Melanoma

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Mohs micrographic surgery (MMS) may be a viable alternative to wide margin excision (WME) in selected patients with early-stage invasive melanoma, according to a retrospective cohort study.

In the study, which was published in JAMA Dermatology, patients who underwent MMS had a “modest survival advantage” when compared with those who were treated with WME, the approach recommended for treatment of invasive melanoma without nodal or extralymphatic metastases in national guidelines, reported the investigators.

“We sought herein to investigate the association of the type of surgical excision – WME or MMS – with overall survival for cases of American Joint Committee on Cancer Cancer Staging Manual 8th edition (AJCC-8) stage I invasive melanoma,” wrote Shayan Cheraghlou, of Yale University, New Haven, Conn., and colleagues.

The researchers identified a total of 70,319 patients diagnosed with stage I invasive melanoma between Jan. 1, 2004, and Dec. 31, 2014. Data were collected from the National Cancer Database, including 3,234 (4.6%) and 67,085 (95.4%) patients who underwent MMS and WME, respectively. The median age of patients in the cohort was 57 years; 47.7% were female, and almost 97% were white.

In the survival analysis, the team adjusted for clinical and tumor-specific variables and conducted a matched analysis using propensity scores. The primary outcome measured was overall survival.

After analysis, the researchers found that MMS was associated with modestly better overall survival when compared with WME after adjustments (hazard ratio, 0.86; 95% confidence interval, 0.76-0.97). In the propensity score–matched analysis, a similar modest survival advantage was seen for patients who underwent MMS (hazard ratio, 0.82; 95% CI, 0.68-0.98).

“Significant differences in treatment practices based on the treatment facility were noted, with academic facilities more than twice as likely as nonacademic facilities to use MMS,” they wrote.

The researchers acknowledged a key limitation of the study was the use of a convenience sample, as opposed to a population-based sample. As a result, the generalizability of the findings may be limited to certain treatment facilities.

“These data suggest that MMS is an effective approach compared with WME for AJCC-8 stage I invasive melanoma,” they concluded.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Cheraghlou S et al. JAMA Dermatol. 2019 Sep 25. doi: 10.1001/jamadermatol.2019.2890.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

Combination therapy with the immune checkpoint inhibitors nivolumab and ipilimumab has durable efficacy in patients with untreated advanced melanoma, with more than half still alive at 5 years and almost three-fourths of them no longer on any treatment, found an update of the CheckMate 067 trial. The combination also had a manageable safety profile and generally maintained health-related quality of life in the long term.

“The apparent plateau with nivolumab plus ipilimumab has continued with longer follow-up … nivolumab plus ipilimumab is … currently the only treatment for metastatic melanoma for which median overall survival has not been reached at 5 years,” noted the investigators, led by James Larkin, FRCP, PhD, a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust, London. “The current results of the CheckMate 067 trial set a new foundation on which to make improvements in long-term efficacy outcomes with the combination of nivolumab plus ipilimumab.”

The phase 3, randomized, controlled trial pitted nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy and nivolumab monotherapy against ipilimumab monotherapy among 945 adults with previously untreated or unresectable metastatic melanoma. Initial results at a median follow-up of about 1 year showed a progression-free survival benefit of the nivolumab regimens (N Engl J Med. 2015;373:23-34), a pattern that has persisted in updates and has been augmented by an overall survival benefit, as seen most recently at a median follow-up of about 4 years (Lancet Oncol. 2018;19:1480-92).

Dr. Larkin and colleagues performed another update, now at a minimum follow-up of 5 years in all patients. This update additionally looked at subsequent therapies and health-related quality of life.

Results reported in the New England Journal of Medicine showed that median overall survival was now 19.9 months with ipilimumab. In comparison, it was not reached with nivolumab-ipilimumab (hazard ratio for death, 0.52) and was 36.9 months with nivolumab alone (HR, 0.63). The 5-year overall survival rate was 26%, compared with 52% and 44%, respectively.

In all groups, complete response rates continued an increase seen since the trial’s initial results were reported. “[T]his indicates that the best response can improve over time with immune checkpoint inhibitors,” Dr. Larkin and coinvestigators maintained.

“The treatment-free interval continued to lengthen in the nivolumab-plus-ipilimumab group, and the percentage of patients who were alive and not receiving treatment continued to increase across the groups,” they further noted. As of the update, the median treatment-free interval was 18.1 months with nivolumab-ipilimumab, 1.8 months with nivolumab, and 1.9 months with ipilimumab. The percentage of those alive who were not receiving any trial treatment or subsequent systemic therapy was 74%, 58%, and 45%, respectively.

Meanwhile, the data did not show any new safety signals. And health-related quality of life, measured with European Quality of Life 5-Dimensions 3-Level questionnaire, was generally sustained during and after treatment, with limited fluctuations outside a 0.08-point clinically meaningful boundary, in the combination-therapy group and the nivolumab group, whereas it deteriorated more often in the ipilimumab group.

Dr. Larkin disclosed grants and personal fees from numerous pharmaceutical companies. The trial was supported by Bristol-Myers Squibb, a grant from the National Cancer Institute, and a grant (to Dr. Larkin) from the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre.

SOURCE: Larkin J et al. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910836.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

Join us on Tuesday, October 8, 2019, at 8:00 pm EST on Twitter at #MDedgeChats as we discuss skin cancer, and what’s new in sunscreen, skin of color, and melanoma. 

