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High-fiber diet may improve melanoma immunotherapy response, outcomes
a new study shows.
Investigators found that the patients who reported consuming at least 20 g of dietary fiber daily had significantly better progression-free survival (PFS) than those who reported consuming lower amounts of dietary fiber. However, patients who took a probiotic supplement in the past month had slightly shorter PFS, but the results were not statistically significant.
And after adjusting for clinical factors, each 5-g increase in daily dietary fiber intake corresponded to a 30% lower risk of disease progression, according to the analysis, published online Dec. 23, 2021, in Science.
“Our study sheds light on the potential effects of a patient’s diet and supplement use when starting treatment with immune checkpoint blockade,” co–lead study author Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at University of Texas MD Anderson Cancer Center, Houston, said in a press release. “These results provide further support for clinical trials to modulate the microbiome with the goal of improving cancer outcomes using dietary and other strategies.”
Previous research has suggested that the microbiome can influence patients’ response to immunotherapy. One recent analysis, for instance, found that fecal microbiota transplant can improve response to immunotherapy in advanced melanoma. And a small 2019 analysis from Dr. Dr. Wargo and colleagues hinted that a high-fiber diet may enhance patients’ ability to respond to immunotherapy in advanced melanoma, while probiotics appear to dampen that response.
Still, the role diet and probiotic supplements play in treatment response remains poorly understood.
In the current study, Dr. Wargo and colleagues assessed fecal microbiota profiles and dietary habits, including fiber intake and probiotic use, in 158 patients with advanced melanoma who received immune checkpoint blockade inhibitors.
In the cohort, 31% (49 of 158) of late-stage melanoma patients reported taking a commercially available probiotic in the past month. When assessing whether probiotic use influenced patient outcomes, the investigators observed a shorter but not statistically significant difference in PFS in those who took a probiotic (median, 17 months) versus those who did not (23 months).
Higher dietary fiber, however, was associated with significantly improved PFS in a subset of 128 patients. The team divided patients into a higher-fiber intake group (those consuming at least 20 g/day) and a low-fiber group (those consuming less than 20 g).
The 37 patients reporting higher fiber intake demonstrated improved PFS, compared with those in the low-intake group (median PFS not reached vs. 13 months), plus a 30% lower risk of disease progression or death for each additional 5 g consumed each day.
“The observed protective effect of dietary fiber intake in relation to PFS and response remained consistent among the subset of patients treated with anti–PD-1 monotherapy, with the exclusion of patients reporting recent antibiotic use,” the authors noted.
When assessing fiber and probiotic intake together, the researchers found that immunotherapy response rate was higher (82%) in the 22 patients who reported sufficient dietary fiber intake with no probiotic use versus 59% in 101 patients who reported either insufficient fiber intake or probiotic use.
Overall, the research suggests that “consuming a diet rich in fiber, like fruits, vegetables, and legumes, could improve your ability to respond to immunotherapy,” co–lead author Giorgio Trinchieri, MD, chief of the Laboratory of Integrative Cancer Immunology in the National Cancer Institute’s Center for Cancer Research, Bethesda, Md., said in a press statement. “The data also suggest that it’s probably better for people with cancer receiving immunotherapy not to use commercially available probiotics.”
The investigators also explored whether dietary fiber intake enhanced treatment response in preclinical mouse models of melanoma. In this instance, mice receiving a fiber-rich diet showed delayed tumor growth after anti–PD-1 treatment, compared with mice given a low-fiber diet or probiotics.
According to the authors, “our preclinical models support the hypothesis that dietary fiber and probiotics modulate the microbiome and that antitumor immunity is impaired in mice receiving a low-fiber diet and in those receiving probiotics – with suppression of intratumoral [interferon-gamma] T-cell responses in both cases.”
Dietary fiber may exert beneficial effect by increasing specific types of bacteria in the gut, such as Ruminococcaceae, which “produce high levels of certain short-chain fatty acids that have an antitumor effect,” Dr. Trinchieri explained.
However, “the impact of dietary fiber and probiotics on the gut microbiota is only part of the bigger picture,” Dr. Trinchieri said in a press release. “Many factors can affect the ability of a patient with melanoma to respond to immunotherapy” but, according to this analysis, “the microbiota seems to be one of the dominant factors.”
While Jeffrey S. Weber, MD, PhD, applauded the “innovative and interesting” research, he believes the patient population is too small to confirm that a high-fiber diet does indeed contribute to improved immunotherapy response and PFS in patients with advanced melanoma.
Additional data are needed to clarify these findings. “I will believe it if I could see it replicated in a larger study,” Dr. Weber, professor and deputy director of the Laura and Isaac Perlmutter Cancer Center, New York University, said in an interview.
Dr. Wargo noted that a randomized clinical trial exploring how diets with varying fiber content affect the microbiome and immune response is currently enrolling patients with stage III and IV melanoma receiving immunotherapy.
This study was supported by the Melanoma Moon Shot, among others. Dr. Wargo is a collaborator on a U.S. patent application that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome. Dr. Weber reported relationships with Bristol-Myers Squibb, GlaxoSmithKline, Genentech BioOncology, Merck, Novartis, EMD Serono, Celldex, CytomX, Nektar, Roche, Altor, Daiichi Sankyo, and Eli Lilly, and is named on patents filed for biomarkers for ipilimumab and nivolumab.
A version of this article first appeared on Medscape.com.
a new study shows.
Investigators found that the patients who reported consuming at least 20 g of dietary fiber daily had significantly better progression-free survival (PFS) than those who reported consuming lower amounts of dietary fiber. However, patients who took a probiotic supplement in the past month had slightly shorter PFS, but the results were not statistically significant.
And after adjusting for clinical factors, each 5-g increase in daily dietary fiber intake corresponded to a 30% lower risk of disease progression, according to the analysis, published online Dec. 23, 2021, in Science.
“Our study sheds light on the potential effects of a patient’s diet and supplement use when starting treatment with immune checkpoint blockade,” co–lead study author Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at University of Texas MD Anderson Cancer Center, Houston, said in a press release. “These results provide further support for clinical trials to modulate the microbiome with the goal of improving cancer outcomes using dietary and other strategies.”
Previous research has suggested that the microbiome can influence patients’ response to immunotherapy. One recent analysis, for instance, found that fecal microbiota transplant can improve response to immunotherapy in advanced melanoma. And a small 2019 analysis from Dr. Dr. Wargo and colleagues hinted that a high-fiber diet may enhance patients’ ability to respond to immunotherapy in advanced melanoma, while probiotics appear to dampen that response.
Still, the role diet and probiotic supplements play in treatment response remains poorly understood.
In the current study, Dr. Wargo and colleagues assessed fecal microbiota profiles and dietary habits, including fiber intake and probiotic use, in 158 patients with advanced melanoma who received immune checkpoint blockade inhibitors.
In the cohort, 31% (49 of 158) of late-stage melanoma patients reported taking a commercially available probiotic in the past month. When assessing whether probiotic use influenced patient outcomes, the investigators observed a shorter but not statistically significant difference in PFS in those who took a probiotic (median, 17 months) versus those who did not (23 months).
Higher dietary fiber, however, was associated with significantly improved PFS in a subset of 128 patients. The team divided patients into a higher-fiber intake group (those consuming at least 20 g/day) and a low-fiber group (those consuming less than 20 g).
The 37 patients reporting higher fiber intake demonstrated improved PFS, compared with those in the low-intake group (median PFS not reached vs. 13 months), plus a 30% lower risk of disease progression or death for each additional 5 g consumed each day.
“The observed protective effect of dietary fiber intake in relation to PFS and response remained consistent among the subset of patients treated with anti–PD-1 monotherapy, with the exclusion of patients reporting recent antibiotic use,” the authors noted.
When assessing fiber and probiotic intake together, the researchers found that immunotherapy response rate was higher (82%) in the 22 patients who reported sufficient dietary fiber intake with no probiotic use versus 59% in 101 patients who reported either insufficient fiber intake or probiotic use.
Overall, the research suggests that “consuming a diet rich in fiber, like fruits, vegetables, and legumes, could improve your ability to respond to immunotherapy,” co–lead author Giorgio Trinchieri, MD, chief of the Laboratory of Integrative Cancer Immunology in the National Cancer Institute’s Center for Cancer Research, Bethesda, Md., said in a press statement. “The data also suggest that it’s probably better for people with cancer receiving immunotherapy not to use commercially available probiotics.”
The investigators also explored whether dietary fiber intake enhanced treatment response in preclinical mouse models of melanoma. In this instance, mice receiving a fiber-rich diet showed delayed tumor growth after anti–PD-1 treatment, compared with mice given a low-fiber diet or probiotics.
According to the authors, “our preclinical models support the hypothesis that dietary fiber and probiotics modulate the microbiome and that antitumor immunity is impaired in mice receiving a low-fiber diet and in those receiving probiotics – with suppression of intratumoral [interferon-gamma] T-cell responses in both cases.”
Dietary fiber may exert beneficial effect by increasing specific types of bacteria in the gut, such as Ruminococcaceae, which “produce high levels of certain short-chain fatty acids that have an antitumor effect,” Dr. Trinchieri explained.
However, “the impact of dietary fiber and probiotics on the gut microbiota is only part of the bigger picture,” Dr. Trinchieri said in a press release. “Many factors can affect the ability of a patient with melanoma to respond to immunotherapy” but, according to this analysis, “the microbiota seems to be one of the dominant factors.”
While Jeffrey S. Weber, MD, PhD, applauded the “innovative and interesting” research, he believes the patient population is too small to confirm that a high-fiber diet does indeed contribute to improved immunotherapy response and PFS in patients with advanced melanoma.
Additional data are needed to clarify these findings. “I will believe it if I could see it replicated in a larger study,” Dr. Weber, professor and deputy director of the Laura and Isaac Perlmutter Cancer Center, New York University, said in an interview.
Dr. Wargo noted that a randomized clinical trial exploring how diets with varying fiber content affect the microbiome and immune response is currently enrolling patients with stage III and IV melanoma receiving immunotherapy.
This study was supported by the Melanoma Moon Shot, among others. Dr. Wargo is a collaborator on a U.S. patent application that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome. Dr. Weber reported relationships with Bristol-Myers Squibb, GlaxoSmithKline, Genentech BioOncology, Merck, Novartis, EMD Serono, Celldex, CytomX, Nektar, Roche, Altor, Daiichi Sankyo, and Eli Lilly, and is named on patents filed for biomarkers for ipilimumab and nivolumab.
A version of this article first appeared on Medscape.com.
a new study shows.
Investigators found that the patients who reported consuming at least 20 g of dietary fiber daily had significantly better progression-free survival (PFS) than those who reported consuming lower amounts of dietary fiber. However, patients who took a probiotic supplement in the past month had slightly shorter PFS, but the results were not statistically significant.
And after adjusting for clinical factors, each 5-g increase in daily dietary fiber intake corresponded to a 30% lower risk of disease progression, according to the analysis, published online Dec. 23, 2021, in Science.
“Our study sheds light on the potential effects of a patient’s diet and supplement use when starting treatment with immune checkpoint blockade,” co–lead study author Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at University of Texas MD Anderson Cancer Center, Houston, said in a press release. “These results provide further support for clinical trials to modulate the microbiome with the goal of improving cancer outcomes using dietary and other strategies.”
Previous research has suggested that the microbiome can influence patients’ response to immunotherapy. One recent analysis, for instance, found that fecal microbiota transplant can improve response to immunotherapy in advanced melanoma. And a small 2019 analysis from Dr. Dr. Wargo and colleagues hinted that a high-fiber diet may enhance patients’ ability to respond to immunotherapy in advanced melanoma, while probiotics appear to dampen that response.
Still, the role diet and probiotic supplements play in treatment response remains poorly understood.
In the current study, Dr. Wargo and colleagues assessed fecal microbiota profiles and dietary habits, including fiber intake and probiotic use, in 158 patients with advanced melanoma who received immune checkpoint blockade inhibitors.
In the cohort, 31% (49 of 158) of late-stage melanoma patients reported taking a commercially available probiotic in the past month. When assessing whether probiotic use influenced patient outcomes, the investigators observed a shorter but not statistically significant difference in PFS in those who took a probiotic (median, 17 months) versus those who did not (23 months).
Higher dietary fiber, however, was associated with significantly improved PFS in a subset of 128 patients. The team divided patients into a higher-fiber intake group (those consuming at least 20 g/day) and a low-fiber group (those consuming less than 20 g).
The 37 patients reporting higher fiber intake demonstrated improved PFS, compared with those in the low-intake group (median PFS not reached vs. 13 months), plus a 30% lower risk of disease progression or death for each additional 5 g consumed each day.
“The observed protective effect of dietary fiber intake in relation to PFS and response remained consistent among the subset of patients treated with anti–PD-1 monotherapy, with the exclusion of patients reporting recent antibiotic use,” the authors noted.
When assessing fiber and probiotic intake together, the researchers found that immunotherapy response rate was higher (82%) in the 22 patients who reported sufficient dietary fiber intake with no probiotic use versus 59% in 101 patients who reported either insufficient fiber intake or probiotic use.
Overall, the research suggests that “consuming a diet rich in fiber, like fruits, vegetables, and legumes, could improve your ability to respond to immunotherapy,” co–lead author Giorgio Trinchieri, MD, chief of the Laboratory of Integrative Cancer Immunology in the National Cancer Institute’s Center for Cancer Research, Bethesda, Md., said in a press statement. “The data also suggest that it’s probably better for people with cancer receiving immunotherapy not to use commercially available probiotics.”
The investigators also explored whether dietary fiber intake enhanced treatment response in preclinical mouse models of melanoma. In this instance, mice receiving a fiber-rich diet showed delayed tumor growth after anti–PD-1 treatment, compared with mice given a low-fiber diet or probiotics.
According to the authors, “our preclinical models support the hypothesis that dietary fiber and probiotics modulate the microbiome and that antitumor immunity is impaired in mice receiving a low-fiber diet and in those receiving probiotics – with suppression of intratumoral [interferon-gamma] T-cell responses in both cases.”
Dietary fiber may exert beneficial effect by increasing specific types of bacteria in the gut, such as Ruminococcaceae, which “produce high levels of certain short-chain fatty acids that have an antitumor effect,” Dr. Trinchieri explained.
However, “the impact of dietary fiber and probiotics on the gut microbiota is only part of the bigger picture,” Dr. Trinchieri said in a press release. “Many factors can affect the ability of a patient with melanoma to respond to immunotherapy” but, according to this analysis, “the microbiota seems to be one of the dominant factors.”
While Jeffrey S. Weber, MD, PhD, applauded the “innovative and interesting” research, he believes the patient population is too small to confirm that a high-fiber diet does indeed contribute to improved immunotherapy response and PFS in patients with advanced melanoma.
Additional data are needed to clarify these findings. “I will believe it if I could see it replicated in a larger study,” Dr. Weber, professor and deputy director of the Laura and Isaac Perlmutter Cancer Center, New York University, said in an interview.
Dr. Wargo noted that a randomized clinical trial exploring how diets with varying fiber content affect the microbiome and immune response is currently enrolling patients with stage III and IV melanoma receiving immunotherapy.
