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Comprehensive Genomic Profiles of Melanoma in Veterans Compared to Reference Databases
Comprehensive Genomic Profiles of Melanoma in Veterans Compared to Reference Databases
The veteran population, with its unique and diverse types of exposure and military service experiences, faces distinct health factors compared with the general population. These factors can be categorized into exposures during military service and those occurring postservice. While the latter phase incorporates psychological issues that may arise while transitioning to civilian life, the service period is associated with major physical, chemical, and psychological exposures that can impact veterans’ health. Carcinogenesis related to military exposures is concerning, and different types of malignancies have been associated with military exposures.1 The 2022 introduction of the Cancer Moonshot initiative served as a breeding ground for multiple projects aimed at investigation of exposure-related carcinogenesis, prompting increased attention and efforts to linking specific exposures to specific malignancies.2
Melanoma is the deadliest skin cancer, accounting for 1.3% of all cancer deaths.3 Although it may only account for 1% to 5% of skin cancer diagnoses, its incidence in the United States’ population has been increasing.4,5 There were 97,610 estimated new cases of melanoma in 2023, according to the National Cancer Institute.6
The incidence of melanoma may be higher in the military population compared with the general population.7 Melanoma is the fourth-most common cancer diagnosed in veterans.8
Several demographic characteristics of the US military population are associated with higher melanoma incidence and poorer prognosis, including male sex, older age, and White race. Apart from sun exposure—a known risk factor for melanoma development—other factors, such as service branch, seem to contribute to risk, with the highest melanoma rates noted in the Air Force.9 According to a study by Chang et al, veterans have a higher risk of stage III (18%) or stage IV (13%) melanoma at initial diagnosis.8
Molecular testing of metastatic melanoma is currently the standard of care for guiding the use of US Food and Drug Administration-approved targeted therapies such as BRAF, MEK, and KIT inhibitors. This comparative analysis details the melanoma comprehensive genomic profiles observed at a large US Department of Veterans Affairs (VA) medical center (VAMC) and those reported in reference databases.
Methods
A query to select all metastatic melanomas sent for comprehensive genomic profiling from the Kansas City VAMC (KCVAMC), identified 35 cases from 2019 through 2023 as the study population. The health records of these patients were reviewed to collect demographic information, military service history, melanoma history, other medical, social, and family histories. The comprehensive genomic profiling reports were reviewed to collect the reported pathogenic variants, microsatellite instability (MSI) status, and tumor mutational burden (TMB) for each case.
The Catalogue of Somatic Mutations in Cancer (COSMIC) was used to identify the most commonly mutated genes in melanomas from The Cancer Genome Atlas for the general population.4,5 The literature was consulted to determine the MSI status and TMB in melanomas from The Cancer Genome Atlas for separate reference populations.6,7 The frequency of MSI-high (MSI-H) status, TMB ≥ 10 mutations/megabase (mut/Mb), and mutations in each of the 20 most commonly mutated genes was determined and compared between melanomas from The Cancer Genome Atlas and KCVAMC cases. Corresponding P values were calculated to identify significant differences. Values were calculated for the entire sample as well as a subgroup with Agent Orange (AO) exposure. The study was approved by the KCVAMC Institutional Review Board.
Results
The mean (SD) age of study participants was 72.9 (9.4) years (range, 39-90 years). The mean (SD) duration of military service was 1654 (1421) days (about 4 years, 6 months, and 10 days). Of the 35 patients included, 22 (63%) served during the Vietnam era (November 1, 1965, to April 30, 1975) and 2 (6%) served during the Persian Gulf War era (August 2, 1990, to February 28, 1991). Seventeen veterans (49%) served in the Army, 9 in the Navy (26%), 5 in the Air Force (14%), and 4 in the Marine Corps (11%). Definitive AO exposure was noted in 13 patients (37%) (Table 1).

Of the 35 patients, 24 (69%) had metastatic disease and the primary site of melanoma was unknown in 14 patients (40%). One patient (Patient 32) had an intraocular melanoma. The primary site was the trunk for 11 patients (31%), the face/head for 7 patients (20%) and extremities for 3 patients (9%). Eight patients (23%) were pT3 stage (thickness > 2 mm but < 4 mm), 7 patients (20%) were pT4 stage (thickness > 4 mm), and 5 patients (14%) were pT1 (thickness ≥ 1 mm). One patient had a primary lesion at pT2 stage, and 1 had a Tis stage lesion. Three patients (9%) had a family history of melanoma in a first-degree relative.