Special guests include physicians with expertise in dermatology and skin cancer, Anthony Rossi, MD (@DrAnthonyRossi), Julie Amthor Croley, MD, 15k followers on IG (@Drskinandsmiles), and Candrice Heath, MD (@DrCandriceHeath). Background information about the chat can be found below.

What will the conversation cover?

Q1: What are the most common types of skin cancer? 
Q2: What recent research findings can better inform patients about skin cancer risks?
Q3: What’s the difference between melanoma in fair skin vs. darker skin?
Q4: How does the risk of skin cancer differ in people with darker skin?
Q5: Why should sunscreen be used even in the fall and winter?

About Dr. Rossi: 

Dr. Anthony Rossi (@DrAnthonyRossi) is a board-certified dermatologist with fellowship training in Mohs micrographic surgery, cosmetic and laser surgery, and advanced cutaneous oncology at the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College program, both in New York.  He specializes in skin cancer surgery, cosmetic dermatologic surgery, and laser surgery.  

His research includes quality of life in cancer survivors, the use of noninvasive imaging of the skin, and nonsurgical treatments of skin cancer. Additionally, Dr. Rossi is active in dermatologic organizations and advocacy for medicine.

Research and Publications by Dr. Rossi 

About Dr. Heath:
 

Dr. Candrice Heath (@DrCandriceHeath) is Assistant Professor of Dermatology at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania with fellowship training in pediatric dermatology at Johns Hopkins University in Baltimore, Maryland. Dr. Heath is triple board certified in pediatrics, dermatology, and pediatric dermatology. She specializes in adult and pediatric dermatology, skin of color, acne, and eczema. Dr. Heath also enjoys educating primary care physicians on the front lines of health care and delivering easy to understand information to consumers. 

Research and publications by Dr. Heath 
Guest host of MDedge podcast: A sunscreen update with Dr. Vincent DeLeo. 
 

About Dr. Croley:  

Dr. Julie Amthor Croley (@Drskinandsmiles) also known as “Dr. Skin and Smiles” has 15,000 followers on Instagram, and is a Chief Dermatology Resident at the University of Texas Medical Branch in Galveston, Texas. She has a special interest in skin cancer and dermatological surgery and hopes to complete a fellowship in Mohs micrographic surgery after residency. In her free time, Dr. Croley enjoys spending time with her husband (an orthopedic surgeon), running and competing in marathons, and spending time on the beach. 

Media coverage by Dr. Croley

Cutaneous melanoma is the most fatal form of skin cancer and is a considerable public health concern in the United States. Early detection and management of skin cancer can lead to decreased morbidity and mortality from skin cancer. As a result, the American Academy of Dermatology Association supports safe sun-protective practices and diligent self-screening for changing lesions.

Sunscreen use is an essential component of sun protection. New regulations from the US Food and Drug Administration (FDA) have left consumers concerned about the safety of sunscreens. According to a recent Cutis editorial from Vincent A. DeLeo, MD, “There is no question that, as physicians, we want to ‘first, do no harm,’ so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data.”

Patients with skin of color experience disproportionately higher morbidity and mortality when diagnosed with melanoma. “Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis,” according to a recent Cutis article. 

Population-based skin cancer screening performed exclusively by dermatologists is not practical. Primary care physicians and other experts in melanoma and public health need to be involved in reducing melanoma mortality. 

In this chat, we will provide expert recommendations on the diagnosis of skin cancer, preventive measures, and the latest research discussed among physicians.

Research & Resources

• “Doctor, Do I Need a Skin Check?”
• Assessing the effectiveness of knowledge-based interventions in skin of color populations.
• Melanoma in US Hispanics
• Podcast: Sunscreen update from Dr. Vincent DeLeo
• Windshield and UV exposure  
• Racial, ethnic minorities often don’t practice sun-protective behaviors.
• Sunscreen regulations and advice for your patients.

Join us on Tuesday, October 8, 2019, at 8:00 pm EST on Twitter at #MDedgeChats as we discuss skin cancer, and what’s new in sunscreen, skin of color, and melanoma. 

Special guests include physicians with expertise in dermatology and skin cancer, Anthony Rossi, MD (@DrAnthonyRossi), Julie Amthor Croley, MD, 15k followers on IG (@Drskinandsmiles), and Candrice Heath, MD (@DrCandriceHeath). Background information about the chat can be found below.

What will the conversation cover?

Q1: What are the most common types of skin cancer? 
Q2: What recent research findings can better inform patients about skin cancer risks?
Q3: What’s the difference between melanoma in fair skin vs. darker skin?
Q4: How does the risk of skin cancer differ in people with darker skin?
Q5: Why should sunscreen be used even in the fall and winter?

About Dr. Rossi: 

Dr. Anthony Rossi (@DrAnthonyRossi) is a board-certified dermatologist with fellowship training in Mohs micrographic surgery, cosmetic and laser surgery, and advanced cutaneous oncology at the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College program, both in New York.  He specializes in skin cancer surgery, cosmetic dermatologic surgery, and laser surgery.  

His research includes quality of life in cancer survivors, the use of noninvasive imaging of the skin, and nonsurgical treatments of skin cancer. Additionally, Dr. Rossi is active in dermatologic organizations and advocacy for medicine.