This study was supported by the Melanoma Moon Shot, among others. Dr. Wargo is a collaborator on a U.S. patent application that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome. Dr. Weber reported relationships with Bristol-Myers Squibb, GlaxoSmithKline, Genentech BioOncology, Merck, Novartis, EMD Serono, Celldex, CytomX, Nektar, Roche, Altor, Daiichi Sankyo, and Eli Lilly, and is named on patents filed for biomarkers for ipilimumab and nivolumab.
A version of this article first appeared on Medscape.com.
FROM NATURE
Skin imaging working group releases first guidelines for AI algorithms used in dermatology
The
The guidelines, published in JAMA Dermatology on Dec. 1, 2021, contain a broad range of recommendations stakeholders should consider when developing and assessing image-based AI algorithms in dermatology. The recommendations are divided into categories of data, technique, technical assessment, and application. ISIC is “an academia and industry partnership designed to facilitate the application of digital skin imaging to help reduce melanoma mortality,” and is organized into different working groups, including the AI working group, according to its website.
“Our goal with these guidelines was to create higher-quality reporting of dataset and algorithm characteristics for dermatology AI,” first author Roxana Daneshjou, MD, PhD, clinical scholar in dermatology, in the department of dermatology at Stanford (Calif.) University, said in an interview. “We hope these guidelines also aid regulatory bodies around the world when they are assessing algorithms to be used in dermatology.”
Recommendations for data
The authors recommended that datasets used by AI algorithms have image descriptions and details on image artifacts. “For photography, these include the type of camera used; whether images were taken under standardized or varying conditions; whether they were taken by professional photographers, laymen, or health care professionals; and image quality,” they wrote. They also recommended that developers include in an image description the type of lighting used and whether the photo contains pen markings, hair, tattoos, injuries, surgical effects, or other “physical perturbations.”
Exchangeable image file format data obtained from the camera, and preprocessing procedures like color normalization and “postprocessing” of images, such as filtering, should also be disclosed. In addition, developers should disclose and justify inclusion of images that have been created by an algorithm within a dataset. Any public images used in the datasets should have references, and privately used images should be made public where possible, the authors said.
The ISIC working group guidelines also provided recommendations for patient-level metadata. Each image should include a patient’s geographical location and medical center they visited as well as their age, sex and gender, ethnicity and/or race, and skin tone. Dr. Daneshjou said this was one area where she and her colleagues found a lack of transparency in AI datasets in algorithms in a recent review. “We found that many AI papers provided sparse details about the images used to train and test their algorithms,” Dr. Daneshjou explained. “For example, only 7 out of 70 papers had any information about the skin tones in the images used for developing and/or testing AI algorithms. Understanding the diversity of images used to train and test algorithms is important because algorithms that are developed on images of predominantly white skin likely won’t work as well on Black and brown skin.”
The guideline authors also asked algorithm developers to describe the limitations of not including patient-level metadata information when it is incomplete or unavailable. In addition, “we ask that algorithm developers comment on potential biases of their algorithms,” Dr. Daneshjou said. “For example, an algorithm based only on telemedicine images may not capture the full range of diseases seen within an in-person clinic.”
When describing their AI algorithm, developers should detail their reasoning for the dataset size and partitions, inclusion and exclusion criteria for images, and use of any external samples for test sets. “Authors should consider any differences between the image characteristics used for algorithm development and those that might be encountered in the real world,” the guidelines stated.
Recommendations for technique
How the images in a dataset are labeled is a unique challenge in developing AI algorithms for dermatology, the authors noted. Developers should use histopathological diagnosis in their labeling, but this can sometimes result in label noise.
“Many of the AI algorithms in dermatology use supervised learning, which requires labeled examples to help the algorithm ‘learn’ features for discriminating between lesions. We found that some papers use consensus labeling – dermatologists providing a label – to label skin cancers; however, the standard for diagnosing skin cancer is using histopathology from a biopsy,” she said. “Dermatologists can biopsy seven to eight suspected melanomas before discovering a true melanoma, so dermatologist labeling of skin cancers is prone to label noise.”
ISIC’s guidelines stated a gold standard of labeling for dermatologic images is one area that still needs future research, but currently, “diagnoses, labels and diagnostic groups used in data repositories as well as public ontologies” such as ICD-11, AnatomyMapper, and SNOMED-CT should be included in dermatologic image datasets.
AI developers should also provide a detailed description of their algorithm, which includes methods, work flows, mathematical formulas as well as the generalizability of the algorithm across more than one dataset.
Recommendations for technical assessment
“Another important recommendation is that algorithm developers should provide a way for algorithms to be publicly evaluable by researchers,” Dr. Daneshjou said. “Many dermatology AI algorithms do not share either their data or their algorithm. Algorithm sharing is important for assessing reproducibility and robustness.”
Google’s recently announced AI-powered dermatology assistant tool, for example, “has made claims about its accuracy and ability to diagnose skin disease at a dermatologist level, but there is no way for researchers to independently test these claims,” she said. Other options like Model Dermatology, developed by Seung Seog Han, MD, PhD, of the Dermatology Clinic in Seoul, South Korea, and colleagues, offer an application programming interface “that allows researchers to test the algorithm,” Dr. Daneshjou said. “This kind of openness is key for assessing algorithm robustness.”
Developers should also note in their algorithm explanations how performance markers and benchmarks would translate to proposed clinical application. “In this context,” the use case – the context in which the AI application is being used – “should be clearly described – who are the intended users and under what clinical scenario are they using the algorithm,” the authors wrote.
Recommendations for application
The guidelines note that use case for the model should also be described by the AI developers. “Our checklist includes delineating use cases for algorithms and describing what use cases may be within the scope of the algorithm versus which use cases are out of scope,” Dr. Daneshjou said. “For example, an algorithm developed to provide decision support to dermatologists, with a human in the loop, may not be accurate enough to release directly to consumers.”
As the goal of AI algorithms in dermatology is eventual implementation for clinicians and patients, the authors asked developers to consider shortcomings and potential harms of the algorithm during implementation. “Ethical considerations and impact on vulnerable populations should also be considered and discussed,” they wrote. An algorithm “suggesting aesthetic medical treatments may have negative effects given the biased nature of beauty standards,” and “an algorithm that diagnoses basal cell carcinomas but lacks any pigmented basal cell carcinomas, which are more often seen in skin of color, will not perform equitably across populations.”
Prior to implementing an AI algorithm, the ISIC working group recommended developers perform prospective clinical trials for validation. Checklists and guidelines like SPIRIT-AI and CONSORT-AI “provide guidance on how to design clinical trials to test AI algorithms,” Dr. Daneshjou said.
After implementation, “I believe we need additional research in how we monitor algorithms after they are deployed clinically, Dr. Daneshjou said. “Currently there are no [Food and Drug Administration]–approved AI algorithms in dermatology; however, there are several applications that have CE mark in Europe, and there are no mechanisms for postmarket surveillance there.
'Timely' recommendations
Commenting on the ISIC working group guidelines, Justin M. Ko, MD, MBA, director and chief of medical dermatology for Stanford Health Care, who was not involved with the work, said that the recommendations are timely and provide “a framework for a ‘common language’ around AI datasets specifically tailored to dermatology.” Dr. Ko, chair of the American Academy of Dermatology’s Ad Hoc Task Force on Augmented Intelligence, noted the work by Dr. Daneshjou and colleagues “is consistent with and builds further details” on the position statement released by the AAD AI task force in 2019.
“As machine-learning capabilities and commercial efforts continue to mature, it becomes increasingly important that we are able to ‘look under the hood,’ and evaluate all the critical factors that influence development of these capabilities,” he said in an interview. “A standard set of reporting guidelines not only allows for transparency in evaluating data and performance of models and algorithms, but also forces the consideration of issues of equity, fairness, mitigation of bias, and clinically meaningful outcomes.”
One concern is the impact of AI algorithms on societal or health systems, he noted, which is brought up in the guidelines. “The last thing we would want is the development of robust AI systems that exacerbate access challenges, or generate patient anxiety/worry, or drive low-value utilization, or adds to care team burden, or create a technological barrier to care, or increases inequity in dermatologic care,” he said.
In developing AI algorithms for dermatology, a “major practical issue” is how performance on paper will translate to real-world use, Dr. Ko explained, and the ISIC guidelines “provide a critical step in empowering clinicians, practices, and our field to shape the advent of the AI and augmented intelligence tools and systems to promote and enhance meaningful clinical outcomes, and augment the core patient-clinician relationship and ensure they are grounded in principles of fairness, equity and transparency.”
This research was funded by awards and grants to individual authors from the Charina Fund, a Google Research Award, Melanoma Research Alliance, National Health and Medical Research Council, National Institutes of Health/National Cancer Institute, National Science Foundation, and the Department of Veterans Affairs. The authors disclosed relationships with governmental entities, pharmaceutical companies, technology startups, medical publishers, charitable trusts, consulting firms, dermatology training companies, providers of medical devices, manufacturers of dermatologic products, and other organizations related to the paper in the form of supplied equipment, having founded a company; receiving grants, patents, or personal fees; holding shares; and medical reporting. Dr. Ko reported that he serves as a clinical advisor for Skin Analytics, and has an ongoing research collaboration with Google.
The
The guidelines, published in JAMA Dermatology on Dec. 1, 2021, contain a broad range of recommendations stakeholders should consider when developing and assessing image-based AI algorithms in dermatology. The recommendations are divided into categories of data, technique, technical assessment, and application. ISIC is “an academia and industry partnership designed to facilitate the application of digital skin imaging to help reduce melanoma mortality,” and is organized into different working groups, including the AI working group, according to its website.
“Our goal with these guidelines was to create higher-quality reporting of dataset and algorithm characteristics for dermatology AI,” first author Roxana Daneshjou, MD, PhD, clinical scholar in dermatology, in the department of dermatology at Stanford (Calif.) University, said in an interview. “We hope these guidelines also aid regulatory bodies around the world when they are assessing algorithms to be used in dermatology.”
Recommendations for data
The authors recommended that datasets used by AI algorithms have image descriptions and details on image artifacts. “For photography, these include the type of camera used; whether images were taken under standardized or varying conditions; whether they were taken by professional photographers, laymen, or health care professionals; and image quality,” they wrote. They also recommended that developers include in an image description the type of lighting used and whether the photo contains pen markings, hair, tattoos, injuries, surgical effects, or other “physical perturbations.”
Exchangeable image file format data obtained from the camera, and preprocessing procedures like color normalization and “postprocessing” of images, such as filtering, should also be disclosed. In addition, developers should disclose and justify inclusion of images that have been created by an algorithm within a dataset. Any public images used in the datasets should have references, and privately used images should be made public where possible, the authors said.
The ISIC working group guidelines also provided recommendations for patient-level metadata. Each image should include a patient’s geographical location and medical center they visited as well as their age, sex and gender, ethnicity and/or race, and skin tone. Dr. Daneshjou said this was one area where she and her colleagues found a lack of transparency in AI datasets in algorithms in a recent review. “We found that many AI papers provided sparse details about the images used to train and test their algorithms,” Dr. Daneshjou explained. “For example, only 7 out of 70 papers had any information about the skin tones in the images used for developing and/or testing AI algorithms. Understanding the diversity of images used to train and test algorithms is important because algorithms that are developed on images of predominantly white skin likely won’t work as well on Black and brown skin.”
The guideline authors also asked algorithm developers to describe the limitations of not including patient-level metadata information when it is incomplete or unavailable. In addition, “we ask that algorithm developers comment on potential biases of their algorithms,” Dr. Daneshjou said. “For example, an algorithm based only on telemedicine images may not capture the full range of diseases seen within an in-person clinic.”
When describing their AI algorithm, developers should detail their reasoning for the dataset size and partitions, inclusion and exclusion criteria for images, and use of any external samples for test sets. “Authors should consider any differences between the image characteristics used for algorithm development and those that might be encountered in the real world,” the guidelines stated.
Recommendations for technique
How the images in a dataset are labeled is a unique challenge in developing AI algorithms for dermatology, the authors noted. Developers should use histopathological diagnosis in their labeling, but this can sometimes result in label noise.
“Many of the AI algorithms in dermatology use supervised learning, which requires labeled examples to help the algorithm ‘learn’ features for discriminating between lesions. We found that some papers use consensus labeling – dermatologists providing a label – to label skin cancers; however, the standard for diagnosing skin cancer is using histopathology from a biopsy,” she said. “Dermatologists can biopsy seven to eight suspected melanomas before discovering a true melanoma, so dermatologist labeling of skin cancers is prone to label noise.”
ISIC’s guidelines stated a gold standard of labeling for dermatologic images is one area that still needs future research, but currently, “diagnoses, labels and diagnostic groups used in data repositories as well as public ontologies” such as ICD-11, AnatomyMapper, and SNOMED-CT should be included in dermatologic image datasets.
AI developers should also provide a detailed description of their algorithm, which includes methods, work flows, mathematical formulas as well as the generalizability of the algorithm across more than one dataset.
Recommendations for technical assessment
“Another important recommendation is that algorithm developers should provide a way for algorithms to be publicly evaluable by researchers,” Dr. Daneshjou said. “Many dermatology AI algorithms do not share either their data or their algorithm. Algorithm sharing is important for assessing reproducibility and robustness.”
Google’s recently announced AI-powered dermatology assistant tool, for example, “has made claims about its accuracy and ability to diagnose skin disease at a dermatologist level, but there is no way for researchers to independently test these claims,” she said. Other options like Model Dermatology, developed by Seung Seog Han, MD, PhD, of the Dermatology Clinic in Seoul, South Korea, and colleagues, offer an application programming interface “that allows researchers to test the algorithm,” Dr. Daneshjou said. “This kind of openness is key for assessing algorithm robustness.”
Developers should also note in their algorithm explanations how performance markers and benchmarks would translate to proposed clinical application. “In this context,” the use case – the context in which the AI application is being used – “should be clearly described – who are the intended users and under what clinical scenario are they using the algorithm,” the authors wrote.
Recommendations for application
The guidelines note that use case for the model should also be described by the AI developers. “Our checklist includes delineating use cases for algorithms and describing what use cases may be within the scope of the algorithm versus which use cases are out of scope,” Dr. Daneshjou said. “For example, an algorithm developed to provide decision support to dermatologists, with a human in the loop, may not be accurate enough to release directly to consumers.”
As the goal of AI algorithms in dermatology is eventual implementation for clinicians and patients, the authors asked developers to consider shortcomings and potential harms of the algorithm during implementation. “Ethical considerations and impact on vulnerable populations should also be considered and discussed,” they wrote. An algorithm “suggesting aesthetic medical treatments may have negative effects given the biased nature of beauty standards,” and “an algorithm that diagnoses basal cell carcinomas but lacks any pigmented basal cell carcinomas, which are more often seen in skin of color, will not perform equitably across populations.”
Prior to implementing an AI algorithm, the ISIC working group recommended developers perform prospective clinical trials for validation. Checklists and guidelines like SPIRIT-AI and CONSORT-AI “provide guidance on how to design clinical trials to test AI algorithms,” Dr. Daneshjou said.