The list of genes mutated in melanoma cells in the study population is provided in the eAppendix.10,11 Twenty-seven patients (77%) had mutations in TERT promoter, 15 (43%) in CDKN2A/B, 13 (37%) in BRAF, 11 (31%) in NF1, 9 (26%) in TP53, and 8 (23%) in NRAS (Table 2). The majority of mutations in TERT promoter were c.- 146C>T (18 of 27 patients [67%]), whereas c.-124C>T was the second-most common (8 of 27 patients [30%]). The 2 observed mutations in the 13 patients with BRAF mutations were V600E and V600K, with almost equal distribution (54% and 46%, respectively). The mean (SD) TMB was 33.2 (39) mut/Mb (range, 1-203 mut/Mb). Ten patients (29%) had a TMB < 10 mut/Mb, whereas 24 (69%) had a TMB > 10 mut/Mb. The TMB could not be determined in 1 case. The frequency of TMB-high tumors in the study population compared with frequency in the reference population is shown in Table 3.12 Only 3 patients (0.64%) in the reference population had MSI-H tumors, and the microsatellite status could not be determined in those tumors (Table 4).13 Table 5 outlines statistically significant findings.




Agent Orange Subgroup
AO was a tactical herbicide used by the US military, named for the orange band around the storage barrels. Possible mutagenic properties of AO have been attributed to its byproduct, dioxin. Among the most common cancers known to be associated with AO exposure are bladder and prostate carcinoma and hematopoietic neoplasms. The association between genetic alterations and AO exposure was studied in veterans with prostate cancer.14 However, to our knowledge, insufficient information is available to determine whether an association exists between exposure to herbicides used in Vietnam or the contaminant dioxin and melanoma. Because a significant proportion of this study population had a well-documented history of AO exposure (37.1%), we were able to analyze them as a subgroup and to separately compare their mutation frequency with the general population.
Results were notable for different distributions of the most frequently mutated genes in the AO subgroup compared with the whole study population. As such, TERT promoter remained the most frequently mutated gene (92%), followed by CDKN2A/B (46%); however, frequency of mutations in NF1 (46%) outnumbered those of BRAF (31%), the fourth-most common mutation. Moreover, when compared with the general melanoma population, a significantly higher frequency of mutations in the NF1 gene was observed in the AO subgroup—not the entire study population.
Discussion
Given that veterans constitute a distinct population, there is reasonable interest in investigating characteristic health issues related to military service. Skin cancer—melanoma in particular—has been researched recently in a veteran population. The differences in demographics, tumor characteristics, and melanoma- specific survival in veterans compared with the general population have already been assessed. According to Chang et al, compared with the general population, veterans are more likely to present with metastatic disease and have lower 5-year survival rates.8
Melanoma is one of the most highly mutated malignancies.15 Fortunately, the most common mutation in melanoma, BRAF V600E, is now considered therapeutically targetable. However, there are still many mutations that are less often discussed and not well understood. Regardless of therapeutic implications, all mutations observed in melanoma are worth investigating because a tumor’s genomic profile also can provide prognostic and etiologic information. Developing comprehensive descriptions of melanoma mutational profiles in specific populations is critical to advancing etiologic understanding and informing prevention strategies.
Our results demonstrate the high prevalence of TERT promoter mutations with characteristic ultraviolet signature (C>T) in the study population. This aligns with general evidence that TERT promoter mutations are common in cutaneous melanomas: 77% of this study sample and up to 86% of all mutations are TERT promoter mutations, according to Davis et al.15 TERT promoter mutations are positively associated with the initiation, invasion, and metastasis of melanoma. In certain subtypes, there is evidence that the presence of TERT promoter mutations is significantly associated with risk for extranodal metastasis and death.16 The second-most common mutated gene in the veteran study population was CDKN2A/B (43%), and the third-most mutated gene was BRAF (37%).