Research and Publications by Dr. Rossi 

About Dr. Heath:
 

Dr. Candrice Heath (@DrCandriceHeath) is Assistant Professor of Dermatology at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania with fellowship training in pediatric dermatology at Johns Hopkins University in Baltimore, Maryland. Dr. Heath is triple board certified in pediatrics, dermatology, and pediatric dermatology. She specializes in adult and pediatric dermatology, skin of color, acne, and eczema. Dr. Heath also enjoys educating primary care physicians on the front lines of health care and delivering easy to understand information to consumers. 

Research and publications by Dr. Heath 
Guest host of MDedge podcast: A sunscreen update with Dr. Vincent DeLeo. 
 

About Dr. Croley:  

Dr. Julie Amthor Croley (@Drskinandsmiles) also known as “Dr. Skin and Smiles” has 15,000 followers on Instagram, and is a Chief Dermatology Resident at the University of Texas Medical Branch in Galveston, Texas. She has a special interest in skin cancer and dermatological surgery and hopes to complete a fellowship in Mohs micrographic surgery after residency. In her free time, Dr. Croley enjoys spending time with her husband (an orthopedic surgeon), running and competing in marathons, and spending time on the beach. 

Media coverage by Dr. Croley

Cutaneous melanoma is the most fatal form of skin cancer and is a considerable public health concern in the United States. Early detection and management of skin cancer can lead to decreased morbidity and mortality from skin cancer. As a result, the American Academy of Dermatology Association supports safe sun-protective practices and diligent self-screening for changing lesions.

Sunscreen use is an essential component of sun protection. New regulations from the US Food and Drug Administration (FDA) have left consumers concerned about the safety of sunscreens. According to a recent Cutis editorial from Vincent A. DeLeo, MD, “There is no question that, as physicians, we want to ‘first, do no harm,’ so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data.”

Patients with skin of color experience disproportionately higher morbidity and mortality when diagnosed with melanoma. “Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis,” according to a recent Cutis article. 

Population-based skin cancer screening performed exclusively by dermatologists is not practical. Primary care physicians and other experts in melanoma and public health need to be involved in reducing melanoma mortality. 

In this chat, we will provide expert recommendations on the diagnosis of skin cancer, preventive measures, and the latest research discussed among physicians.

Research & Resources

• “Doctor, Do I Need a Skin Check?”
• Assessing the effectiveness of knowledge-based interventions in skin of color populations.
• Melanoma in US Hispanics
• Podcast: Sunscreen update from Dr. Vincent DeLeo
• Windshield and UV exposure  
• Racial, ethnic minorities often don’t practice sun-protective behaviors.
• Sunscreen regulations and advice for your patients.

Join us on Tuesday, October 8, 2019, at 8:00 pm EST on Twitter at #MDedgeChats as we discuss skin cancer, and what’s new in sunscreen, skin of color, and melanoma. 

Special guests include physicians with expertise in dermatology and skin cancer, Anthony Rossi, MD (@DrAnthonyRossi), Julie Amthor Croley, MD, 15k followers on IG (@Drskinandsmiles), and Candrice Heath, MD (@DrCandriceHeath). Background information about the chat can be found below.

What will the conversation cover?

Q1: What are the most common types of skin cancer? 
Q2: What recent research findings can better inform patients about skin cancer risks?
Q3: What’s the difference between melanoma in fair skin vs. darker skin?
Q4: How does the risk of skin cancer differ in people with darker skin?
Q5: Why should sunscreen be used even in the fall and winter?

About Dr. Rossi: 

Dr. Anthony Rossi (@DrAnthonyRossi) is a board-certified dermatologist with fellowship training in Mohs micrographic surgery, cosmetic and laser surgery, and advanced cutaneous oncology at the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College program, both in New York.  He specializes in skin cancer surgery, cosmetic dermatologic surgery, and laser surgery.  

His research includes quality of life in cancer survivors, the use of noninvasive imaging of the skin, and nonsurgical treatments of skin cancer. Additionally, Dr. Rossi is active in dermatologic organizations and advocacy for medicine.

Research and Publications by Dr. Rossi 

About Dr. Heath:
 

Dr. Candrice Heath (@DrCandriceHeath) is Assistant Professor of Dermatology at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania with fellowship training in pediatric dermatology at Johns Hopkins University in Baltimore, Maryland. Dr. Heath is triple board certified in pediatrics, dermatology, and pediatric dermatology. She specializes in adult and pediatric dermatology, skin of color, acne, and eczema. Dr. Heath also enjoys educating primary care physicians on the front lines of health care and delivering easy to understand information to consumers. 

Research and publications by Dr. Heath 
Guest host of MDedge podcast: A sunscreen update with Dr. Vincent DeLeo. 
 

About Dr. Croley:  

Dr. Julie Amthor Croley (@Drskinandsmiles) also known as “Dr. Skin and Smiles” has 15,000 followers on Instagram, and is a Chief Dermatology Resident at the University of Texas Medical Branch in Galveston, Texas. She has a special interest in skin cancer and dermatological surgery and hopes to complete a fellowship in Mohs micrographic surgery after residency. In her free time, Dr. Croley enjoys spending time with her husband (an orthopedic surgeon), running and competing in marathons, and spending time on the beach. 