After implementation, “I believe we need additional research in how we monitor algorithms after they are deployed clinically, Dr. Daneshjou said. “Currently there are no [Food and Drug Administration]–approved AI algorithms in dermatology; however, there are several applications that have CE mark in Europe, and there are no mechanisms for postmarket surveillance there.
'Timely' recommendations
Commenting on the ISIC working group guidelines, Justin M. Ko, MD, MBA, director and chief of medical dermatology for Stanford Health Care, who was not involved with the work, said that the recommendations are timely and provide “a framework for a ‘common language’ around AI datasets specifically tailored to dermatology.” Dr. Ko, chair of the American Academy of Dermatology’s Ad Hoc Task Force on Augmented Intelligence, noted the work by Dr. Daneshjou and colleagues “is consistent with and builds further details” on the position statement released by the AAD AI task force in 2019.
“As machine-learning capabilities and commercial efforts continue to mature, it becomes increasingly important that we are able to ‘look under the hood,’ and evaluate all the critical factors that influence development of these capabilities,” he said in an interview. “A standard set of reporting guidelines not only allows for transparency in evaluating data and performance of models and algorithms, but also forces the consideration of issues of equity, fairness, mitigation of bias, and clinically meaningful outcomes.”
One concern is the impact of AI algorithms on societal or health systems, he noted, which is brought up in the guidelines. “The last thing we would want is the development of robust AI systems that exacerbate access challenges, or generate patient anxiety/worry, or drive low-value utilization, or adds to care team burden, or create a technological barrier to care, or increases inequity in dermatologic care,” he said.
In developing AI algorithms for dermatology, a “major practical issue” is how performance on paper will translate to real-world use, Dr. Ko explained, and the ISIC guidelines “provide a critical step in empowering clinicians, practices, and our field to shape the advent of the AI and augmented intelligence tools and systems to promote and enhance meaningful clinical outcomes, and augment the core patient-clinician relationship and ensure they are grounded in principles of fairness, equity and transparency.”
This research was funded by awards and grants to individual authors from the Charina Fund, a Google Research Award, Melanoma Research Alliance, National Health and Medical Research Council, National Institutes of Health/National Cancer Institute, National Science Foundation, and the Department of Veterans Affairs. The authors disclosed relationships with governmental entities, pharmaceutical companies, technology startups, medical publishers, charitable trusts, consulting firms, dermatology training companies, providers of medical devices, manufacturers of dermatologic products, and other organizations related to the paper in the form of supplied equipment, having founded a company; receiving grants, patents, or personal fees; holding shares; and medical reporting. Dr. Ko reported that he serves as a clinical advisor for Skin Analytics, and has an ongoing research collaboration with Google.
The
The guidelines, published in JAMA Dermatology on Dec. 1, 2021, contain a broad range of recommendations stakeholders should consider when developing and assessing image-based AI algorithms in dermatology. The recommendations are divided into categories of data, technique, technical assessment, and application. ISIC is “an academia and industry partnership designed to facilitate the application of digital skin imaging to help reduce melanoma mortality,” and is organized into different working groups, including the AI working group, according to its website.
“Our goal with these guidelines was to create higher-quality reporting of dataset and algorithm characteristics for dermatology AI,” first author Roxana Daneshjou, MD, PhD, clinical scholar in dermatology, in the department of dermatology at Stanford (Calif.) University, said in an interview. “We hope these guidelines also aid regulatory bodies around the world when they are assessing algorithms to be used in dermatology.”
Recommendations for data
The authors recommended that datasets used by AI algorithms have image descriptions and details on image artifacts. “For photography, these include the type of camera used; whether images were taken under standardized or varying conditions; whether they were taken by professional photographers, laymen, or health care professionals; and image quality,” they wrote. They also recommended that developers include in an image description the type of lighting used and whether the photo contains pen markings, hair, tattoos, injuries, surgical effects, or other “physical perturbations.”
Exchangeable image file format data obtained from the camera, and preprocessing procedures like color normalization and “postprocessing” of images, such as filtering, should also be disclosed. In addition, developers should disclose and justify inclusion of images that have been created by an algorithm within a dataset. Any public images used in the datasets should have references, and privately used images should be made public where possible, the authors said.
The ISIC working group guidelines also provided recommendations for patient-level metadata. Each image should include a patient’s geographical location and medical center they visited as well as their age, sex and gender, ethnicity and/or race, and skin tone. Dr. Daneshjou said this was one area where she and her colleagues found a lack of transparency in AI datasets in algorithms in a recent review. “We found that many AI papers provided sparse details about the images used to train and test their algorithms,” Dr. Daneshjou explained. “For example, only 7 out of 70 papers had any information about the skin tones in the images used for developing and/or testing AI algorithms. Understanding the diversity of images used to train and test algorithms is important because algorithms that are developed on images of predominantly white skin likely won’t work as well on Black and brown skin.”
The guideline authors also asked algorithm developers to describe the limitations of not including patient-level metadata information when it is incomplete or unavailable. In addition, “we ask that algorithm developers comment on potential biases of their algorithms,” Dr. Daneshjou said. “For example, an algorithm based only on telemedicine images may not capture the full range of diseases seen within an in-person clinic.”
When describing their AI algorithm, developers should detail their reasoning for the dataset size and partitions, inclusion and exclusion criteria for images, and use of any external samples for test sets. “Authors should consider any differences between the image characteristics used for algorithm development and those that might be encountered in the real world,” the guidelines stated.
Recommendations for technique
How the images in a dataset are labeled is a unique challenge in developing AI algorithms for dermatology, the authors noted. Developers should use histopathological diagnosis in their labeling, but this can sometimes result in label noise.
“Many of the AI algorithms in dermatology use supervised learning, which requires labeled examples to help the algorithm ‘learn’ features for discriminating between lesions. We found that some papers use consensus labeling – dermatologists providing a label – to label skin cancers; however, the standard for diagnosing skin cancer is using histopathology from a biopsy,” she said. “Dermatologists can biopsy seven to eight suspected melanomas before discovering a true melanoma, so dermatologist labeling of skin cancers is prone to label noise.”
ISIC’s guidelines stated a gold standard of labeling for dermatologic images is one area that still needs future research, but currently, “diagnoses, labels and diagnostic groups used in data repositories as well as public ontologies” such as ICD-11, AnatomyMapper, and SNOMED-CT should be included in dermatologic image datasets.
AI developers should also provide a detailed description of their algorithm, which includes methods, work flows, mathematical formulas as well as the generalizability of the algorithm across more than one dataset.
Recommendations for technical assessment
“Another important recommendation is that algorithm developers should provide a way for algorithms to be publicly evaluable by researchers,” Dr. Daneshjou said. “Many dermatology AI algorithms do not share either their data or their algorithm. Algorithm sharing is important for assessing reproducibility and robustness.”
Google’s recently announced AI-powered dermatology assistant tool, for example, “has made claims about its accuracy and ability to diagnose skin disease at a dermatologist level, but there is no way for researchers to independently test these claims,” she said. Other options like Model Dermatology, developed by Seung Seog Han, MD, PhD, of the Dermatology Clinic in Seoul, South Korea, and colleagues, offer an application programming interface “that allows researchers to test the algorithm,” Dr. Daneshjou said. “This kind of openness is key for assessing algorithm robustness.”
Developers should also note in their algorithm explanations how performance markers and benchmarks would translate to proposed clinical application. “In this context,” the use case – the context in which the AI application is being used – “should be clearly described – who are the intended users and under what clinical scenario are they using the algorithm,” the authors wrote.
Recommendations for application
The guidelines note that use case for the model should also be described by the AI developers. “Our checklist includes delineating use cases for algorithms and describing what use cases may be within the scope of the algorithm versus which use cases are out of scope,” Dr. Daneshjou said. “For example, an algorithm developed to provide decision support to dermatologists, with a human in the loop, may not be accurate enough to release directly to consumers.”
As the goal of AI algorithms in dermatology is eventual implementation for clinicians and patients, the authors asked developers to consider shortcomings and potential harms of the algorithm during implementation. “Ethical considerations and impact on vulnerable populations should also be considered and discussed,” they wrote. An algorithm “suggesting aesthetic medical treatments may have negative effects given the biased nature of beauty standards,” and “an algorithm that diagnoses basal cell carcinomas but lacks any pigmented basal cell carcinomas, which are more often seen in skin of color, will not perform equitably across populations.”
Prior to implementing an AI algorithm, the ISIC working group recommended developers perform prospective clinical trials for validation. Checklists and guidelines like SPIRIT-AI and CONSORT-AI “provide guidance on how to design clinical trials to test AI algorithms,” Dr. Daneshjou said.
After implementation, “I believe we need additional research in how we monitor algorithms after they are deployed clinically, Dr. Daneshjou said. “Currently there are no [Food and Drug Administration]–approved AI algorithms in dermatology; however, there are several applications that have CE mark in Europe, and there are no mechanisms for postmarket surveillance there.
'Timely' recommendations
Commenting on the ISIC working group guidelines, Justin M. Ko, MD, MBA, director and chief of medical dermatology for Stanford Health Care, who was not involved with the work, said that the recommendations are timely and provide “a framework for a ‘common language’ around AI datasets specifically tailored to dermatology.” Dr. Ko, chair of the American Academy of Dermatology’s Ad Hoc Task Force on Augmented Intelligence, noted the work by Dr. Daneshjou and colleagues “is consistent with and builds further details” on the position statement released by the AAD AI task force in 2019.
“As machine-learning capabilities and commercial efforts continue to mature, it becomes increasingly important that we are able to ‘look under the hood,’ and evaluate all the critical factors that influence development of these capabilities,” he said in an interview. “A standard set of reporting guidelines not only allows for transparency in evaluating data and performance of models and algorithms, but also forces the consideration of issues of equity, fairness, mitigation of bias, and clinically meaningful outcomes.”
One concern is the impact of AI algorithms on societal or health systems, he noted, which is brought up in the guidelines. “The last thing we would want is the development of robust AI systems that exacerbate access challenges, or generate patient anxiety/worry, or drive low-value utilization, or adds to care team burden, or create a technological barrier to care, or increases inequity in dermatologic care,” he said.
In developing AI algorithms for dermatology, a “major practical issue” is how performance on paper will translate to real-world use, Dr. Ko explained, and the ISIC guidelines “provide a critical step in empowering clinicians, practices, and our field to shape the advent of the AI and augmented intelligence tools and systems to promote and enhance meaningful clinical outcomes, and augment the core patient-clinician relationship and ensure they are grounded in principles of fairness, equity and transparency.”
This research was funded by awards and grants to individual authors from the Charina Fund, a Google Research Award, Melanoma Research Alliance, National Health and Medical Research Council, National Institutes of Health/National Cancer Institute, National Science Foundation, and the Department of Veterans Affairs. The authors disclosed relationships with governmental entities, pharmaceutical companies, technology startups, medical publishers, charitable trusts, consulting firms, dermatology training companies, providers of medical devices, manufacturers of dermatologic products, and other organizations related to the paper in the form of supplied equipment, having founded a company; receiving grants, patents, or personal fees; holding shares; and medical reporting. Dr. Ko reported that he serves as a clinical advisor for Skin Analytics, and has an ongoing research collaboration with Google.
FROM JAMA DERMATOLOGY
Metastatic uveal melanoma: New drugs in pipeline, but prognoses remain grim
No one’s quite sure what causes uveal melanoma (UM). Unlike skin cancers, UM doesn’t seem to have any link to exposure to ultraviolet rays, although it’s most likely to strike people who are vulnerable to sun damage, like Caucasians and people with lighter eyes and lighter skin (but not lighter hair), and an inability to tan. Up to half of those affected by the disease will recover after treatment. In the other half, the cancer spreads from the eye – typically to the liver – and patient prognoses remain extremely poor despite extensive efforts to develop effective treatments.
“The median survival is probably about 2 years, and there are a number of papers out there that talk about life expectancy as short as 6 months,” said Marlana Orloff, MD, an associate professor of medical oncology at Thomas Jefferson University Hospital, Philadelphia.
But there is hope on the horizon, even if it’s not as near as patients would prefer. “Just over the last 5-10 years, we’ve gained a lot more knowledge about this disease as we try to understand how distinctly different it is, how mutations drive it, and how we can approach it using immunotherapy,” Dr. Orloff said. “I hope we’ll come up with better options for prolonging survival.”
Tracking uveal melanoma’s dangerous course
All melanomas, including UM, strike the melanocytes (cells) that provide pigment. According to a 2017 report1 in the journal Eye, “uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in the iris (4%), ciliary body (6%), or choroid (90%) . … As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma.”
The median age of diagnosis is 59-62 years, the report says, although non-Whites seem to develop the disease earlier.
The vast majority of patients receive treatment by plaque brachytherapy via radioactive seeds. “It’s like brachytherapy of the prostate,” said medical oncologist Rino S. Seedor, MD, of Thomas Jefferson University Hospital. “If the eye tumor is too big or invasive, they’ll cut out the eye.”
As many as 50% of patients will develop metastasis, sometimes within 2-3 years in those who have large tumors and high genetic risk, said ophthalmologist and radiation oncologist Miguel Materin, MD, of Duke University Eye Center, Durham, N.C. “There’s probably micrometastasis early in the development of the tumor,” he said. “The metastasis might develop before we or the patient knows there’s a tumor.”
Some physicians question the value of prognostic testing in patients who don’t yet show signs of metastasis, Dr. Materin said, because the findings can be grim.
Unlike his more cautious colleagues, Dr. Materin prefers to pursue testing, he said. Most patients agree to it. “It’s up to them to decide if they want to know if they have a bad prognosis,” he said, and the findings can be helpful to physicians because they provide useful genetic information about tumors.
Monitoring for liver metastasis is key
UM metastases are most likely to strike the liver, and prognoses are especially poor when they do. According to a 2019 analysis of 175 patients with metastatic UM in the Netherlands, “the presence of liver metastases is negatively associated with survival (hazard ratio = 2.09; 95% confidence interval, 1.07-4.08). … In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases.”2
As a result, physicians recommend close monitoring in patients with UM. Thomas Jefferson University’s Dr. Orloff uses tumor stages and genetic risk profiles to guide surveillance. “Very large tumors and/or monosomy 3 and 8q amplification or a Class 2 gene signature would suggest a higher-risk tumor,” she said. “For these patients we recommend MRI of the abdomen every 3 months for 2 years, CT of the chest every 6 months for 2 years, labs every 3 months for 2 years, then MRI every 6 months until year 5 with chest imaging yearly, then at 5 years everything yearly. For lower- or intermediate-risk patients we recommend MRI of the abdomen every 6 months for 5 years, chest imaging yearly, labs every 6 months, then at 5 years everything yearly.”
In the United States, patients with metastatic disease are typically sent to referral centers at institutions such as Duke, Yale (New Haven, Conn.), and Thomas Jefferson universities.