In chronically sun-exposed skin NF1, NRAS, and occasionally BRAF V600K mutations tend to predominate. BRAF V600E mutations, on the other hand, are rare in these melanomas.15 In our study population, the most prevalent melanoma site was the trunk (31%), which is considered a location with an intermittent pattern of sun exposure.17
This study population also had a higher frequency of CDKN2A/B mutations. High frequencies of CDKN2A/B mutations have been reported in familial melanomas, but only 1 patient with CDKN2A/B mutations had a known family history of melanoma.15 Tumors in the study population showed significantly lower frequency of mutations in ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 (P < .05).
In this study the subgroup of veterans with AO exposure differed from the whole study population. As such, CDKN2A/B mutations were observed with the same frequency as NF1 mutations (46% each); however, BRAF mutations constituted only 31% of the mutations. In addition, the frequency of NF1 mutations was significantly higher in the AO subgroup compared with the general population, but not in the whole study population.
Our sample also differed from the reference population by showing a significantly higher frequency of TMB-high (ie, ≥ 10 mut/Mb) tumors (71% vs 49%; P = .01).12 Interestingly, no significant difference in the frequency of TMB-high tumors was observed between the AO subgroup and the reference population (69% vs 49%; P = .16). There also was no statistically significant difference between the frequency of MSI-H tumors in our study population and the reference population (P = .64).13
One patient in the study population had uveal melanoma. Mutations encountered in this patient’s tumor differed from the general mutational profile of tumors. None of the 21 mutations depicted in Table 2 were present in this sample.10,11 On the other hand, those mutations frequently observed in intraocular melanomas, BAP1 and GNA11, were present in this patient.18 Additionally, this particular melanoma possessed mutations in genes RICTOR, RAD21, and PIK3R1.
Limitations
This study population consisted exclusively of male patients, introducing sex as a potential confounder in analyzing differences between the study population and the general population. As noted in a 2020 systematic review, there were no sex-based differences in the frequency of mutations in BRAF, NRAS, and KIT genes.19
Regarding NF1 mutations, only NF1-mutated acral and mucosal melanomas were more frequently observed in female patients, whereas nonacral NF1-mutated melanomas were more frequently observed in male patients.20 However, there is currently no clear evidence of whether the mutational landscapes of cutaneous melanoma differ by sex.21 Among the 11 cases with NF1-mutatation, site of origin was known in 6, 5 of which originated at nonacral sites. Although the AO subgroup also consisted entirely of male patients, this does not explain the observed increased frequency of NF1 mutations relative to the general population. No such difference was observed between the whole study population, which also consisted exclusively of male patients, and the general population. The similar frequencies of nonacral location in the whole study population (3 acral, 18 nonacral, 14 unknown site of origin) and AO subgroup (1 acral, 7 nonacral, 5 unknown site of origin) preclude location as an explanation.
The Cancer Genome Atlas Network proposed a framework for genomic classification of melanoma into 4 subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and triple–wild-type. According to that study, BRAF mutations were indeed associated with younger age, in contrast to the NF1-mutant genomic subtype, which was more prevalent in older individuals with higher TMB.22 This emphasizes the need to interpret the potential association of AO exposure and NF1 mutation in melanoma with caution, although additional studies are required to observe the difference between the veteran population and age-matched general population.
On the other hand, Yu et al reported no significant differences of TMB values between patients aged < 60 and ≥ 60 years with melanoma.23 In short, the observed differences we report in our limited study warrant additional investigation with larger sample sizes, sex-matched controlling, and age-matched controlling. The study was limited by its small sample size and the single location.
Conclusion
The genomic profile of melanomas in the veteran population appears to be similar to that of the general population with a few possible differences. Melanomas in the veteran study population showed a higher frequency of CDKN2A/B mutations; lower frequency of ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 mutations; and higher TMB. In addition, melanomas in the AO subgroup showed higher frequencies of NF1 mutations. The significance of such findings remains to be determined by further investigation.