Media coverage by Dr. Croley

Cutaneous melanoma is the most fatal form of skin cancer and is a considerable public health concern in the United States. Early detection and management of skin cancer can lead to decreased morbidity and mortality from skin cancer. As a result, the American Academy of Dermatology Association supports safe sun-protective practices and diligent self-screening for changing lesions.

Sunscreen use is an essential component of sun protection. New regulations from the US Food and Drug Administration (FDA) have left consumers concerned about the safety of sunscreens. According to a recent Cutis editorial from Vincent A. DeLeo, MD, “There is no question that, as physicians, we want to ‘first, do no harm,’ so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data.”

Patients with skin of color experience disproportionately higher morbidity and mortality when diagnosed with melanoma. “Poor prognosis in patients with skin of color is multifactorial and may be due to poor use of sun protection, misconceptions about melanoma risk, atypical clinical presentation, impaired access to care, and delay in diagnosis,” according to a recent Cutis article. 

Population-based skin cancer screening performed exclusively by dermatologists is not practical. Primary care physicians and other experts in melanoma and public health need to be involved in reducing melanoma mortality. 

In this chat, we will provide expert recommendations on the diagnosis of skin cancer, preventive measures, and the latest research discussed among physicians.

Research & Resources

• “Doctor, Do I Need a Skin Check?”
• Assessing the effectiveness of knowledge-based interventions in skin of color populations.
• Melanoma in US Hispanics
• Podcast: Sunscreen update from Dr. Vincent DeLeo
• Windshield and UV exposure  
• Racial, ethnic minorities often don’t practice sun-protective behaviors.
• Sunscreen regulations and advice for your patients.

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Australian patients with systemic sclerosis were at greater risk for lung cancer, early breast cancer, and early melanoma when compared with the general population in a population-linked cohort study published in Arthritis Care & Research.

Kathleen Morrisroe, MBBS, PhD, of St. Vincent’s Hospital Melbourne and colleagues matched deidentified patient data in the Australian Scleroderma Cohort Study (ASCS) with patients’ respective state cancer registry data between January 2008 and December 2015. The researchers also used the Australian Medical Benefit Schedule (MBS) to track health care costs for hospital admissions, presentations to the ED, other health visits, pathology, and imaging, as well as other associated costs for care, in each state. Based on this information, Dr. Morrisroe and colleagues calculated standardized incidence ratios (SIR) and standardized mortality ratios (SMR) for these patients by comparing them with the general population in Australia.

The results included 1,727 patients with systemic sclerosis (SSc) and cancer in the cohort, which consisted of mostly white (92.1%) women (85.9%) who had limited cutaneous SSc (73.9%). They were a mean of 46.6 years old when they were diagnosed with SSc and had a mean disease duration of 10.9 years. The incidence of cancer was 1.3% per year, and the overall prevalence for the cohort was 14.2%, which was higher than the general Australian population (SIR, 2.15; 95% confidence interval, 1.84-2.49). Breast cancer, melanoma, hematologic cancer, and lung cancer were the most common types of cancers found in the cohort, with early breast cancer (SIR, 3.07; 95% CI, 1.47-5.64), lung cancer (SIR, 3.07; 95% CI, 1.21-3.44), and early melanoma (SIR, 3.40; 95% CI, 1.10-7.93) having a higher incidence than the general population.

Patients with RNA polymerase III (RNAP) autoantibody had a higher incidence of early onset cancer (odds ratio, 2.9; P = .044), defined as a cancer diagnosis within 5 years of SSc diagnosis. Interstitial lung disease was also linked to an increased risk of lung cancer (OR, 2.83; P = .031), which persisted after the researchers performed a multivariate analysis.

Another factor that increased the overall risk of cancer was calcium channel blockers (OR, 1.47; P = .016), which also increased the risk of breast (OR, 1.61; P = .051) and melanoma-specific cancers (OR, 2.01; P = .042), a finding the researchers said was “unexpected, but has been reported in the literature with conflicting results.”

“This association is hypothesized to be related to the role of calcium in cell apoptosis, such as activation of the caspase pathway, induction of endonuclease activity and mitochondrial permeation,” Dr. Morrisroe and colleagues wrote.

SSc patients had more than a doubling of risk of mortality with incident cancer in comparison with SSc patients who did not have cancer (hazard ratio, 2.85; 95% CI, 1.51-5.37; P = .001). The average cost of health care annually for an SSc patient with cancer was AUD $1,496 (P less than .001), the researchers said.

This study was funded in part by Scleroderma Australia, Arthritis Australia, Actelion Australia, Bayer, CSL Biotherapies, GlaxoSmithKline Australia, and Pfizer. Dr. Morrisroe reported receiving support from Arthritis Australia and Royal Australasian College of Physicians Research Establishment Fellowships. Another author reported receiving a fellowship from the National Health and Medical Research Council of Australia. The other authors reported no relevant conflicts of interest.

SOURCE: Morrisroe K et al. Arthritis Care Res. 2019 Sep 20. doi: 10.1002/acr.24076

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

Prior antibiotic use may be associated with a reduced treatment response to checkpoint inhibitors, and worse outcomes, in patients with cancer, according to investigators.

In a prospective cohort study, researchers followed 196 patients with cancer who were treated with immune checkpoint inhibitors in routine clinical practice.

A total of 22 patients had been treated with a 7-day or less course of broad-spectrum beta-lactam–based antibiotics in the 30 days prior to starting immune checkpoint inhibitor therapy, and 68 patients were concurrently taking broad-spectrum beta-lactam–based antibiotics with their checkpoint inhibitor therapy.