Metastasis treatments offer limited relief
There are no FDA-approved treatments for metastatic MU, and the treatments that physicians do use don’t seem to have much of an effect on life span. A 2019 study examined 73 patients with MU metastasis to the liver who were treated from 2004 to 2011 and 2012 to 2016. Among both cohorts, those who had no treatment lived nearly as long (median of 15 months) as those treated with local therapy (median of 18.7 months). Median survival for the entire population was 15 months (95% CI: 11–18 months). There was no statistically significant difference between the periods.3
However, there are signs that a move away from first-line chemotherapy in recent decades has led to longer life spans. Dr. Seedor led a 2018 study4 that compared two cohorts of MU patients with liver metastasis at her university: 98 patients from 1971 to 1993 (81% received systemic chemotherapy as their initial therapy) and 574 from 2000 to 2017 (they received various liver-directed initial treatments such as chemoembolization, drug-eluting beads, immunoembolization, and radioembolization).
The patients in the second group lived longer after treatment of initial UM than the first group (5.1 years vs. 3.3 years, P < .001) and after the development of liver metastasis (16.4 months vs. 4.8 months, P < .001). A 2020 follow-up study reported similar findings and noted that a “combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.”5
At Thomas Jefferson Medical Center, liver-directed therapy includes radioembolization, chemomobilization, and microwave ablation, Dr. Seedor said. “Which one we choose is based on how big the tumors are.”
Treatments in development could make advances
Physicians are working on several fronts to develop new treatments. A 2021 review of clinical trials found numerous trials regarding checkpoint inhibition, one devoted to a vaccine, and several involving checkpoint inhibitors. The review author notes that “the low mutational burden and poor immunogenicity of UM tumors may underlie poor responses and resistance to [immune checkpoint inhibitors] alone.”6
Earlier this year, grant-funded researchers reported encouraging news on the G protein inhibitor front. Their study found that FR900359, a selective inhibitor of the Gq/11/14 subfamily of heterotrimeric G proteins, could hold promise for “treating UM and potentially other diseases caused by constitutively active Gq/11.”7
In another 2021 study, this one with no reported funding, researchers explored the tumor microenvironment of UM and reported that their findings “provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.”8
Experimental drug may add months of life
Physicians often recommend that patients take part in clinical trials. Earlier this year, researchers reported that a drug called tebentafusp – a bispecific fusion protein – slightly boosted metastatic UM survival in an open-label, phase 3 clinical trial when used as a first-line treatment. Patients were randomly assigned to tebentafusp, 1 of 2 immunotherapy drugs (ipilimumab or pembrolizumab), or the chemotherapy drug dacarbazine. Those who took tebentafusp vs. the other options lived longer with an estimated 1-year overall rate of 73.2% (95% CI: 66.3-78.9) vs. 57.5% (95% CI: 47.0-66.6), respectively. Fewer than 4% of those on tebentafusp needed to stop it because of adverse effects, and no treatment-related deaths occurred.9
Dr. Orloff is one of the coauthors of this study.
The National Cancer Institute provided more details about the industry-funded research and noted that median overall survival for patients who received the drug was 21.7 months vs. 16 months for the control group.
Not every patient is eligible for this treatment, however. A coauthor told the American Association for Cancer Research that “the major limitation of tebentafusp is that it can only be used in patients who have a specific HLA [human leukocyte antigen] type.” Patients must be HLA-A*0201-positive.10
In August 2021, the FDA granted priority review for tebentafusp.11 And in September 2021, a company called TriSalus announced the first patient enrollment in a “clinical study evaluating the administration of SD-101, an investigational toll-like receptor 9 (TLR9) agonist in adults with metastatic uveal melanoma.”12
According to the company, the research “is designed to evaluate the intravascular administration of SD-101 into uveal melanoma liver metastasis lesions in combination with checkpoint inhibitors using the novel Pressure-Enabled Drug Delivery (PEDD) approach.” This strategy is “designed to overcome the inherent intratumoral pressure of solid tumors,” the company said.
Dr. Materin serves on a scientific advisory board for Castle Biosciences. Dr. Orloff is a consultant for Immunocore, which funded the tebentafusp study, and serves on a scientific advisory board for TriSalus. Dr. Seedor reports no disclosures.
References
1.Kaliki S and Shields C. Eye. 2017 Feb;31:241-57.
2.Jochems A et al. Cancers. 2019 July;11(7):1007.
3.Xu LT et al. Ocul Oncol Pathol. 2019;5:323-32.
4.Seedor RS et al. J Clin Oncol. 2018 May;36(15_suppl):9592.
5.Seedor RS et al. Cancers (Basel). 2020 Jan 1;12(1):117.
6.Orloff M. Ocul Oncol Pathol. 2021 July;7:168-76.
7.Onken MD et al. J Biol Chem. 2021;296:100403.
8.Lei S and Zhang Y. Int Immunopharmacol. 2021 July;96:107816.
9.Piperno-Neumann S et al. Proceedings of the 112th Annual Meeting of the American Association for Cancer Research; 2021 April 10-15. Philadelphia (Pa.): AACR; 2021. Abstract nr 5133.
10.National Cancer Institute: https://www.cancer.gov/news-events/cancer-currents-blog/2021/tebentafusp-uveal-melanoma-improves-survival
11.Immunocore press release: https://ir.immunocore.com/news-releases/news-release-details/immunocore-announces-us-food-and-drug-administration-and
12.Trisalus announcement: https://finance.yahoo.com/news/trisalus-life-sciences-announces-first-130000215.html?guccounter=1
No one’s quite sure what causes uveal melanoma (UM). Unlike skin cancers, UM doesn’t seem to have any link to exposure to ultraviolet rays, although it’s most likely to strike people who are vulnerable to sun damage, like Caucasians and people with lighter eyes and lighter skin (but not lighter hair), and an inability to tan. Up to half of those affected by the disease will recover after treatment. In the other half, the cancer spreads from the eye – typically to the liver – and patient prognoses remain extremely poor despite extensive efforts to develop effective treatments.
“The median survival is probably about 2 years, and there are a number of papers out there that talk about life expectancy as short as 6 months,” said Marlana Orloff, MD, an associate professor of medical oncology at Thomas Jefferson University Hospital, Philadelphia.
But there is hope on the horizon, even if it’s not as near as patients would prefer. “Just over the last 5-10 years, we’ve gained a lot more knowledge about this disease as we try to understand how distinctly different it is, how mutations drive it, and how we can approach it using immunotherapy,” Dr. Orloff said. “I hope we’ll come up with better options for prolonging survival.”
Tracking uveal melanoma’s dangerous course
All melanomas, including UM, strike the melanocytes (cells) that provide pigment. According to a 2017 report1 in the journal Eye, “uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in the iris (4%), ciliary body (6%), or choroid (90%) . … As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma.”
The median age of diagnosis is 59-62 years, the report says, although non-Whites seem to develop the disease earlier.
The vast majority of patients receive treatment by plaque brachytherapy via radioactive seeds. “It’s like brachytherapy of the prostate,” said medical oncologist Rino S. Seedor, MD, of Thomas Jefferson University Hospital. “If the eye tumor is too big or invasive, they’ll cut out the eye.”
As many as 50% of patients will develop metastasis, sometimes within 2-3 years in those who have large tumors and high genetic risk, said ophthalmologist and radiation oncologist Miguel Materin, MD, of Duke University Eye Center, Durham, N.C. “There’s probably micrometastasis early in the development of the tumor,” he said. “The metastasis might develop before we or the patient knows there’s a tumor.”
Some physicians question the value of prognostic testing in patients who don’t yet show signs of metastasis, Dr. Materin said, because the findings can be grim.
Unlike his more cautious colleagues, Dr. Materin prefers to pursue testing, he said. Most patients agree to it. “It’s up to them to decide if they want to know if they have a bad prognosis,” he said, and the findings can be helpful to physicians because they provide useful genetic information about tumors.
Monitoring for liver metastasis is key
UM metastases are most likely to strike the liver, and prognoses are especially poor when they do. According to a 2019 analysis of 175 patients with metastatic UM in the Netherlands, “the presence of liver metastases is negatively associated with survival (hazard ratio = 2.09; 95% confidence interval, 1.07-4.08). … In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases.”2
As a result, physicians recommend close monitoring in patients with UM. Thomas Jefferson University’s Dr. Orloff uses tumor stages and genetic risk profiles to guide surveillance. “Very large tumors and/or monosomy 3 and 8q amplification or a Class 2 gene signature would suggest a higher-risk tumor,” she said. “For these patients we recommend MRI of the abdomen every 3 months for 2 years, CT of the chest every 6 months for 2 years, labs every 3 months for 2 years, then MRI every 6 months until year 5 with chest imaging yearly, then at 5 years everything yearly. For lower- or intermediate-risk patients we recommend MRI of the abdomen every 6 months for 5 years, chest imaging yearly, labs every 6 months, then at 5 years everything yearly.”
In the United States, patients with metastatic disease are typically sent to referral centers at institutions such as Duke, Yale (New Haven, Conn.), and Thomas Jefferson universities.
Metastasis treatments offer limited relief
There are no FDA-approved treatments for metastatic MU, and the treatments that physicians do use don’t seem to have much of an effect on life span. A 2019 study examined 73 patients with MU metastasis to the liver who were treated from 2004 to 2011 and 2012 to 2016. Among both cohorts, those who had no treatment lived nearly as long (median of 15 months) as those treated with local therapy (median of 18.7 months). Median survival for the entire population was 15 months (95% CI: 11–18 months). There was no statistically significant difference between the periods.3
However, there are signs that a move away from first-line chemotherapy in recent decades has led to longer life spans. Dr. Seedor led a 2018 study4 that compared two cohorts of MU patients with liver metastasis at her university: 98 patients from 1971 to 1993 (81% received systemic chemotherapy as their initial therapy) and 574 from 2000 to 2017 (they received various liver-directed initial treatments such as chemoembolization, drug-eluting beads, immunoembolization, and radioembolization).
The patients in the second group lived longer after treatment of initial UM than the first group (5.1 years vs. 3.3 years, P < .001) and after the development of liver metastasis (16.4 months vs. 4.8 months, P < .001). A 2020 follow-up study reported similar findings and noted that a “combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.”5
At Thomas Jefferson Medical Center, liver-directed therapy includes radioembolization, chemomobilization, and microwave ablation, Dr. Seedor said. “Which one we choose is based on how big the tumors are.”
Treatments in development could make advances
Physicians are working on several fronts to develop new treatments. A 2021 review of clinical trials found numerous trials regarding checkpoint inhibition, one devoted to a vaccine, and several involving checkpoint inhibitors. The review author notes that “the low mutational burden and poor immunogenicity of UM tumors may underlie poor responses and resistance to [immune checkpoint inhibitors] alone.”6
Earlier this year, grant-funded researchers reported encouraging news on the G protein inhibitor front. Their study found that FR900359, a selective inhibitor of the Gq/11/14 subfamily of heterotrimeric G proteins, could hold promise for “treating UM and potentially other diseases caused by constitutively active Gq/11.”7
In another 2021 study, this one with no reported funding, researchers explored the tumor microenvironment of UM and reported that their findings “provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.”8
Experimental drug may add months of life
Physicians often recommend that patients take part in clinical trials. Earlier this year, researchers reported that a drug called tebentafusp – a bispecific fusion protein – slightly boosted metastatic UM survival in an open-label, phase 3 clinical trial when used as a first-line treatment. Patients were randomly assigned to tebentafusp, 1 of 2 immunotherapy drugs (ipilimumab or pembrolizumab), or the chemotherapy drug dacarbazine. Those who took tebentafusp vs. the other options lived longer with an estimated 1-year overall rate of 73.2% (95% CI: 66.3-78.9) vs. 57.5% (95% CI: 47.0-66.6), respectively. Fewer than 4% of those on tebentafusp needed to stop it because of adverse effects, and no treatment-related deaths occurred.9
Dr. Orloff is one of the coauthors of this study.
The National Cancer Institute provided more details about the industry-funded research and noted that median overall survival for patients who received the drug was 21.7 months vs. 16 months for the control group.
Not every patient is eligible for this treatment, however. A coauthor told the American Association for Cancer Research that “the major limitation of tebentafusp is that it can only be used in patients who have a specific HLA [human leukocyte antigen] type.” Patients must be HLA-A*0201-positive.10
In August 2021, the FDA granted priority review for tebentafusp.11 And in September 2021, a company called TriSalus announced the first patient enrollment in a “clinical study evaluating the administration of SD-101, an investigational toll-like receptor 9 (TLR9) agonist in adults with metastatic uveal melanoma.”12
According to the company, the research “is designed to evaluate the intravascular administration of SD-101 into uveal melanoma liver metastasis lesions in combination with checkpoint inhibitors using the novel Pressure-Enabled Drug Delivery (PEDD) approach.” This strategy is “designed to overcome the inherent intratumoral pressure of solid tumors,” the company said.
Dr. Materin serves on a scientific advisory board for Castle Biosciences. Dr. Orloff is a consultant for Immunocore, which funded the tebentafusp study, and serves on a scientific advisory board for TriSalus. Dr. Seedor reports no disclosures.
References
1.Kaliki S and Shields C. Eye. 2017 Feb;31:241-57.
2.Jochems A et al. Cancers. 2019 July;11(7):1007.
3.Xu LT et al. Ocul Oncol Pathol. 2019;5:323-32.
4.Seedor RS et al. J Clin Oncol. 2018 May;36(15_suppl):9592.
5.Seedor RS et al. Cancers (Basel). 2020 Jan 1;12(1):117.
6.Orloff M. Ocul Oncol Pathol. 2021 July;7:168-76.
7.Onken MD et al. J Biol Chem. 2021;296:100403.
8.Lei S and Zhang Y. Int Immunopharmacol. 2021 July;96:107816.
9.Piperno-Neumann S et al. Proceedings of the 112th Annual Meeting of the American Association for Cancer Research; 2021 April 10-15. Philadelphia (Pa.): AACR; 2021. Abstract nr 5133.
10.National Cancer Institute: https://www.cancer.gov/news-events/cancer-currents-blog/2021/tebentafusp-uveal-melanoma-improves-survival
11.Immunocore press release: https://ir.immunocore.com/news-releases/news-release-details/immunocore-announces-us-food-and-drug-administration-and
12.Trisalus announcement: https://finance.yahoo.com/news/trisalus-life-sciences-announces-first-130000215.html?guccounter=1
No one’s quite sure what causes uveal melanoma (UM). Unlike skin cancers, UM doesn’t seem to have any link to exposure to ultraviolet rays, although it’s most likely to strike people who are vulnerable to sun damage, like Caucasians and people with lighter eyes and lighter skin (but not lighter hair), and an inability to tan. Up to half of those affected by the disease will recover after treatment. In the other half, the cancer spreads from the eye – typically to the liver – and patient prognoses remain extremely poor despite extensive efforts to develop effective treatments.
“The median survival is probably about 2 years, and there are a number of papers out there that talk about life expectancy as short as 6 months,” said Marlana Orloff, MD, an associate professor of medical oncology at Thomas Jefferson University Hospital, Philadelphia.
But there is hope on the horizon, even if it’s not as near as patients would prefer. “Just over the last 5-10 years, we’ve gained a lot more knowledge about this disease as we try to understand how distinctly different it is, how mutations drive it, and how we can approach it using immunotherapy,” Dr. Orloff said. “I hope we’ll come up with better options for prolonging survival.”