- Bytnar JA, McGlynn KA, et al. Cancer incidence in the US military: An updated analysis. Cancer. 2024;130(1):96-106. doi:10.1002/cncr.34978
- Singer DS. A new phase of the Cancer Moonshot to end cancer as we know it. Nat Med. 2022;28(7):1345-1347. doi:10.1038/s41591-022-01881-5
- Koczkodaj P, Sulkowska U, Didkowska J, et al. Melanoma mortality trends in 28 European countries: a retrospective analysis for the years 1960-2020. Cancers (Basel). 2023;15(5):1514. Published 2023 Feb 28. doi:10.3390/cancers15051514
- Okobi OE, Abreo E, Sams NP, et al. Trends in melanoma incidence, prevalence, stage at diagnosis, and survival: an analysis of the United States Cancer Statistics (USCS) database. Cureus. 2024;16(10):e70697. doi:10.7759/cureus.70697
- Bartling SJ, Rivard SC, Meyerle JH. Melanoma in an active duty marine. Mil Med. 2017;182:e2034-e2039. doi:10.7205/MILMED-D-17-00127
- American Cancer Society. Cancer facts & figures 2023. American Cancer Society; 2023. Accessed June 20, 2025. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
- Rezaei SJ, Kim J, Onyeka S, et al. Skin cancer and other dermatologic conditions among US veterans. JAMA Dermatol. 2024;160(10):1107-1111. doi:10.1001/jamadermatol.2024.3043
- Chang MS, La J, Trepanowski N, et al. Increased relative proportions of advanced melanoma among veterans: a comparative analysis with the Surveillance, Epidemiology, and End Results registry. J Am Acad Dermatol. 2022;87:72-79. doi:10.1016/j.jaad.2022.02.063
- Riemenschneider K, Liu J, Powers JG. Skin cancer in the military: a systematic review of melanoma and nonmelanoma skin cancer incidence, prevention, and screening among active duty and veteran personnel. J Am Acad Dermatol. 2018;78:1185-1192. doi:10.1016/j.jaad.2017.11.062
- Huang FW, Hodis E, Xu MJ, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339:957-959. doi:10.1126/science.1229259
- Tate JG, Bamford S, Jubb HC, et al. COSMIC: the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2019;47:D941-D947. doi:10.1093/nar/gky1015
- Li M, Gao X, Wang X. Identification of tumor mutation burden-associated molecular and clinical features in cancer by analyzing multi-omics data. Front Immunol. 2023;14:1090838. doi:10.3389/fimmu.2023.1090838
- Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017:PO.17.00073. doi:10.1200/PO.17.00073
- Lui AJ, Pagadala MS, Zhong AY, et al. Agent Orange exposure and prostate cancer risk in the Million Veteran Program. medRxiv [Preprint]. 2023:2023.06.14.23291413. doi:10.1101/2023.06.14.23291413
- Davis EJ, Johnson DB, Sosman JA, et al. Melanoma: what do all the mutations mean? Cancer. 2018;124:3490-3499. doi:10.1002/cncr.31345
- Guo Y, Chen Y, Zhang L, et al. TERT promoter mutations and telomerase in melanoma. J Oncol. 2022;2022:6300329. doi:10.1155/2022/6300329
- Whiteman DC, Stickley M, Watt P, et al. Anatomic site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol. 2006;24:3172-3177. doi:10.1200/JCO.2006.06.1325
- Decatur CL, Ong E, Garg N, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 2016;134:728-733. doi:10.1001/jamaophthalmol.2016.0903
- Gutiérrez-Castañeda LD, Nova JA, Tovar-Parra JD. Frequency of mutations in BRAF, NRAS, and KIT in different populations and histological subtypes of melanoma: a systemic review. Melanoma Res. 2020;30:62- 70. doi:10.1097/CMR.0000000000000628
- Thielmann CM, Chorti E, Matull J, et al. NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors. Eur J Cancer. 2021;159:113-124. doi:10.1016/j.ejca.2021.09.035
- D’Ecclesiis O, Caini S, Martinoli C, et al. Gender-dependent specificities in cutaneous melanoma predisposition, risk factors, somatic mutations, prognostic and predictive factors: a systematic review. Int J Environ Res Public Health. 2021;18:7945. doi:10.3390/ijerph18157945
- Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681-1696. doi:10.1016/j.cell.2015.05.044
- Yu Z, Wang J, Feng L, et al. Association of tumor mutational burden with age in solid tumors. J Clin Oncol. 2020;38:e13590-e13590. doi:10.1200/JCO.2020.38.15_suppl.e13590
The veteran population, with its unique and diverse types of exposure and military service experiences, faces distinct health factors compared with the general population. These factors can be categorized into exposures during military service and those occurring postservice. While the latter phase incorporates psychological issues that may arise while transitioning to civilian life, the service period is associated with major physical, chemical, and psychological exposures that can impact veterans’ health. Carcinogenesis related to military exposures is concerning, and different types of malignancies have been associated with military exposures.1 The 2022 introduction of the Cancer Moonshot initiative served as a breeding ground for multiple projects aimed at investigation of exposure-related carcinogenesis, prompting increased attention and efforts to linking specific exposures to specific malignancies.2