The analysis revealed that prior antibiotic therapy was associated with nearly a 100% greater likelihood of poor response to checkpoint inhibitor therapy (P less than .001) and significantly worse overall survival (2 vs. 26 months). Patients who had been on prior antibiotic therapy were also more likely to stop checkpoint inhibitor therapy because their disease had progressed, and were more likely to die of progressive disease while on checkpoint inhibitors.

However, concurrent antibiotic use did not appear to affect either treatment response to checkpoint inhibitors or overall survival.

The most common indication for both prior and concurrent antibiotic use was respiratory tract infections. Researchers examined whether cancer type might play a role in contributing to the association; for example, chronic airway disease in lung cancer might mean higher likelihood of antibiotic use but also lower treatment response and survival.

They found that the association between prior antibiotic therapy and overall survival was consistent across the 119 patients with non–small cell lung cancer, the 38 patients with melanoma, and the 39 patients with other tumor types.

The association was also independent of the class of antibiotic used, the patient’s performance status, and their corticosteroid use.

“Broad-spectrum ATB [antibiotic] use can cause prolonged disruption of the gut ecosystem and impair the effectiveness of the cytotoxic T-cell response against cancer, strengthening the biologic plausibility underlying the adverse effect of ATB therapy on immunotherapy outcomes,” wrote Dr. David J. Pinato, from Imperial College London, and coauthors in JAMA Oncology.

Addressing the question of whether comorbidities might be the mediating factor, the authors pointed out that the use of antibiotics during checkpoint inhibitor therapy – which was a potential indicator of patients’ status worsening during treatment – was not associated with reduced response to treatment or lower overall survival.

“Although provision of cATB [concurrent antibiotic] therapy appears to be safe in the context of immunotherapy, clinicians should carefully weigh the pros and cons of prescribing broad-spectrum ATBs prior to ICI [immune checkpoint inhibitor] treatment,” they wrote.

The study was supported by the Imperial College National Institute for Health Research Biomedical Research Centre, the Imperial College Tissue Bank, the Imperial Cancer Research U.K. Centre, the National Institute for Health Research, and the Wellcome Trust Strategic Fund. Two authors reported receiving grant funding and personal fees from the pharmaceutical sector unrelated to the study.

SOURCE: Pinato D et al. JAMA Oncol. 2019 Sep 12. doi: 10.1001/jamaoncol.2019.2785.

Prior antibiotic use may be associated with a reduced treatment response to checkpoint inhibitors, and worse outcomes, in patients with cancer, according to investigators.

In a prospective cohort study, researchers followed 196 patients with cancer who were treated with immune checkpoint inhibitors in routine clinical practice.

A total of 22 patients had been treated with a 7-day or less course of broad-spectrum beta-lactam–based antibiotics in the 30 days prior to starting immune checkpoint inhibitor therapy, and 68 patients were concurrently taking broad-spectrum beta-lactam–based antibiotics with their checkpoint inhibitor therapy.

The analysis revealed that prior antibiotic therapy was associated with nearly a 100% greater likelihood of poor response to checkpoint inhibitor therapy (P less than .001) and significantly worse overall survival (2 vs. 26 months). Patients who had been on prior antibiotic therapy were also more likely to stop checkpoint inhibitor therapy because their disease had progressed, and were more likely to die of progressive disease while on checkpoint inhibitors.

However, concurrent antibiotic use did not appear to affect either treatment response to checkpoint inhibitors or overall survival.

The most common indication for both prior and concurrent antibiotic use was respiratory tract infections. Researchers examined whether cancer type might play a role in contributing to the association; for example, chronic airway disease in lung cancer might mean higher likelihood of antibiotic use but also lower treatment response and survival.

They found that the association between prior antibiotic therapy and overall survival was consistent across the 119 patients with non–small cell lung cancer, the 38 patients with melanoma, and the 39 patients with other tumor types.

The association was also independent of the class of antibiotic used, the patient’s performance status, and their corticosteroid use.

“Broad-spectrum ATB [antibiotic] use can cause prolonged disruption of the gut ecosystem and impair the effectiveness of the cytotoxic T-cell response against cancer, strengthening the biologic plausibility underlying the adverse effect of ATB therapy on immunotherapy outcomes,” wrote Dr. David J. Pinato, from Imperial College London, and coauthors in JAMA Oncology.

Addressing the question of whether comorbidities might be the mediating factor, the authors pointed out that the use of antibiotics during checkpoint inhibitor therapy – which was a potential indicator of patients’ status worsening during treatment – was not associated with reduced response to treatment or lower overall survival.

“Although provision of cATB [concurrent antibiotic] therapy appears to be safe in the context of immunotherapy, clinicians should carefully weigh the pros and cons of prescribing broad-spectrum ATBs prior to ICI [immune checkpoint inhibitor] treatment,” they wrote.

The study was supported by the Imperial College National Institute for Health Research Biomedical Research Centre, the Imperial College Tissue Bank, the Imperial Cancer Research U.K. Centre, the National Institute for Health Research, and the Wellcome Trust Strategic Fund. Two authors reported receiving grant funding and personal fees from the pharmaceutical sector unrelated to the study.

