however, other apps such as the Amazon Kindle app (categorized under Books) providing access to multiple e-books within one app were not included. Some apps included study aid features (eg, flash cards, quizzes), and topics spanned both dermatology and dermatopathology. Apps provide a unique way for on-the-go studying for dermatologists in training, and if the usage continues to grow, there may be a need for increased formal integration in dermatology education in the future.

Journals
Journal apps were not among those listed in the top-ranked apps we evaluated, which we suspect may be because journals were categorized differently from one journal to the next; for example, the Journal of the American Academy of Dermatology was ranked 1168 in the Magazines and Newspapers category. On the other hand, Dermatology World was ranked 1363 in the Reference category. An article’s citation affects the publishing journal’s impact factor, which is one of the most important variables in measuring a journal’s influence. In the future, there may be other variables that could aid in understanding journal impact as it relates to the journal’s accessibility.

Limitations

Our study did not look at Android apps. The top chart apps in the Android and Apple App Stores use undisclosed algorithms likely involving different characteristics such as number of downloads, frequency of updates, number of reviews, ratings, and more. Thus, the rankings across these different markets would not be comparable. Although our choice of keywords stemmed from the majority of prior studies looking at dermatology apps, our search was limited due to the use of these specific keywords. To avoid skewing data by cross-comparison of noncomparable categories, we could not compare apps in the Medical category versus those in other categories.

CONCLUSION

There seems to be a disconnect between the apps that are popular among patients and the scientific validity of the apps. As app usage increases among dermatology providers, whose demographic is shifting younger and younger, apps may become more incorporated in our education, and as such, it will become more critical to develop formal scientific standards. Given these future trends, we may need to increase our current literature and understanding of apps in dermatology with regard to their impact on both patients and health care providers.

A patient with melanoma experienced antiphospholipid syndrome following multiple infusions of the PD-1 inhibitor pembrolizumab, according to authors of a recent case report.

Presence of Raynaud phenomenon and high levels of antiphospholipid antibodies led to the diagnosis of antiphospholipid syndrome in the patient, who had stage IIIB unresectable melanoma.

This report provides additional evidence that this syndrome is an immune-related adverse event associated with checkpoint inhibitor therapy, said Alexandra Picard, MD, of Hôpital Archet, Nice, France, and coauthors.

“Due to the increased use of anti PD-1 therapies, clinicians should be aware of this new potential immune-mediated toxic effect that manifests as antiphospholipid syndrome,” the researchers wrote. The report is in JAMA Dermatology.

“Great caution” should be exercised when considering use of immune checkpoint inhibitors in patients with a history of antiphospholipid syndrome, the authors added.

The woman in this report was over 60 years of age and had first presented with superficial melanoma on her right calf, followed by recurrent lymph node metastases over the next few years, all of which were surgically treated.

Following a PET-CT scan showing a new metastatic lymph node, the woman started pembrolizumab 2 mg/kg every 3 weeks and had a partial response within 3 months, the investigators reported.

After the tenth infusion, however, the patient developed bilateral secondary Raynaud phenomenon that followed a typical discoloration sequence and resulted in a necrotic lesion at the tip of one finger.

The patient had no personal or family history of Raynaud phenomenon.

While beta2-glycoprotein 1 antibodies were not elevated, laboratory tests did show anticardiolipin antibodies and lupus anticoagulants at elevated levels, the investigators said, noting that repeat testing at 12 weeks confirmed positivity of antiphospholipid antibodies.

The Raynaud phenomenon disappeared and the necrotic lesion healed after pembrolizumab was stopped and prednisolone treatment was started, they added.

No recurrence of either was noted at the last follow-up.

Previous reports have described antiphospholipid syndrome in advanced melanoma patients treated with alfa-2b interferon alone or in combination with anti-interleukin 2, the authors said in their discussion of the case.

In addition, there has been another recent report of antiphospholipid syndrome associated with the CTLA4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab, they said. In that case, testing for antiphospholipid antibodies revealed elevated beta2-glycoprotein 1 antibody levels.

“We hypothesize that [antiphospholipid syndrome] is a kind of autoimmunity induced by anti–PD-1 due to the expansive expression of the immune system against tumor cells,” the researchers wrote.

Although a case of cancer-associated antiphospholipid syndrome could not be ruled out in the present report, the rapid and complete resolution of symptoms after treatment discontinuation suggested that pembrolizumab, a “known immunostimulant,” was the cause, they said.

While antibodies against PD-1 have improved melanoma prognosis, they are associated with a wide range of immune-related adverse effects in the skin, gastrointestinal tract, liver, and endocrine system, Dr. Picard and coauthors noted.

They reported having no conflicts of interest.

SOURCE: Sanchez A, et al. JAMA Derm. 2018 Sep 19. doi: 10.1001/jamadermatol.2018.2770.

A patient with melanoma experienced antiphospholipid syndrome following multiple infusions of the PD-1 inhibitor pembrolizumab, according to authors of a recent case report.

Presence of Raynaud phenomenon and high levels of antiphospholipid antibodies led to the diagnosis of antiphospholipid syndrome in the patient, who had stage IIIB unresectable melanoma.

This report provides additional evidence that this syndrome is an immune-related adverse event associated with checkpoint inhibitor therapy, said Alexandra Picard, MD, of Hôpital Archet, Nice, France, and coauthors.

“Due to the increased use of anti PD-1 therapies, clinicians should be aware of this new potential immune-mediated toxic effect that manifests as antiphospholipid syndrome,” the researchers wrote. The report is in JAMA Dermatology.