Tracking uveal melanoma’s dangerous course
All melanomas, including UM, strike the melanocytes (cells) that provide pigment. According to a 2017 report1 in the journal Eye, “uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in the iris (4%), ciliary body (6%), or choroid (90%) . … As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma.”
The median age of diagnosis is 59-62 years, the report says, although non-Whites seem to develop the disease earlier.
The vast majority of patients receive treatment by plaque brachytherapy via radioactive seeds. “It’s like brachytherapy of the prostate,” said medical oncologist Rino S. Seedor, MD, of Thomas Jefferson University Hospital. “If the eye tumor is too big or invasive, they’ll cut out the eye.”
As many as 50% of patients will develop metastasis, sometimes within 2-3 years in those who have large tumors and high genetic risk, said ophthalmologist and radiation oncologist Miguel Materin, MD, of Duke University Eye Center, Durham, N.C. “There’s probably micrometastasis early in the development of the tumor,” he said. “The metastasis might develop before we or the patient knows there’s a tumor.”
Some physicians question the value of prognostic testing in patients who don’t yet show signs of metastasis, Dr. Materin said, because the findings can be grim.
Unlike his more cautious colleagues, Dr. Materin prefers to pursue testing, he said. Most patients agree to it. “It’s up to them to decide if they want to know if they have a bad prognosis,” he said, and the findings can be helpful to physicians because they provide useful genetic information about tumors.
Monitoring for liver metastasis is key
UM metastases are most likely to strike the liver, and prognoses are especially poor when they do. According to a 2019 analysis of 175 patients with metastatic UM in the Netherlands, “the presence of liver metastases is negatively associated with survival (hazard ratio = 2.09; 95% confidence interval, 1.07-4.08). … In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases.”2
As a result, physicians recommend close monitoring in patients with UM. Thomas Jefferson University’s Dr. Orloff uses tumor stages and genetic risk profiles to guide surveillance. “Very large tumors and/or monosomy 3 and 8q amplification or a Class 2 gene signature would suggest a higher-risk tumor,” she said. “For these patients we recommend MRI of the abdomen every 3 months for 2 years, CT of the chest every 6 months for 2 years, labs every 3 months for 2 years, then MRI every 6 months until year 5 with chest imaging yearly, then at 5 years everything yearly. For lower- or intermediate-risk patients we recommend MRI of the abdomen every 6 months for 5 years, chest imaging yearly, labs every 6 months, then at 5 years everything yearly.”
In the United States, patients with metastatic disease are typically sent to referral centers at institutions such as Duke, Yale (New Haven, Conn.), and Thomas Jefferson universities.
Metastasis treatments offer limited relief
There are no FDA-approved treatments for metastatic MU, and the treatments that physicians do use don’t seem to have much of an effect on life span. A 2019 study examined 73 patients with MU metastasis to the liver who were treated from 2004 to 2011 and 2012 to 2016. Among both cohorts, those who had no treatment lived nearly as long (median of 15 months) as those treated with local therapy (median of 18.7 months). Median survival for the entire population was 15 months (95% CI: 11–18 months). There was no statistically significant difference between the periods.3
However, there are signs that a move away from first-line chemotherapy in recent decades has led to longer life spans. Dr. Seedor led a 2018 study4 that compared two cohorts of MU patients with liver metastasis at her university: 98 patients from 1971 to 1993 (81% received systemic chemotherapy as their initial therapy) and 574 from 2000 to 2017 (they received various liver-directed initial treatments such as chemoembolization, drug-eluting beads, immunoembolization, and radioembolization).
The patients in the second group lived longer after treatment of initial UM than the first group (5.1 years vs. 3.3 years, P < .001) and after the development of liver metastasis (16.4 months vs. 4.8 months, P < .001). A 2020 follow-up study reported similar findings and noted that a “combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.”5
At Thomas Jefferson Medical Center, liver-directed therapy includes radioembolization, chemomobilization, and microwave ablation, Dr. Seedor said. “Which one we choose is based on how big the tumors are.”
Treatments in development could make advances
Physicians are working on several fronts to develop new treatments. A 2021 review of clinical trials found numerous trials regarding checkpoint inhibition, one devoted to a vaccine, and several involving checkpoint inhibitors. The review author notes that “the low mutational burden and poor immunogenicity of UM tumors may underlie poor responses and resistance to [immune checkpoint inhibitors] alone.”6
Earlier this year, grant-funded researchers reported encouraging news on the G protein inhibitor front. Their study found that FR900359, a selective inhibitor of the Gq/11/14 subfamily of heterotrimeric G proteins, could hold promise for “treating UM and potentially other diseases caused by constitutively active Gq/11.”7
In another 2021 study, this one with no reported funding, researchers explored the tumor microenvironment of UM and reported that their findings “provided a robust gene-based prognostic signature for predicting prognosis of UM patients and proposed a potential targeted therapy for preventing UM metastasis.”8
Experimental drug may add months of life
Physicians often recommend that patients take part in clinical trials. Earlier this year, researchers reported that a drug called tebentafusp – a bispecific fusion protein – slightly boosted metastatic UM survival in an open-label, phase 3 clinical trial when used as a first-line treatment. Patients were randomly assigned to tebentafusp, 1 of 2 immunotherapy drugs (ipilimumab or pembrolizumab), or the chemotherapy drug dacarbazine. Those who took tebentafusp vs. the other options lived longer with an estimated 1-year overall rate of 73.2% (95% CI: 66.3-78.9) vs. 57.5% (95% CI: 47.0-66.6), respectively. Fewer than 4% of those on tebentafusp needed to stop it because of adverse effects, and no treatment-related deaths occurred.9
Dr. Orloff is one of the coauthors of this study.
The National Cancer Institute provided more details about the industry-funded research and noted that median overall survival for patients who received the drug was 21.7 months vs. 16 months for the control group.
Not every patient is eligible for this treatment, however. A coauthor told the American Association for Cancer Research that “the major limitation of tebentafusp is that it can only be used in patients who have a specific HLA [human leukocyte antigen] type.” Patients must be HLA-A*0201-positive.10
In August 2021, the FDA granted priority review for tebentafusp.11 And in September 2021, a company called TriSalus announced the first patient enrollment in a “clinical study evaluating the administration of SD-101, an investigational toll-like receptor 9 (TLR9) agonist in adults with metastatic uveal melanoma.”12
According to the company, the research “is designed to evaluate the intravascular administration of SD-101 into uveal melanoma liver metastasis lesions in combination with checkpoint inhibitors using the novel Pressure-Enabled Drug Delivery (PEDD) approach.” This strategy is “designed to overcome the inherent intratumoral pressure of solid tumors,” the company said.
Dr. Materin serves on a scientific advisory board for Castle Biosciences. Dr. Orloff is a consultant for Immunocore, which funded the tebentafusp study, and serves on a scientific advisory board for TriSalus. Dr. Seedor reports no disclosures.
References
1.Kaliki S and Shields C. Eye. 2017 Feb;31:241-57.
2.Jochems A et al. Cancers. 2019 July;11(7):1007.
3.Xu LT et al. Ocul Oncol Pathol. 2019;5:323-32.
4.Seedor RS et al. J Clin Oncol. 2018 May;36(15_suppl):9592.
5.Seedor RS et al. Cancers (Basel). 2020 Jan 1;12(1):117.
6.Orloff M. Ocul Oncol Pathol. 2021 July;7:168-76.
7.Onken MD et al. J Biol Chem. 2021;296:100403.
8.Lei S and Zhang Y. Int Immunopharmacol. 2021 July;96:107816.
9.Piperno-Neumann S et al. Proceedings of the 112th Annual Meeting of the American Association for Cancer Research; 2021 April 10-15. Philadelphia (Pa.): AACR; 2021. Abstract nr 5133.
10.National Cancer Institute: https://www.cancer.gov/news-events/cancer-currents-blog/2021/tebentafusp-uveal-melanoma-improves-survival
11.Immunocore press release: https://ir.immunocore.com/news-releases/news-release-details/immunocore-announces-us-food-and-drug-administration-and
12.Trisalus announcement: https://finance.yahoo.com/news/trisalus-life-sciences-announces-first-130000215.html?guccounter=1
FDA expands pembrolizumab approval for advanced melanoma
The over age 12 years. The FDA also extended the approval to those with stage III disease.
The FDA approval on Dec. 3 was based on first interim findings from the randomized, placebo-controlled KEYNOTE-716 trial, which evaluated patients with stage IIB and IIC disease.
Since the anti-PD-1 therapy was approved in metastatic melanoma 7 years ago, “we have built on this foundation in melanoma and have expanded the use of KEYTRUDA into earlier stages of this disease,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “With today’s approval, we can now offer health care providers and patients 12 years and older the opportunity to help prevent melanoma recurrence with Keytruda across resected stage IIB, stage IIC, and stage III melanoma.”
In KEYNOTE-716, patients with completely resected stage IIB or IIC melanoma were randomly assigned to receive 200 mg of intravenous pembrolizumab, the pediatric dose 2 mg/kg (up to a maximum of 200 mg) every 3 weeks, or placebo for up to 1 year until disease recurrence or unacceptable toxicity.
After a median follow-up of 14.4 months, investigators reported a statistically significant 35% improvement in recurrence-free survival (RFS) in those treated with pembrolizumab, compared with those who received placebo (hazard ratio, 0.65).
The most common adverse reactions reported in patients receiving pembrolizumab in KEYNOTE-716 were fatigue, diarrhea, pruritus, and arthralgia, each occurring in at least 20% of patients.
“Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda,” according to Merck.
A version of this article first appeared on Medscape.com.
The over age 12 years. The FDA also extended the approval to those with stage III disease.
The FDA approval on Dec. 3 was based on first interim findings from the randomized, placebo-controlled KEYNOTE-716 trial, which evaluated patients with stage IIB and IIC disease.
Since the anti-PD-1 therapy was approved in metastatic melanoma 7 years ago, “we have built on this foundation in melanoma and have expanded the use of KEYTRUDA into earlier stages of this disease,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “With today’s approval, we can now offer health care providers and patients 12 years and older the opportunity to help prevent melanoma recurrence with Keytruda across resected stage IIB, stage IIC, and stage III melanoma.”
In KEYNOTE-716, patients with completely resected stage IIB or IIC melanoma were randomly assigned to receive 200 mg of intravenous pembrolizumab, the pediatric dose 2 mg/kg (up to a maximum of 200 mg) every 3 weeks, or placebo for up to 1 year until disease recurrence or unacceptable toxicity.
After a median follow-up of 14.4 months, investigators reported a statistically significant 35% improvement in recurrence-free survival (RFS) in those treated with pembrolizumab, compared with those who received placebo (hazard ratio, 0.65).
The most common adverse reactions reported in patients receiving pembrolizumab in KEYNOTE-716 were fatigue, diarrhea, pruritus, and arthralgia, each occurring in at least 20% of patients.
“Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda,” according to Merck.
A version of this article first appeared on Medscape.com.
The over age 12 years. The FDA also extended the approval to those with stage III disease.
The FDA approval on Dec. 3 was based on first interim findings from the randomized, placebo-controlled KEYNOTE-716 trial, which evaluated patients with stage IIB and IIC disease.
Since the anti-PD-1 therapy was approved in metastatic melanoma 7 years ago, “we have built on this foundation in melanoma and have expanded the use of KEYTRUDA into earlier stages of this disease,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “With today’s approval, we can now offer health care providers and patients 12 years and older the opportunity to help prevent melanoma recurrence with Keytruda across resected stage IIB, stage IIC, and stage III melanoma.”
In KEYNOTE-716, patients with completely resected stage IIB or IIC melanoma were randomly assigned to receive 200 mg of intravenous pembrolizumab, the pediatric dose 2 mg/kg (up to a maximum of 200 mg) every 3 weeks, or placebo for up to 1 year until disease recurrence or unacceptable toxicity.
After a median follow-up of 14.4 months, investigators reported a statistically significant 35% improvement in recurrence-free survival (RFS) in those treated with pembrolizumab, compared with those who received placebo (hazard ratio, 0.65).
The most common adverse reactions reported in patients receiving pembrolizumab in KEYNOTE-716 were fatigue, diarrhea, pruritus, and arthralgia, each occurring in at least 20% of patients.
“Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda,” according to Merck.
A version of this article first appeared on Medscape.com.
‘Highest survival’ with combo immunotherapy in advanced melanoma
An researchers say.
Nearly half the patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) were alive at 6½ years. Within this group, 77% had not received further systemic treatment after coming off the study drugs.
After a minimum follow-up of 77 months, median overall survival was 72.1 months in patients on the combination, which was more than three times longer than the 19.9 months with ipilimumab alone (hazard ratio, 0.52; 95% confidence interval, 0.43-0.64) and twice as long as the 36.9 months with nivolumab alone (HR, 0.84; 95% CI, 0.67-1.04).
The results represent the longest median overall survival seen in a phase 3 trial of advanced melanoma and are evidence of “a substantial development in the melanoma treatment landscape versus the standard median survival of 8 months a decade ago,” researchers wrote in a study published online in the Journal of Clinical Oncology.
However, lead author Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, noted that the study was not designed to compare nivolumab alone with the combination. “It wasn’t powered for that. [But] what we can say is that the highest survival was in the combination group,” Dr. Wolchok told this news organization.
Dr. Wolchok cautioned that the combination therapy is not currently standard of care. “PD-1 blockade – either nivolumab or the combination – are both excellent options for care,” he added. “I can’t tell you that one of them is the standard of care because that’s too complex of a decision.”
For example, he explained, “for a patient who only has lung metastases, a single-agent PD-1 blockade might be sufficient. But if it has spread to other organs, such as the liver or bones, which are more difficult to treat, that’s when we often reach for the combination.”
Other factors that weigh into the therapeutic decision are the patient’s performance status and their so-called clinical reserve for tolerating side effects. “The likelihood of having a high-grade side effect with the combination is more than twice that of the single agent,” Dr. Wolchok said.
Until 2011, only two therapies were approved for metastatic melanoma: Chemotherapy with dacarbazine and immunotherapy with high-dose interleukin-2, neither of which was very effective at prolonging life. But patient survival changed with the advent of targeted therapies and immunotherapy. Some patients are now living for years, and as the current study shows, many have surpassed the 5-year mark and are treatment free.
The updated CheckMate 067 analysis included patients with previously untreated, unresectable stage III/IV melanoma who were randomly assigned to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (four doses) followed by nivolumab 3 mg/kg every 2 weeks (n = 314), nivolumab 3 mg/kg every 2 weeks (n = 316), or ipilimumab 3 mg/ kg every 3 weeks (four doses; n = 315).
The authors reported the 5-year overall survival rates from the trial, published in the New England Journal of Medicine in 2019 – 52% with the combination, 44% with nivolumab alone, and 26% with ipilimumab alone.
In the updated study, overall survival at 6½ years had dropped slightly to 49%, 42%, and 23%, respectively. Patients with BRAF-mutant tumors had overall survival rates of 57%, 43%, and 25% versus 46%, 42%, and 22% in those with BRAF wild-type tumors.
Overall, median investigator-assessed progression-free survival was 11.5 months with the combination, 6.9 months with nivolumab alone, and 2.9 months with ipilimumab.