SOURCE: Pinato D et al. JAMA Oncol. 2019 Sep 12. doi: 10.1001/jamaoncol.2019.2785.

Prior antibiotic use may be associated with a reduced treatment response to checkpoint inhibitors, and worse outcomes, in patients with cancer, according to investigators.

In a prospective cohort study, researchers followed 196 patients with cancer who were treated with immune checkpoint inhibitors in routine clinical practice.

A total of 22 patients had been treated with a 7-day or less course of broad-spectrum beta-lactam–based antibiotics in the 30 days prior to starting immune checkpoint inhibitor therapy, and 68 patients were concurrently taking broad-spectrum beta-lactam–based antibiotics with their checkpoint inhibitor therapy.

The analysis revealed that prior antibiotic therapy was associated with nearly a 100% greater likelihood of poor response to checkpoint inhibitor therapy (P less than .001) and significantly worse overall survival (2 vs. 26 months). Patients who had been on prior antibiotic therapy were also more likely to stop checkpoint inhibitor therapy because their disease had progressed, and were more likely to die of progressive disease while on checkpoint inhibitors.

However, concurrent antibiotic use did not appear to affect either treatment response to checkpoint inhibitors or overall survival.

The most common indication for both prior and concurrent antibiotic use was respiratory tract infections. Researchers examined whether cancer type might play a role in contributing to the association; for example, chronic airway disease in lung cancer might mean higher likelihood of antibiotic use but also lower treatment response and survival.

They found that the association between prior antibiotic therapy and overall survival was consistent across the 119 patients with non–small cell lung cancer, the 38 patients with melanoma, and the 39 patients with other tumor types.

The association was also independent of the class of antibiotic used, the patient’s performance status, and their corticosteroid use.

“Broad-spectrum ATB [antibiotic] use can cause prolonged disruption of the gut ecosystem and impair the effectiveness of the cytotoxic T-cell response against cancer, strengthening the biologic plausibility underlying the adverse effect of ATB therapy on immunotherapy outcomes,” wrote Dr. David J. Pinato, from Imperial College London, and coauthors in JAMA Oncology.

Addressing the question of whether comorbidities might be the mediating factor, the authors pointed out that the use of antibiotics during checkpoint inhibitor therapy – which was a potential indicator of patients’ status worsening during treatment – was not associated with reduced response to treatment or lower overall survival.

“Although provision of cATB [concurrent antibiotic] therapy appears to be safe in the context of immunotherapy, clinicians should carefully weigh the pros and cons of prescribing broad-spectrum ATBs prior to ICI [immune checkpoint inhibitor] treatment,” they wrote.

The study was supported by the Imperial College National Institute for Health Research Biomedical Research Centre, the Imperial College Tissue Bank, the Imperial Cancer Research U.K. Centre, the National Institute for Health Research, and the Wellcome Trust Strategic Fund. Two authors reported receiving grant funding and personal fees from the pharmaceutical sector unrelated to the study.

SOURCE: Pinato D et al. JAMA Oncol. 2019 Sep 12. doi: 10.1001/jamaoncol.2019.2785.

To the Editor:

A 43-year-old woman presented with a mole on the central back that had been present since childhood and had changed and grown over the last few years. The patient reported that her 2-year-old rescue dog frequently sniffed the mole and would subsequently get agitated and try to scratch and bite the lesion. This behavior prompted the patient to visit a dermatologist.

She reported no personal history of melanoma or nonmelanoma skin cancer, tanning booth exposure, blistering sunburns, or use of immunosuppressant medications. Her family history was remarkable for basal cell carcinoma in her father but no family history of melanoma. Physical examination revealed a 1.2×1.5-cm brown patch along with a 1×1-cm ulcerated nodule on the lower aspect of the lesion (Figure 1). Dermoscopy showed a blue-white veil and an irregular vascular pattern (Figure 2). No cervical, axillary, or inguinal lymphadenopathy was appreciated on physical examination. Reflectance confocal microscopy showed pagetoid spread of atypical round melanocytes as well as melanocytes in the stratum corneum (Figure 3).

The patient was referred to a surgical oncologist for wide local excision and sentinel lymph node biopsy. Pathology showed a 4-mm-thick melanoma with numerous positive lymph nodes (Figure 4). The patient subsequently underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. After surgery, the patient reported that her dog would now sniff her back and calmly rest his head in her lap.

Both anecdotal and systematic evidence have emerged on the role of canine olfaction in the detection of lung, breast, colorectal, ovarian, prostate, and skin cancers, including malignant melanoma.^1-6 A 1989 case report described a woman who was prompted to seek dermatologic evaluation of a pigmented lesion because her dog consistently targeted the lesion. Excision and subsequent histopathologic examination of the lesion revealed that it was malignant melanoma.⁵ Another case report described a patient whose dog, which was not trained to detect cancers in humans, persistently licked a lesion behind the patient’s ear that eventually was found to be malignant melanoma.⁶ These reports have inspired considerable research interest regarding canine olfaction as a potential method to noninvasively screen for and even diagnose malignant melanomas in humans.