“Great caution” should be exercised when considering use of immune checkpoint inhibitors in patients with a history of antiphospholipid syndrome, the authors added.

The woman in this report was over 60 years of age and had first presented with superficial melanoma on her right calf, followed by recurrent lymph node metastases over the next few years, all of which were surgically treated.

Following a PET-CT scan showing a new metastatic lymph node, the woman started pembrolizumab 2 mg/kg every 3 weeks and had a partial response within 3 months, the investigators reported.

After the tenth infusion, however, the patient developed bilateral secondary Raynaud phenomenon that followed a typical discoloration sequence and resulted in a necrotic lesion at the tip of one finger.

The patient had no personal or family history of Raynaud phenomenon.

While beta2-glycoprotein 1 antibodies were not elevated, laboratory tests did show anticardiolipin antibodies and lupus anticoagulants at elevated levels, the investigators said, noting that repeat testing at 12 weeks confirmed positivity of antiphospholipid antibodies.

The Raynaud phenomenon disappeared and the necrotic lesion healed after pembrolizumab was stopped and prednisolone treatment was started, they added.

No recurrence of either was noted at the last follow-up.

Previous reports have described antiphospholipid syndrome in advanced melanoma patients treated with alfa-2b interferon alone or in combination with anti-interleukin 2, the authors said in their discussion of the case.

In addition, there has been another recent report of antiphospholipid syndrome associated with the CTLA4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab, they said. In that case, testing for antiphospholipid antibodies revealed elevated beta2-glycoprotein 1 antibody levels.

“We hypothesize that [antiphospholipid syndrome] is a kind of autoimmunity induced by anti–PD-1 due to the expansive expression of the immune system against tumor cells,” the researchers wrote.

Although a case of cancer-associated antiphospholipid syndrome could not be ruled out in the present report, the rapid and complete resolution of symptoms after treatment discontinuation suggested that pembrolizumab, a “known immunostimulant,” was the cause, they said.

While antibodies against PD-1 have improved melanoma prognosis, they are associated with a wide range of immune-related adverse effects in the skin, gastrointestinal tract, liver, and endocrine system, Dr. Picard and coauthors noted.

They reported having no conflicts of interest.

SOURCE: Sanchez A, et al. JAMA Derm. 2018 Sep 19. doi: 10.1001/jamadermatol.2018.2770.

A patient with melanoma experienced antiphospholipid syndrome following multiple infusions of the PD-1 inhibitor pembrolizumab, according to authors of a recent case report.

Presence of Raynaud phenomenon and high levels of antiphospholipid antibodies led to the diagnosis of antiphospholipid syndrome in the patient, who had stage IIIB unresectable melanoma.

This report provides additional evidence that this syndrome is an immune-related adverse event associated with checkpoint inhibitor therapy, said Alexandra Picard, MD, of Hôpital Archet, Nice, France, and coauthors.

“Due to the increased use of anti PD-1 therapies, clinicians should be aware of this new potential immune-mediated toxic effect that manifests as antiphospholipid syndrome,” the researchers wrote. The report is in JAMA Dermatology.

“Great caution” should be exercised when considering use of immune checkpoint inhibitors in patients with a history of antiphospholipid syndrome, the authors added.

The woman in this report was over 60 years of age and had first presented with superficial melanoma on her right calf, followed by recurrent lymph node metastases over the next few years, all of which were surgically treated.

Following a PET-CT scan showing a new metastatic lymph node, the woman started pembrolizumab 2 mg/kg every 3 weeks and had a partial response within 3 months, the investigators reported.

After the tenth infusion, however, the patient developed bilateral secondary Raynaud phenomenon that followed a typical discoloration sequence and resulted in a necrotic lesion at the tip of one finger.

The patient had no personal or family history of Raynaud phenomenon.

While beta2-glycoprotein 1 antibodies were not elevated, laboratory tests did show anticardiolipin antibodies and lupus anticoagulants at elevated levels, the investigators said, noting that repeat testing at 12 weeks confirmed positivity of antiphospholipid antibodies.

The Raynaud phenomenon disappeared and the necrotic lesion healed after pembrolizumab was stopped and prednisolone treatment was started, they added.

No recurrence of either was noted at the last follow-up.

Previous reports have described antiphospholipid syndrome in advanced melanoma patients treated with alfa-2b interferon alone or in combination with anti-interleukin 2, the authors said in their discussion of the case.

In addition, there has been another recent report of antiphospholipid syndrome associated with the CTLA4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab, they said. In that case, testing for antiphospholipid antibodies revealed elevated beta2-glycoprotein 1 antibody levels.

“We hypothesize that [antiphospholipid syndrome] is a kind of autoimmunity induced by anti–PD-1 due to the expansive expression of the immune system against tumor cells,” the researchers wrote.

Although a case of cancer-associated antiphospholipid syndrome could not be ruled out in the present report, the rapid and complete resolution of symptoms after treatment discontinuation suggested that pembrolizumab, a “known immunostimulant,” was the cause, they said.

While antibodies against PD-1 have improved melanoma prognosis, they are associated with a wide range of immune-related adverse effects in the skin, gastrointestinal tract, liver, and endocrine system, Dr. Picard and coauthors noted.

They reported having no conflicts of interest.

SOURCE: Sanchez A, et al. JAMA Derm. 2018 Sep 19. doi: 10.1001/jamadermatol.2018.2770.