The new analysis also evaluated melanoma-specific survival (MSS), which removes competing causes of deaths from the long-term follow-up. The MSS was not reached in the combination group, and was 58.7 months in the nivolumab group and 21.9 months for ipilimumab, with MSS rates at 6.5 years of 56%, 48%, and 27%, respectively.
No new safety signals were detected, but there was more immune-mediated toxicity in the combination group, the researchers reported.
“The patients will continue to be followed,” said Dr. Wolchok, “And data are still being collected.”
The trial was supported by Bristol-Myers Squibb, the National Cancer Institute, and the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre. Dr. Wolchok and coauthors reported relationships with Bristol-Myers Squibb and other drugmakers.
A version of this article first appeared on Medscape.com.
An researchers say.
Nearly half the patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) were alive at 6½ years. Within this group, 77% had not received further systemic treatment after coming off the study drugs.
After a minimum follow-up of 77 months, median overall survival was 72.1 months in patients on the combination, which was more than three times longer than the 19.9 months with ipilimumab alone (hazard ratio, 0.52; 95% confidence interval, 0.43-0.64) and twice as long as the 36.9 months with nivolumab alone (HR, 0.84; 95% CI, 0.67-1.04).
The results represent the longest median overall survival seen in a phase 3 trial of advanced melanoma and are evidence of “a substantial development in the melanoma treatment landscape versus the standard median survival of 8 months a decade ago,” researchers wrote in a study published online in the Journal of Clinical Oncology.
However, lead author Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, noted that the study was not designed to compare nivolumab alone with the combination. “It wasn’t powered for that. [But] what we can say is that the highest survival was in the combination group,” Dr. Wolchok told this news organization.
Dr. Wolchok cautioned that the combination therapy is not currently standard of care. “PD-1 blockade – either nivolumab or the combination – are both excellent options for care,” he added. “I can’t tell you that one of them is the standard of care because that’s too complex of a decision.”
For example, he explained, “for a patient who only has lung metastases, a single-agent PD-1 blockade might be sufficient. But if it has spread to other organs, such as the liver or bones, which are more difficult to treat, that’s when we often reach for the combination.”
Other factors that weigh into the therapeutic decision are the patient’s performance status and their so-called clinical reserve for tolerating side effects. “The likelihood of having a high-grade side effect with the combination is more than twice that of the single agent,” Dr. Wolchok said.
Until 2011, only two therapies were approved for metastatic melanoma: Chemotherapy with dacarbazine and immunotherapy with high-dose interleukin-2, neither of which was very effective at prolonging life. But patient survival changed with the advent of targeted therapies and immunotherapy. Some patients are now living for years, and as the current study shows, many have surpassed the 5-year mark and are treatment free.
The updated CheckMate 067 analysis included patients with previously untreated, unresectable stage III/IV melanoma who were randomly assigned to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (four doses) followed by nivolumab 3 mg/kg every 2 weeks (n = 314), nivolumab 3 mg/kg every 2 weeks (n = 316), or ipilimumab 3 mg/ kg every 3 weeks (four doses; n = 315).
The authors reported the 5-year overall survival rates from the trial, published in the New England Journal of Medicine in 2019 – 52% with the combination, 44% with nivolumab alone, and 26% with ipilimumab alone.
In the updated study, overall survival at 6½ years had dropped slightly to 49%, 42%, and 23%, respectively. Patients with BRAF-mutant tumors had overall survival rates of 57%, 43%, and 25% versus 46%, 42%, and 22% in those with BRAF wild-type tumors.
Overall, median investigator-assessed progression-free survival was 11.5 months with the combination, 6.9 months with nivolumab alone, and 2.9 months with ipilimumab.
The new analysis also evaluated melanoma-specific survival (MSS), which removes competing causes of deaths from the long-term follow-up. The MSS was not reached in the combination group, and was 58.7 months in the nivolumab group and 21.9 months for ipilimumab, with MSS rates at 6.5 years of 56%, 48%, and 27%, respectively.
No new safety signals were detected, but there was more immune-mediated toxicity in the combination group, the researchers reported.
“The patients will continue to be followed,” said Dr. Wolchok, “And data are still being collected.”
The trial was supported by Bristol-Myers Squibb, the National Cancer Institute, and the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre. Dr. Wolchok and coauthors reported relationships with Bristol-Myers Squibb and other drugmakers.
A version of this article first appeared on Medscape.com.
An researchers say.
Nearly half the patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) were alive at 6½ years. Within this group, 77% had not received further systemic treatment after coming off the study drugs.
After a minimum follow-up of 77 months, median overall survival was 72.1 months in patients on the combination, which was more than three times longer than the 19.9 months with ipilimumab alone (hazard ratio, 0.52; 95% confidence interval, 0.43-0.64) and twice as long as the 36.9 months with nivolumab alone (HR, 0.84; 95% CI, 0.67-1.04).
The results represent the longest median overall survival seen in a phase 3 trial of advanced melanoma and are evidence of “a substantial development in the melanoma treatment landscape versus the standard median survival of 8 months a decade ago,” researchers wrote in a study published online in the Journal of Clinical Oncology.
However, lead author Jedd D. Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, noted that the study was not designed to compare nivolumab alone with the combination. “It wasn’t powered for that. [But] what we can say is that the highest survival was in the combination group,” Dr. Wolchok told this news organization.
Dr. Wolchok cautioned that the combination therapy is not currently standard of care. “PD-1 blockade – either nivolumab or the combination – are both excellent options for care,” he added. “I can’t tell you that one of them is the standard of care because that’s too complex of a decision.”
For example, he explained, “for a patient who only has lung metastases, a single-agent PD-1 blockade might be sufficient. But if it has spread to other organs, such as the liver or bones, which are more difficult to treat, that’s when we often reach for the combination.”
Other factors that weigh into the therapeutic decision are the patient’s performance status and their so-called clinical reserve for tolerating side effects. “The likelihood of having a high-grade side effect with the combination is more than twice that of the single agent,” Dr. Wolchok said.
Until 2011, only two therapies were approved for metastatic melanoma: Chemotherapy with dacarbazine and immunotherapy with high-dose interleukin-2, neither of which was very effective at prolonging life. But patient survival changed with the advent of targeted therapies and immunotherapy. Some patients are now living for years, and as the current study shows, many have surpassed the 5-year mark and are treatment free.
The updated CheckMate 067 analysis included patients with previously untreated, unresectable stage III/IV melanoma who were randomly assigned to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (four doses) followed by nivolumab 3 mg/kg every 2 weeks (n = 314), nivolumab 3 mg/kg every 2 weeks (n = 316), or ipilimumab 3 mg/ kg every 3 weeks (four doses; n = 315).
The authors reported the 5-year overall survival rates from the trial, published in the New England Journal of Medicine in 2019 – 52% with the combination, 44% with nivolumab alone, and 26% with ipilimumab alone.
In the updated study, overall survival at 6½ years had dropped slightly to 49%, 42%, and 23%, respectively. Patients with BRAF-mutant tumors had overall survival rates of 57%, 43%, and 25% versus 46%, 42%, and 22% in those with BRAF wild-type tumors.
Overall, median investigator-assessed progression-free survival was 11.5 months with the combination, 6.9 months with nivolumab alone, and 2.9 months with ipilimumab.
The new analysis also evaluated melanoma-specific survival (MSS), which removes competing causes of deaths from the long-term follow-up. The MSS was not reached in the combination group, and was 58.7 months in the nivolumab group and 21.9 months for ipilimumab, with MSS rates at 6.5 years of 56%, 48%, and 27%, respectively.
No new safety signals were detected, but there was more immune-mediated toxicity in the combination group, the researchers reported.
“The patients will continue to be followed,” said Dr. Wolchok, “And data are still being collected.”
The trial was supported by Bristol-Myers Squibb, the National Cancer Institute, and the National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre. Dr. Wolchok and coauthors reported relationships with Bristol-Myers Squibb and other drugmakers.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Differences in response to immunotherapy in men versus women
.
In a population-based cohort study, women with advanced melanoma and prior ipilimumab treatment who then received combination nivolumab and ipilimumab immunotherapy had a more than twofold increase in the risk for death in comparison with their male counterparts.
The hazard ratio (HR) for mortality among women versus men treated with the combination immunotherapy after prior ipilimumab treatment was 2.06 (P = .003). No such difference was observed among those receiving single-agent therapy with pembrolizumab or nivolumab (HR for mortality in women vs. men, 0.97; P = .85) or among patients without prior ipilimumab use (HR, 0.85; P = .16).
Women with prior ipilimumab use also had a nearly threefold increase in the risk for death with combination immunotherapy versus with single-agent anti–programmed cell death protein–1 (anti-PD-1) therapy (HR, 2.82), but no such difference was seen among the men in the study.
The findings were published online Dec. 2 in JAMA Network Open.
They come from an analysis of Surveillance, Epidemiology, and End Results (SEERS)–Medicare linked data for 982 men and 387 women with stage III or IV melanoma whose median age was 75 years.
The findings suggest that the patient’s sex should be considered in treatment planning to optimize outcomes, the authors noted.
“These novel findings suggest that, for women with a prior history of ipilimumab, treatment with anti-PD-1 therapy may be preferable to combination therapy, whereas for men, it is unclear which treatment is better,” they wrote.
In a press release, principal author Grace Lu-Yao, PhD, a professor at Thomas Jefferson University, Philadelphia, acknowledged that it remains unclear whether the increased risk for death in women is a result of treatment side effects or lack of efficacy, but she stressed that “this is a powerful signal in real-world data that we need to investigate further.
“This data is a wake-up call based on the experience of hundreds of patients on these drugs,” said Dr. Lu-Yao. “This real-world data demonstrates that the results derived from men might not be applicable to women and it is critical to design studies with sufficient power to evaluate treatment effectiveness by sex.”
Relevance for routine practice is unclear
The relevance of the findings for routine practice is unclear, given the median age of the cohort and a lack of data on whether excess mortality was cancer- or toxicity-related or due to another cause, Jeffrey S. Weber, MD, PhD, told this news organization. Dr. Weber is a professor and deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University.
“The study is interesting and detailed, but it is a rather narrowly defined cohort that is over 65 and has a median of age 75, [which is] very different than most melanoma patient cohorts of patients treated with immunotherapy, whose median age is 10 years younger,” Dr. Weber said in an interview.
Furthermore, “in practice, almost no current patients will have been previously treated with ipilimumab and then receive combination immunotherapy,” he said. “Overall, these data would not impact on how I treat patients,” he said.
Gender differences in response
This study is not the first to show a gender-based difference in outcomes after immunotherapy. As previously reported by this news organization, a meta-analysis published in The Lancet Oncology in 2018 showed that immune checkpoint inhibitors are twice as effective as standard cancer therapies in men with advanced solid tumors, compared with their female counterparts.
However, sex-based differences remain under-assessed despite “accumulating evidence of the potential role played by sex in drug effectiveness owing to the biological differences between men and women,” wrote the authors of the latest study in melanoma.
“This lack of attention on the association of sex with the effectiveness of immune checkpoint inhibitor (ICI)–based immunotherapy may have significant negative consequences, especially because these treatments are associated with high toxicity and high treatment cost. For future trials, it would be crucial to examine effect modification by sex,” they added.
The study was funded by the Sidney Kimmel Cancer Center. Dr. Lu-Yao and coauthors have disclosed no relevant financial relationships. Dr. Weber is a regular contributor to Medscape. He reports relationships with Bristol-Myers Squibb, GlaxoSmithKline, Genentech BioOncology, Merck & Co, Novartis, EMD Serono, Celldex, CytomX, Nektar, Roche, Altor, Daiichi-Sankyo, and Eli Lilly and is named on patents filed for biomarkers for ipilimumab and nivolumab.
A version of this article first appeared on Medscape.com.
.
In a population-based cohort study, women with advanced melanoma and prior ipilimumab treatment who then received combination nivolumab and ipilimumab immunotherapy had a more than twofold increase in the risk for death in comparison with their male counterparts.
The hazard ratio (HR) for mortality among women versus men treated with the combination immunotherapy after prior ipilimumab treatment was 2.06 (P = .003). No such difference was observed among those receiving single-agent therapy with pembrolizumab or nivolumab (HR for mortality in women vs. men, 0.97; P = .85) or among patients without prior ipilimumab use (HR, 0.85; P = .16).
Women with prior ipilimumab use also had a nearly threefold increase in the risk for death with combination immunotherapy versus with single-agent anti–programmed cell death protein–1 (anti-PD-1) therapy (HR, 2.82), but no such difference was seen among the men in the study.
The findings were published online Dec. 2 in JAMA Network Open.
They come from an analysis of Surveillance, Epidemiology, and End Results (SEERS)–Medicare linked data for 982 men and 387 women with stage III or IV melanoma whose median age was 75 years.
The findings suggest that the patient’s sex should be considered in treatment planning to optimize outcomes, the authors noted.
“These novel findings suggest that, for women with a prior history of ipilimumab, treatment with anti-PD-1 therapy may be preferable to combination therapy, whereas for men, it is unclear which treatment is better,” they wrote.
In a press release, principal author Grace Lu-Yao, PhD, a professor at Thomas Jefferson University, Philadelphia, acknowledged that it remains unclear whether the increased risk for death in women is a result of treatment side effects or lack of efficacy, but she stressed that “this is a powerful signal in real-world data that we need to investigate further.
“This data is a wake-up call based on the experience of hundreds of patients on these drugs,” said Dr. Lu-Yao. “This real-world data demonstrates that the results derived from men might not be applicable to women and it is critical to design studies with sufficient power to evaluate treatment effectiveness by sex.”
Relevance for routine practice is unclear
The relevance of the findings for routine practice is unclear, given the median age of the cohort and a lack of data on whether excess mortality was cancer- or toxicity-related or due to another cause, Jeffrey S. Weber, MD, PhD, told this news organization. Dr. Weber is a professor and deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University.
“The study is interesting and detailed, but it is a rather narrowly defined cohort that is over 65 and has a median of age 75, [which is] very different than most melanoma patient cohorts of patients treated with immunotherapy, whose median age is 10 years younger,” Dr. Weber said in an interview.
Furthermore, “in practice, almost no current patients will have been previously treated with ipilimumab and then receive combination immunotherapy,” he said. “Overall, these data would not impact on how I treat patients,” he said.
Gender differences in response
This study is not the first to show a gender-based difference in outcomes after immunotherapy. As previously reported by this news organization, a meta-analysis published in The Lancet Oncology in 2018 showed that immune checkpoint inhibitors are twice as effective as standard cancer therapies in men with advanced solid tumors, compared with their female counterparts.
However, sex-based differences remain under-assessed despite “accumulating evidence of the potential role played by sex in drug effectiveness owing to the biological differences between men and women,” wrote the authors of the latest study in melanoma.
“This lack of attention on the association of sex with the effectiveness of immune checkpoint inhibitor (ICI)–based immunotherapy may have significant negative consequences, especially because these treatments are associated with high toxicity and high treatment cost. For future trials, it would be crucial to examine effect modification by sex,” they added.