Both physiologic and pathologic metabolic processes result in the production of volatile organic compounds (VOCs), or small odorant molecules that evaporate at normal temperatures and pressures.¹ Individual cells release VOCs in extremely low concentrations into the blood, urine, feces, and breath, as well as onto the skin’s surface, but there are methods for detecting these VOCs, including gas chromatography–mass spectrometry and canine olfaction.^7,8 Pathologic processes, such as infection and malignancy, result in irregular protein synthesis and metabolism, producing new VOCs or differing concentrations of VOCs as compared to normal processes.¹

Dimethyl disulfide and dimethyl trisulfide compounds have been identified in malignant melanoma, and these compounds are not produced by normal melanocytes.⁷ Furthermore, malignant melanoma produces differing quantities of these compounds as compared to normal melanocytes, including isovaleric acid, 2-methylbutyric acid, isoamyl alcohol (3-methyl-1-butanol), and 2-methyl-1-butanol, resulting in a distinct odorant profile that previously has been detected via canine olfaction.⁷ Canine olfaction can identify odorant molecules at up to 1 part per trillion (a magnitude more sensitive than the currently available gas chromatography–mass spectrometry technologies) and can detect the production of new VOCs or altered VOC ratios due to pathologic processes.¹ Systematic studies with dogs that are trained to detect cancers in humans have shown that canine olfaction correctly identified malignant melanomas against healthy skin, benign nevi, and even basal cell carcinomas at higher rates than what would have been expected by chance alone.^2,3

Canine olfaction can identify new or altered ratios of odorant VOCs associated with pathologic metabolic processes, and canines can be trained to target odor profiles associated with specific diseases.¹ Canine olfaction for melanoma screening and diagnosis may seem appealing, as it provides an easily transportable, real-time, low-cost method compared to other techniques such as gas chromatography–mass spectrometry.¹ Although preliminary results have shown that canine olfaction detects melanoma at higher rates than would be expected by chance alone, these findings have not approached clinical utility for the widespread use of canine olfaction as a screening method for melanoma.^2,3,9 Further studies are needed to understand the role of canine olfaction in melanoma screening and diagnosis as well as to explore methods to optimize sensitivity and specificity. Until then, patients and dermatologists should not ignore the behavior of dogs toward skin lesions. Dogs may be beneficial in the detection of melanoma and help save lives, as was seen in our case.

To the Editor:

A 43-year-old woman presented with a mole on the central back that had been present since childhood and had changed and grown over the last few years. The patient reported that her 2-year-old rescue dog frequently sniffed the mole and would subsequently get agitated and try to scratch and bite the lesion. This behavior prompted the patient to visit a dermatologist.

She reported no personal history of melanoma or nonmelanoma skin cancer, tanning booth exposure, blistering sunburns, or use of immunosuppressant medications. Her family history was remarkable for basal cell carcinoma in her father but no family history of melanoma. Physical examination revealed a 1.2×1.5-cm brown patch along with a 1×1-cm ulcerated nodule on the lower aspect of the lesion (Figure 1). Dermoscopy showed a blue-white veil and an irregular vascular pattern (Figure 2). No cervical, axillary, or inguinal lymphadenopathy was appreciated on physical examination. Reflectance confocal microscopy showed pagetoid spread of atypical round melanocytes as well as melanocytes in the stratum corneum (Figure 3).

The patient was referred to a surgical oncologist for wide local excision and sentinel lymph node biopsy. Pathology showed a 4-mm-thick melanoma with numerous positive lymph nodes (Figure 4). The patient subsequently underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. After surgery, the patient reported that her dog would now sniff her back and calmly rest his head in her lap.

Both anecdotal and systematic evidence have emerged on the role of canine olfaction in the detection of lung, breast, colorectal, ovarian, prostate, and skin cancers, including malignant melanoma.^1-6 A 1989 case report described a woman who was prompted to seek dermatologic evaluation of a pigmented lesion because her dog consistently targeted the lesion. Excision and subsequent histopathologic examination of the lesion revealed that it was malignant melanoma.⁵ Another case report described a patient whose dog, which was not trained to detect cancers in humans, persistently licked a lesion behind the patient’s ear that eventually was found to be malignant melanoma.⁶ These reports have inspired considerable research interest regarding canine olfaction as a potential method to noninvasively screen for and even diagnose malignant melanomas in humans.

Both physiologic and pathologic metabolic processes result in the production of volatile organic compounds (VOCs), or small odorant molecules that evaporate at normal temperatures and pressures.¹ Individual cells release VOCs in extremely low concentrations into the blood, urine, feces, and breath, as well as onto the skin’s surface, but there are methods for detecting these VOCs, including gas chromatography–mass spectrometry and canine olfaction.^7,8 Pathologic processes, such as infection and malignancy, result in irregular protein synthesis and metabolism, producing new VOCs or differing concentrations of VOCs as compared to normal processes.¹

Dimethyl disulfide and dimethyl trisulfide compounds have been identified in malignant melanoma, and these compounds are not produced by normal melanocytes.⁷ Furthermore, malignant melanoma produces differing quantities of these compounds as compared to normal melanocytes, including isovaleric acid, 2-methylbutyric acid, isoamyl alcohol (3-methyl-1-butanol), and 2-methyl-1-butanol, resulting in a distinct odorant profile that previously has been detected via canine olfaction.⁷ Canine olfaction can identify odorant molecules at up to 1 part per trillion (a magnitude more sensitive than the currently available gas chromatography–mass spectrometry technologies) and can detect the production of new VOCs or altered VOC ratios due to pathologic processes.¹ Systematic studies with dogs that are trained to detect cancers in humans have shown that canine olfaction correctly identified malignant melanomas against healthy skin, benign nevi, and even basal cell carcinomas at higher rates than what would have been expected by chance alone.^2,3

Canine olfaction can identify new or altered ratios of odorant VOCs associated with pathologic metabolic processes, and canines can be trained to target odor profiles associated with specific diseases.¹ Canine olfaction for melanoma screening and diagnosis may seem appealing, as it provides an easily transportable, real-time, low-cost method compared to other techniques such as gas chromatography–mass spectrometry.¹ Although preliminary results have shown that canine olfaction detects melanoma at higher rates than would be expected by chance alone, these findings have not approached clinical utility for the widespread use of canine olfaction as a screening method for melanoma.^2,3,9 Further studies are needed to understand the role of canine olfaction in melanoma screening and diagnosis as well as to explore methods to optimize sensitivity and specificity. Until then, patients and dermatologists should not ignore the behavior of dogs toward skin lesions. Dogs may be beneficial in the detection of melanoma and help save lives, as was seen in our case.

To the Editor:

A 43-year-old woman presented with a mole on the central back that had been present since childhood and had changed and grown over the last few years. The patient reported that her 2-year-old rescue dog frequently sniffed the mole and would subsequently get agitated and try to scratch and bite the lesion. This behavior prompted the patient to visit a dermatologist.

She reported no personal history of melanoma or nonmelanoma skin cancer, tanning booth exposure, blistering sunburns, or use of immunosuppressant medications. Her family history was remarkable for basal cell carcinoma in her father but no family history of melanoma. Physical examination revealed a 1.2×1.5-cm brown patch along with a 1×1-cm ulcerated nodule on the lower aspect of the lesion (Figure 1). Dermoscopy showed a blue-white veil and an irregular vascular pattern (Figure 2). No cervical, axillary, or inguinal lymphadenopathy was appreciated on physical examination. Reflectance confocal microscopy showed pagetoid spread of atypical round melanocytes as well as melanocytes in the stratum corneum (Figure 3).

The patient was referred to a surgical oncologist for wide local excision and sentinel lymph node biopsy. Pathology showed a 4-mm-thick melanoma with numerous positive lymph nodes (Figure 4). The patient subsequently underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. After surgery, the patient reported that her dog would now sniff her back and calmly rest his head in her lap.

Both anecdotal and systematic evidence have emerged on the role of canine olfaction in the detection of lung, breast, colorectal, ovarian, prostate, and skin cancers, including malignant melanoma.^1-6 A 1989 case report described a woman who was prompted to seek dermatologic evaluation of a pigmented lesion because her dog consistently targeted the lesion. Excision and subsequent histopathologic examination of the lesion revealed that it was malignant melanoma.⁵ Another case report described a patient whose dog, which was not trained to detect cancers in humans, persistently licked a lesion behind the patient’s ear that eventually was found to be malignant melanoma.⁶ These reports have inspired considerable research interest regarding canine olfaction as a potential method to noninvasively screen for and even diagnose malignant melanomas in humans.

Both physiologic and pathologic metabolic processes result in the production of volatile organic compounds (VOCs), or small odorant molecules that evaporate at normal temperatures and pressures.¹ Individual cells release VOCs in extremely low concentrations into the blood, urine, feces, and breath, as well as onto the skin’s surface, but there are methods for detecting these VOCs, including gas chromatography–mass spectrometry and canine olfaction.^7,8 Pathologic processes, such as infection and malignancy, result in irregular protein synthesis and metabolism, producing new VOCs or differing concentrations of VOCs as compared to normal processes.¹

Dimethyl disulfide and dimethyl trisulfide compounds have been identified in malignant melanoma, and these compounds are not produced by normal melanocytes.⁷ Furthermore, malignant melanoma produces differing quantities of these compounds as compared to normal melanocytes, including isovaleric acid, 2-methylbutyric acid, isoamyl alcohol (3-methyl-1-butanol), and 2-methyl-1-butanol, resulting in a distinct odorant profile that previously has been detected via canine olfaction.⁷ Canine olfaction can identify odorant molecules at up to 1 part per trillion (a magnitude more sensitive than the currently available gas chromatography–mass spectrometry technologies) and can detect the production of new VOCs or altered VOC ratios due to pathologic processes.¹ Systematic studies with dogs that are trained to detect cancers in humans have shown that canine olfaction correctly identified malignant melanomas against healthy skin, benign nevi, and even basal cell carcinomas at higher rates than what would have been expected by chance alone.^2,3

Canine olfaction can identify new or altered ratios of odorant VOCs associated with pathologic metabolic processes, and canines can be trained to target odor profiles associated with specific diseases.¹ Canine olfaction for melanoma screening and diagnosis may seem appealing, as it provides an easily transportable, real-time, low-cost method compared to other techniques such as gas chromatography–mass spectrometry.¹ Although preliminary results have shown that canine olfaction detects melanoma at higher rates than would be expected by chance alone, these findings have not approached clinical utility for the widespread use of canine olfaction as a screening method for melanoma.^2,3,9 Further studies are needed to understand the role of canine olfaction in melanoma screening and diagnosis as well as to explore methods to optimize sensitivity and specificity. Until then, patients and dermatologists should not ignore the behavior of dogs toward skin lesions. Dogs may be beneficial in the detection of melanoma and help save lives, as was seen in our case.