The study was funded by the Sidney Kimmel Cancer Center. Dr. Lu-Yao and coauthors have disclosed no relevant financial relationships. Dr. Weber is a regular contributor to Medscape. He reports relationships with Bristol-Myers Squibb, GlaxoSmithKline, Genentech BioOncology, Merck & Co, Novartis, EMD Serono, Celldex, CytomX, Nektar, Roche, Altor, Daiichi-Sankyo, and Eli Lilly and is named on patents filed for biomarkers for ipilimumab and nivolumab.
A version of this article first appeared on Medscape.com.
.
In a population-based cohort study, women with advanced melanoma and prior ipilimumab treatment who then received combination nivolumab and ipilimumab immunotherapy had a more than twofold increase in the risk for death in comparison with their male counterparts.
The hazard ratio (HR) for mortality among women versus men treated with the combination immunotherapy after prior ipilimumab treatment was 2.06 (P = .003). No such difference was observed among those receiving single-agent therapy with pembrolizumab or nivolumab (HR for mortality in women vs. men, 0.97; P = .85) or among patients without prior ipilimumab use (HR, 0.85; P = .16).
Women with prior ipilimumab use also had a nearly threefold increase in the risk for death with combination immunotherapy versus with single-agent anti–programmed cell death protein–1 (anti-PD-1) therapy (HR, 2.82), but no such difference was seen among the men in the study.
The findings were published online Dec. 2 in JAMA Network Open.
They come from an analysis of Surveillance, Epidemiology, and End Results (SEERS)–Medicare linked data for 982 men and 387 women with stage III or IV melanoma whose median age was 75 years.
The findings suggest that the patient’s sex should be considered in treatment planning to optimize outcomes, the authors noted.
“These novel findings suggest that, for women with a prior history of ipilimumab, treatment with anti-PD-1 therapy may be preferable to combination therapy, whereas for men, it is unclear which treatment is better,” they wrote.
In a press release, principal author Grace Lu-Yao, PhD, a professor at Thomas Jefferson University, Philadelphia, acknowledged that it remains unclear whether the increased risk for death in women is a result of treatment side effects or lack of efficacy, but she stressed that “this is a powerful signal in real-world data that we need to investigate further.
“This data is a wake-up call based on the experience of hundreds of patients on these drugs,” said Dr. Lu-Yao. “This real-world data demonstrates that the results derived from men might not be applicable to women and it is critical to design studies with sufficient power to evaluate treatment effectiveness by sex.”
Relevance for routine practice is unclear
The relevance of the findings for routine practice is unclear, given the median age of the cohort and a lack of data on whether excess mortality was cancer- or toxicity-related or due to another cause, Jeffrey S. Weber, MD, PhD, told this news organization. Dr. Weber is a professor and deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University.
“The study is interesting and detailed, but it is a rather narrowly defined cohort that is over 65 and has a median of age 75, [which is] very different than most melanoma patient cohorts of patients treated with immunotherapy, whose median age is 10 years younger,” Dr. Weber said in an interview.
Furthermore, “in practice, almost no current patients will have been previously treated with ipilimumab and then receive combination immunotherapy,” he said. “Overall, these data would not impact on how I treat patients,” he said.
Gender differences in response
This study is not the first to show a gender-based difference in outcomes after immunotherapy. As previously reported by this news organization, a meta-analysis published in The Lancet Oncology in 2018 showed that immune checkpoint inhibitors are twice as effective as standard cancer therapies in men with advanced solid tumors, compared with their female counterparts.
However, sex-based differences remain under-assessed despite “accumulating evidence of the potential role played by sex in drug effectiveness owing to the biological differences between men and women,” wrote the authors of the latest study in melanoma.
“This lack of attention on the association of sex with the effectiveness of immune checkpoint inhibitor (ICI)–based immunotherapy may have significant negative consequences, especially because these treatments are associated with high toxicity and high treatment cost. For future trials, it would be crucial to examine effect modification by sex,” they added.
The study was funded by the Sidney Kimmel Cancer Center. Dr. Lu-Yao and coauthors have disclosed no relevant financial relationships. Dr. Weber is a regular contributor to Medscape. He reports relationships with Bristol-Myers Squibb, GlaxoSmithKline, Genentech BioOncology, Merck & Co, Novartis, EMD Serono, Celldex, CytomX, Nektar, Roche, Altor, Daiichi-Sankyo, and Eli Lilly and is named on patents filed for biomarkers for ipilimumab and nivolumab.
A version of this article first appeared on Medscape.com.
Improving statewide reporting of melanoma cases
For years, . I have audited my melanoma cases (biopsies and excisions sent to me) and discovered that of the 240 cases confirmed over the past 5 years, only 41 were reported to the Ohio state health department and are in that database. That amounts to 199 unreported cases – nearly 83% of the total.
This raises the question as to who is responsible for reporting these cases. Dermatology is unique in that our pathology specimens are not routinely passed through a hospital pathology laboratory. The big difference in reporting is that hospital labs have trained data registrars to report all reportable cancers to state health departments. Therefore, in my case, only patients sent to a hospital-based surgeon for sentinel node biopsies or exceptionally large excisions get reported. When I have spoken about this to my dermatology lab and biopsying physicians, the discussion rapidly turns into a finger pointing game of who is responsible. No one, except perhaps the dermatologist who did the biopsy, has all the data.
Unfortunately, these cases are tedious and time consuming to report. Despite state laws requiring reporting, even with penalties for nonreporters, many small dermatology practices do not report these cases and expect their dermatopathology labs to do so, but the labs expect the biopsying dermatologist to report the cases. This is a classic case of an unfunded mandate since small dermatology practices do not have the time or resources for reporting.
I have worked with the Ohio Department of Health to remove any unnecessary data fields and they have managed to reduce the reporting fields (to 59!). This is the minimum amount required to be included in the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) database. Many of these fields are not applicable to thin melanomas and after reviewing the 1-hour online training course, each patient can be entered (once the necessary data are collected) in about 15 minutes. This is still a formidable task for small offices, which cannot be blamed for ducking and hoping someone else reports.
While there is controversy regarding the relevance of thin melanomas to overall survival, more accurate reporting can only bolster either argument.
A solution to underreporting
I believe we have developed a unique solution to this conundrum. Our office is partnering with the local melanoma support group (Melanoma Know More) to train volunteers to help with the data collection and reporting of these thin melanomas. We have also discovered that the local community college has students who are majoring in pathology data registry reporting and are happy to gain a little experience before graduating.
We eventually hope to become a clearinghouse for the entire state of Ohio. The state health department has agreed not to apply punitive measures to physicians who are new reporters. It is our plan to obtain melanoma pathology reports, run these past the state database, identify unreported cases, and obtain further data as needed from the biopsying physicians, and then complete the reporting.
I think dermatologic oncologists in every state should view this as an opportunity for a significant quality improvement project, and as a terrific service to the general dermatology community.
The ramifications of more comprehensive reporting of melanomas are great. I would expect more attention to the disease by researchers, and much more clout with state and national legislators. Think about increased funding for melanoma research, allowing sunscreen use for school children, sunshades for playgrounds, and more responsible tanning bed restrictions.
Now, I must inform you that this is my last column, but I plan to continue writing. Over the past 6 years, I have been able to cover a wide range of topics ranging from human trafficking and the American Medical Association, to the many problems faced by small practices. I have enjoyed myself hugely. To quote Douglas Adams, from The Hitchhiker’s Guide to the Galaxy, “So long and thanks for all the fish!” Keep in touch at [email protected].
Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].
For years, . I have audited my melanoma cases (biopsies and excisions sent to me) and discovered that of the 240 cases confirmed over the past 5 years, only 41 were reported to the Ohio state health department and are in that database. That amounts to 199 unreported cases – nearly 83% of the total.
This raises the question as to who is responsible for reporting these cases. Dermatology is unique in that our pathology specimens are not routinely passed through a hospital pathology laboratory. The big difference in reporting is that hospital labs have trained data registrars to report all reportable cancers to state health departments. Therefore, in my case, only patients sent to a hospital-based surgeon for sentinel node biopsies or exceptionally large excisions get reported. When I have spoken about this to my dermatology lab and biopsying physicians, the discussion rapidly turns into a finger pointing game of who is responsible. No one, except perhaps the dermatologist who did the biopsy, has all the data.
Unfortunately, these cases are tedious and time consuming to report. Despite state laws requiring reporting, even with penalties for nonreporters, many small dermatology practices do not report these cases and expect their dermatopathology labs to do so, but the labs expect the biopsying dermatologist to report the cases. This is a classic case of an unfunded mandate since small dermatology practices do not have the time or resources for reporting.
I have worked with the Ohio Department of Health to remove any unnecessary data fields and they have managed to reduce the reporting fields (to 59!). This is the minimum amount required to be included in the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) database. Many of these fields are not applicable to thin melanomas and after reviewing the 1-hour online training course, each patient can be entered (once the necessary data are collected) in about 15 minutes. This is still a formidable task for small offices, which cannot be blamed for ducking and hoping someone else reports.
While there is controversy regarding the relevance of thin melanomas to overall survival, more accurate reporting can only bolster either argument.
A solution to underreporting
I believe we have developed a unique solution to this conundrum. Our office is partnering with the local melanoma support group (Melanoma Know More) to train volunteers to help with the data collection and reporting of these thin melanomas. We have also discovered that the local community college has students who are majoring in pathology data registry reporting and are happy to gain a little experience before graduating.
We eventually hope to become a clearinghouse for the entire state of Ohio. The state health department has agreed not to apply punitive measures to physicians who are new reporters. It is our plan to obtain melanoma pathology reports, run these past the state database, identify unreported cases, and obtain further data as needed from the biopsying physicians, and then complete the reporting.
I think dermatologic oncologists in every state should view this as an opportunity for a significant quality improvement project, and as a terrific service to the general dermatology community.
The ramifications of more comprehensive reporting of melanomas are great. I would expect more attention to the disease by researchers, and much more clout with state and national legislators. Think about increased funding for melanoma research, allowing sunscreen use for school children, sunshades for playgrounds, and more responsible tanning bed restrictions.
Now, I must inform you that this is my last column, but I plan to continue writing. Over the past 6 years, I have been able to cover a wide range of topics ranging from human trafficking and the American Medical Association, to the many problems faced by small practices. I have enjoyed myself hugely. To quote Douglas Adams, from The Hitchhiker’s Guide to the Galaxy, “So long and thanks for all the fish!” Keep in touch at [email protected].
Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].
For years, . I have audited my melanoma cases (biopsies and excisions sent to me) and discovered that of the 240 cases confirmed over the past 5 years, only 41 were reported to the Ohio state health department and are in that database. That amounts to 199 unreported cases – nearly 83% of the total.
This raises the question as to who is responsible for reporting these cases. Dermatology is unique in that our pathology specimens are not routinely passed through a hospital pathology laboratory. The big difference in reporting is that hospital labs have trained data registrars to report all reportable cancers to state health departments. Therefore, in my case, only patients sent to a hospital-based surgeon for sentinel node biopsies or exceptionally large excisions get reported. When I have spoken about this to my dermatology lab and biopsying physicians, the discussion rapidly turns into a finger pointing game of who is responsible. No one, except perhaps the dermatologist who did the biopsy, has all the data.
Unfortunately, these cases are tedious and time consuming to report. Despite state laws requiring reporting, even with penalties for nonreporters, many small dermatology practices do not report these cases and expect their dermatopathology labs to do so, but the labs expect the biopsying dermatologist to report the cases. This is a classic case of an unfunded mandate since small dermatology practices do not have the time or resources for reporting.
I have worked with the Ohio Department of Health to remove any unnecessary data fields and they have managed to reduce the reporting fields (to 59!). This is the minimum amount required to be included in the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) database. Many of these fields are not applicable to thin melanomas and after reviewing the 1-hour online training course, each patient can be entered (once the necessary data are collected) in about 15 minutes. This is still a formidable task for small offices, which cannot be blamed for ducking and hoping someone else reports.
While there is controversy regarding the relevance of thin melanomas to overall survival, more accurate reporting can only bolster either argument.
A solution to underreporting
I believe we have developed a unique solution to this conundrum. Our office is partnering with the local melanoma support group (Melanoma Know More) to train volunteers to help with the data collection and reporting of these thin melanomas. We have also discovered that the local community college has students who are majoring in pathology data registry reporting and are happy to gain a little experience before graduating.
We eventually hope to become a clearinghouse for the entire state of Ohio. The state health department has agreed not to apply punitive measures to physicians who are new reporters. It is our plan to obtain melanoma pathology reports, run these past the state database, identify unreported cases, and obtain further data as needed from the biopsying physicians, and then complete the reporting.
I think dermatologic oncologists in every state should view this as an opportunity for a significant quality improvement project, and as a terrific service to the general dermatology community.
The ramifications of more comprehensive reporting of melanomas are great. I would expect more attention to the disease by researchers, and much more clout with state and national legislators. Think about increased funding for melanoma research, allowing sunscreen use for school children, sunshades for playgrounds, and more responsible tanning bed restrictions.
Now, I must inform you that this is my last column, but I plan to continue writing. Over the past 6 years, I have been able to cover a wide range of topics ranging from human trafficking and the American Medical Association, to the many problems faced by small practices. I have enjoyed myself hugely. To quote Douglas Adams, from The Hitchhiker’s Guide to the Galaxy, “So long and thanks for all the fish!” Keep in touch at [email protected].
Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].
AI: Skin of color underrepresented in datasets used to identify skin cancer
An in the databases, researchers in the United Kingdom report.
Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”
In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”
The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”
Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).
The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.
“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”
There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”
While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.
“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.
Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”
“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.
‘We need more images of everybody’
Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.
“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.
He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.
A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”
“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”
While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.
“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.
A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.
“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.
Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
An in the databases, researchers in the United Kingdom report.
Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”
In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”
The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”
Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).
The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.
“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”
There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”
While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.
“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.
Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”
“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.
‘We need more images of everybody’
Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.
“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.
He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.
A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”
“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”
While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.
“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.
A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.
“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.
Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
An in the databases, researchers in the United Kingdom report.
Out of 106,950 skin lesions documented in 21 open-access databases and 17 open-access atlases identified by David Wen, BMBCh, from the University of Oxford (England), and colleagues, 2,436 images contained information on Fitzpatrick skin type. Of these, “only 10 images were from individuals with Fitzpatrick skin type V, and only a single image was from an individual with Fitzpatrick skin type VI,” the researchers said. “The ethnicity of these individuals was either Brazilian or unknown.”
In two datasets containing 1,585 images with ethnicity data, “no images were from individuals with an African, Afro-Caribbean, or South Asian background,” Dr. Wen and colleagues noted. “Coupled with the geographical origins of datasets, there was massive under-representation of skin lesion images from darker-skinned populations.”
The results of their systematic review were presented at the National Cancer Research Institute Festival and published on Nov. 9, 2021, in The Lancet Digital Health. To the best of their knowledge, they wrote, this is “the first systematic review of publicly available skin lesion images comprising predominantly dermoscopic and macroscopic images available through open access datasets and atlases.”
Overall, 11 of 14 datasets (79%) were from North America, Europe, or Oceania among datasets with information on country of origin, the researchers said. Either dermoscopic images or macroscopic photographs were the only types of images available in 19 of 21 (91%) datasets. There was some variation in the clinical information available, with 81,662 images (76.4%) containing information on age, 82,848 images (77.5%) having information on gender, and 79,561 images having information about body site (74.4%).
The researchers explained that these datasets might be of limited use in a real-world setting where the images aren’t representative of the population. Artificial intelligence (AI) programs that train using images of patients with one skin type, for example, can potentially misdiagnose patients of another skin type, they said.
“AI programs hold a lot of potential for diagnosing skin cancer because it can look at pictures and quickly and cost-effectively evaluate any worrying spots on the skin,” Dr. Wen said in a press release from the NCRI Festival. “However, it’s important to know about the images and patients used to develop programs, as these influence which groups of people the programs will be most effective for in real-life settings. Research has shown that programs trained on images taken from people with lighter skin types only might not be as accurate for people with darker skin, and vice versa.”
There was also “limited information on who, how and why the images were taken,” Dr. Wen said in the release. “This has implications for the programs developed from these images, due to uncertainty around how they may perform in different groups of people, especially in those who aren’t well represented in datasets, such as those with darker skin. This can potentially lead to the exclusion or even harm of these groups from AI technologies.”
While there are no current guidelines for developing skin image datasets, quality standards are needed, according to the researchers.
“Ensuring equitable digital health includes building unbiased, representative datasets to ensure that the algorithms that are created benefit people of all backgrounds and skin types,” they concluded in the study.
Neil Steven, MBBS, MA, PhD, FRCP, an NCRI Skin Group member who was not involved with the research, stated in the press release that the results from the study by Dr. Wen and colleagues “raise concerns about the ability of AI to assist in skin cancer diagnosis, especially in a global context.”
“I hope this work will continue and help ensure that the progress we make in using AI in medicine will benefit all patients, recognizing that human skin color is highly diverse,” said Dr. Steven, honorary consultant in medical oncology at University Hospitals Birmingham (England) NHS Foundation Trust.
‘We need more images of everybody’
Dermatologist Adewole Adamson, MD, MPP, assistant professor in the department of internal medicine (division of dermatology) at the University of Texas at Austin, said in an interview that a “major potential downside” of algorithms not trained on diverse datasets is the potential for incorrect diagnoses.
“The harms of algorithms used for diagnostic purposes in the skin can be particularly significant because of the scalability of this technology. A lot of thought needs to be put into how these algorithms are developed and tested,” said Dr. Adamson, who reviewed the manuscript of The Lancet Digital Health study but was not involved with the research.
He referred to the results of a recently published study in JAMA Dermatology, which found that only 10% of studies used to develop or test deep-learning algorithms contained metadata on skin tone. “Furthermore, most datasets are from countries where darker skin types are not represented. [These] algorithms therefore likely underperform on people of darker skin types and thus, users should be wary,” Dr. Adamson said.
A consensus guideline should be developed for public AI algorithms, he said, which should have metadata containing information on sex, race/ethnicity, geographic location, skin type, and part of the body. “This distribution should also be reported in any publication of an algorithm so that users can see if the distribution of the population in the training data mirrors that of the population in which it is intended to be used,” he added.
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the research, said that, while this issue of underrepresentation has been known in dermatology for some time, the strength of the Lancet study is that it is a large study, with a message of “we need more images of everybody.”
“This is probably the broadest study looking at every possible accessible resource and taking an organized approach,” Dr. Friedman said in an interview. “But I think it also raises some important points about how we think about skin tones and how we refer to them as well with respect to misusing classification schemes that we currently have.”
While using ethnicity data and certain Fitzpatrick skin types as a proxy for darker skin is a limitation of the metadata the study authors had available, it also highlights “a broader problem with respect to lexicon regarding skin tone,” he explained.
“Skin does not have a race, it doesn’t have an ethnicity,” Dr. Friedman said.
A dataset that contains not only different skin tones but how different dermatologic conditions look across skin tones is important. “If you just look at one photo of one skin tone, you missed the fact that clinical presentations can be so polymorphic, especially because of different skin tones,” Dr. Friedman said.
“We need to keep pushing this message to ensure that images keep getting collected. We [need to] ensure that there’s quality control with these images and that we’re disseminating them in a way that everyone has access, both from self-learning, but also to teach others,” said Dr. Friedman, coeditor of a recently introduced dermatology atlas showing skin conditions in different skin tones.
Adamson reports no relevant financial relationships. Dr. Friedman is a coeditor of a dermatology atlas supported by Allergan Aesthetics and SkinBetter Science. This study was funded by NHSX and the Health Foundation. Three authors reported being paid employees of Databiology at the time of the study. The other authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Does the use of frankincense make sense in dermatology?
The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.7 Over the past 2 decades, .3 This column focuses on some of the emerging data on this ancient botanical agent.
Chemical constituents
Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.7
In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.3
Anti-inflammatory activity
Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.10
Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.11
Anticancer activity
The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.6,12
In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.13
There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.6
Antimicrobial activity
In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.15
Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.9
Transdermal delivery
In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.16 The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.17
Conclusion
The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.
2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.
3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.
4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.
5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.
6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.
7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.
8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.
9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.
10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.
11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.
12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.
13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.
14. Fung K et al. OA Altern Med 2013;1:14.
15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.
16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.
17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.
The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.7 Over the past 2 decades, .3 This column focuses on some of the emerging data on this ancient botanical agent.
Chemical constituents
Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.7
In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.3
Anti-inflammatory activity
Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.10
Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.11
Anticancer activity
The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.6,12
In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.13
There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.6
Antimicrobial activity
In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.15
Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.9
Transdermal delivery
In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.16 The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.17
Conclusion
The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.
2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.
3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.
4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.
5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.
6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.
7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.
8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.
9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.
10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.
11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.
12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.
13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.
14. Fung K et al. OA Altern Med 2013;1:14.
15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.
16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.
17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.
The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.7 Over the past 2 decades, .3 This column focuses on some of the emerging data on this ancient botanical agent.
Chemical constituents
Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.7
In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.3
Anti-inflammatory activity
Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.10
Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.11
Anticancer activity
The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.6,12
In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.13
There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.6
Antimicrobial activity
In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.15
Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.9
Transdermal delivery
In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.16 The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.17
Conclusion
The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.
2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.
3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.
4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.
5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.
6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.
7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.
8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.
9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.
10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.
11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.
12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.
13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.
14. Fung K et al. OA Altern Med 2013;1:14.
15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.
16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.
17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.
Dogs show potential as medical detectives in breast cancer
Breast cancer screening using urine samples based on the volatile organic compounds (VOCs) sensed by a trained dog is feasible, according to a preliminary study published in the journal Biology June 10.
“The extrapolation of our results to widespread implementation is still uncertain,” wrote Shoko Kure, MD, PhD, of Nippon Medical School in Tokyo, and colleagues. “However, even if few dogs could be trained to detect breast cancer, the result may open the door to a robust and inexpensive way to detect breast cancer.” They added that “dog cancer detection is entirely noninvasive, safe and easy for both patients and everyone.”
Early detection of breast cancer, which is the leading cause of death globally, is essential for more efficient treatment. While mammography can detect asymptomatic breast cancer and reduce mortality, it has a poor compliance, is less sensitive in dense breast tissue, detects nonmalignant lesions, and has not been shown to reduce mortality in women younger than 40. VOCs are emitted in the breath, blood, and urine, with different volatile patterns correlated with a variety of diseases including cancers, which dogs can be trained to detect. Breast cancer screening by dog sniffing of the VOCs in urine samples has not been attempted.
Dogs have been used as medical detectives for several cancers and conditions. A study published in 2018 showed that trained dogs who were able to differentiate the specific odor from the metabolic waste of breast cancer in vitro could identify that of colorectal cancer, and vice versa. More recently, research showed that trained dogs could detect advanced prostate cancer in urine samples with high specificity and sensitivity. In this double-blinded pilot study, two dogs were trained to detect Gleason 9 prostate cancer in urine collected from biopsy-confirmed patients. The canine olfaction system was 71% sensitive and as much as 76% specific at detecting Gleason 9 cancer. Along with cancer, trained dogs have been shown to identify people with COVID-19, even those who were asymptomatic. In this study, dogs who sniffed swab samples of armpit sweat could identify which samples came from patients infected with COVID-19 with up to 100% accuracy, while ruling out infection with up to 99% accuracy.
The double-blind study by Dr. Kure aimed to assess the potential of VOCs in urine samples for breast cancer screening by using a single trained sniffer dog – in this case a 9-year-old female Labrador retriever. Urine samples from 40 patients with primary breast cancer and 142 patients with non-breast malignant diseases were included along with samples from 18 healthy volunteers. In 40 times out of 40 runs of the double-blind test, the dog correctly identified urine samples of patients with breast cancer, with 100% sensitivity and 100% specificity.
“The dog in this test successfully differentiated breast cancer from non-breast malignancies and healthy controls,” the authors wrote. “This is the first, preliminary study indicating the feasibility of developing a new breast cancer screening method using urine samples based on VOCs.”
While the authors noted that the study was limited as it relied on one trained dog, they suggested that this method has potential in low-income countries where access to mammography is inadequate.
“Some well-trained sniffing dogs traveling around medically underserved [countries] all over the world could save many lives. Even when a healthy control was indicated by a trained dog, there would be a suspicion of undiagnosed/early-stage cancer, and the person would be advised to undergo medical screening,” the authors wrote.
The authors declared no conflicts of interest.
Breast cancer screening using urine samples based on the volatile organic compounds (VOCs) sensed by a trained dog is feasible, according to a preliminary study published in the journal Biology June 10.
“The extrapolation of our results to widespread implementation is still uncertain,” wrote Shoko Kure, MD, PhD, of Nippon Medical School in Tokyo, and colleagues. “However, even if few dogs could be trained to detect breast cancer, the result may open the door to a robust and inexpensive way to detect breast cancer.” They added that “dog cancer detection is entirely noninvasive, safe and easy for both patients and everyone.”
Early detection of breast cancer, which is the leading cause of death globally, is essential for more efficient treatment. While mammography can detect asymptomatic breast cancer and reduce mortality, it has a poor compliance, is less sensitive in dense breast tissue, detects nonmalignant lesions, and has not been shown to reduce mortality in women younger than 40. VOCs are emitted in the breath, blood, and urine, with different volatile patterns correlated with a variety of diseases including cancers, which dogs can be trained to detect. Breast cancer screening by dog sniffing of the VOCs in urine samples has not been attempted.
Dogs have been used as medical detectives for several cancers and conditions. A study published in 2018 showed that trained dogs who were able to differentiate the specific odor from the metabolic waste of breast cancer in vitro could identify that of colorectal cancer, and vice versa. More recently, research showed that trained dogs could detect advanced prostate cancer in urine samples with high specificity and sensitivity. In this double-blinded pilot study, two dogs were trained to detect Gleason 9 prostate cancer in urine collected from biopsy-confirmed patients. The canine olfaction system was 71% sensitive and as much as 76% specific at detecting Gleason 9 cancer. Along with cancer, trained dogs have been shown to identify people with COVID-19, even those who were asymptomatic. In this study, dogs who sniffed swab samples of armpit sweat could identify which samples came from patients infected with COVID-19 with up to 100% accuracy, while ruling out infection with up to 99% accuracy.
The double-blind study by Dr. Kure aimed to assess the potential of VOCs in urine samples for breast cancer screening by using a single trained sniffer dog – in this case a 9-year-old female Labrador retriever. Urine samples from 40 patients with primary breast cancer and 142 patients with non-breast malignant diseases were included along with samples from 18 healthy volunteers. In 40 times out of 40 runs of the double-blind test, the dog correctly identified urine samples of patients with breast cancer, with 100% sensitivity and 100% specificity.
“The dog in this test successfully differentiated breast cancer from non-breast malignancies and healthy controls,” the authors wrote. “This is the first, preliminary study indicating the feasibility of developing a new breast cancer screening method using urine samples based on VOCs.”
While the authors noted that the study was limited as it relied on one trained dog, they suggested that this method has potential in low-income countries where access to mammography is inadequate.
“Some well-trained sniffing dogs traveling around medically underserved [countries] all over the world could save many lives. Even when a healthy control was indicated by a trained dog, there would be a suspicion of undiagnosed/early-stage cancer, and the person would be advised to undergo medical screening,” the authors wrote.
The authors declared no conflicts of interest.
Breast cancer screening using urine samples based on the volatile organic compounds (VOCs) sensed by a trained dog is feasible, according to a preliminary study published in the journal Biology June 10.
“The extrapolation of our results to widespread implementation is still uncertain,” wrote Shoko Kure, MD, PhD, of Nippon Medical School in Tokyo, and colleagues. “However, even if few dogs could be trained to detect breast cancer, the result may open the door to a robust and inexpensive way to detect breast cancer.” They added that “dog cancer detection is entirely noninvasive, safe and easy for both patients and everyone.”
Early detection of breast cancer, which is the leading cause of death globally, is essential for more efficient treatment. While mammography can detect asymptomatic breast cancer and reduce mortality, it has a poor compliance, is less sensitive in dense breast tissue, detects nonmalignant lesions, and has not been shown to reduce mortality in women younger than 40. VOCs are emitted in the breath, blood, and urine, with different volatile patterns correlated with a variety of diseases including cancers, which dogs can be trained to detect. Breast cancer screening by dog sniffing of the VOCs in urine samples has not been attempted.
Dogs have been used as medical detectives for several cancers and conditions. A study published in 2018 showed that trained dogs who were able to differentiate the specific odor from the metabolic waste of breast cancer in vitro could identify that of colorectal cancer, and vice versa. More recently, research showed that trained dogs could detect advanced prostate cancer in urine samples with high specificity and sensitivity. In this double-blinded pilot study, two dogs were trained to detect Gleason 9 prostate cancer in urine collected from biopsy-confirmed patients. The canine olfaction system was 71% sensitive and as much as 76% specific at detecting Gleason 9 cancer. Along with cancer, trained dogs have been shown to identify people with COVID-19, even those who were asymptomatic. In this study, dogs who sniffed swab samples of armpit sweat could identify which samples came from patients infected with COVID-19 with up to 100% accuracy, while ruling out infection with up to 99% accuracy.
The double-blind study by Dr. Kure aimed to assess the potential of VOCs in urine samples for breast cancer screening by using a single trained sniffer dog – in this case a 9-year-old female Labrador retriever. Urine samples from 40 patients with primary breast cancer and 142 patients with non-breast malignant diseases were included along with samples from 18 healthy volunteers. In 40 times out of 40 runs of the double-blind test, the dog correctly identified urine samples of patients with breast cancer, with 100% sensitivity and 100% specificity.
“The dog in this test successfully differentiated breast cancer from non-breast malignancies and healthy controls,” the authors wrote. “This is the first, preliminary study indicating the feasibility of developing a new breast cancer screening method using urine samples based on VOCs.”
While the authors noted that the study was limited as it relied on one trained dog, they suggested that this method has potential in low-income countries where access to mammography is inadequate.
“Some well-trained sniffing dogs traveling around medically underserved [countries] all over the world could save many lives. Even when a healthy control was indicated by a trained dog, there would be a suspicion of undiagnosed/early-stage cancer, and the person would be advised to undergo medical screening,” the authors wrote.
The authors declared no conflicts of interest.
FROM BIOLOGY