Melanoma is the deadliest skin cancer, accounting for 1.3% of all cancer deaths.3 Although it may only account for 1% to 5% of skin cancer diagnoses, its incidence in the United States’ population has been increasing.4,5 There were 97,610 estimated new cases of melanoma in 2023, according to the National Cancer Institute.6
The incidence of melanoma may be higher in the military population compared with the general population.7 Melanoma is the fourth-most common cancer diagnosed in veterans.8
Several demographic characteristics of the US military population are associated with higher melanoma incidence and poorer prognosis, including male sex, older age, and White race. Apart from sun exposure—a known risk factor for melanoma development—other factors, such as service branch, seem to contribute to risk, with the highest melanoma rates noted in the Air Force.9 According to a study by Chang et al, veterans have a higher risk of stage III (18%) or stage IV (13%) melanoma at initial diagnosis.8
Molecular testing of metastatic melanoma is currently the standard of care for guiding the use of US Food and Drug Administration-approved targeted therapies such as BRAF, MEK, and KIT inhibitors. This comparative analysis details the melanoma comprehensive genomic profiles observed at a large US Department of Veterans Affairs (VA) medical center (VAMC) and those reported in reference databases.
Methods
A query to select all metastatic melanomas sent for comprehensive genomic profiling from the Kansas City VAMC (KCVAMC), identified 35 cases from 2019 through 2023 as the study population. The health records of these patients were reviewed to collect demographic information, military service history, melanoma history, other medical, social, and family histories. The comprehensive genomic profiling reports were reviewed to collect the reported pathogenic variants, microsatellite instability (MSI) status, and tumor mutational burden (TMB) for each case.
The Catalogue of Somatic Mutations in Cancer (COSMIC) was used to identify the most commonly mutated genes in melanomas from The Cancer Genome Atlas for the general population.4,5 The literature was consulted to determine the MSI status and TMB in melanomas from The Cancer Genome Atlas for separate reference populations.6,7 The frequency of MSI-high (MSI-H) status, TMB ≥ 10 mutations/megabase (mut/Mb), and mutations in each of the 20 most commonly mutated genes was determined and compared between melanomas from The Cancer Genome Atlas and KCVAMC cases. Corresponding P values were calculated to identify significant differences. Values were calculated for the entire sample as well as a subgroup with Agent Orange (AO) exposure. The study was approved by the KCVAMC Institutional Review Board.
Results
The mean (SD) age of study participants was 72.9 (9.4) years (range, 39-90 years). The mean (SD) duration of military service was 1654 (1421) days (about 4 years, 6 months, and 10 days). Of the 35 patients included, 22 (63%) served during the Vietnam era (November 1, 1965, to April 30, 1975) and 2 (6%) served during the Persian Gulf War era (August 2, 1990, to February 28, 1991). Seventeen veterans (49%) served in the Army, 9 in the Navy (26%), 5 in the Air Force (14%), and 4 in the Marine Corps (11%). Definitive AO exposure was noted in 13 patients (37%) (Table 1).

Of the 35 patients, 24 (69%) had metastatic disease and the primary site of melanoma was unknown in 14 patients (40%). One patient (Patient 32) had an intraocular melanoma. The primary site was the trunk for 11 patients (31%), the face/head for 7 patients (20%) and extremities for 3 patients (9%). Eight patients (23%) were pT3 stage (thickness > 2 mm but < 4 mm), 7 patients (20%) were pT4 stage (thickness > 4 mm), and 5 patients (14%) were pT1 (thickness ≥ 1 mm). One patient had a primary lesion at pT2 stage, and 1 had a Tis stage lesion. Three patients (9%) had a family history of melanoma in a first-degree relative.
The list of genes mutated in melanoma cells in the study population is provided in the eAppendix.10,11 Twenty-seven patients (77%) had mutations in TERT promoter, 15 (43%) in CDKN2A/B, 13 (37%) in BRAF, 11 (31%) in NF1, 9 (26%) in TP53, and 8 (23%) in NRAS (Table 2). The majority of mutations in TERT promoter were c.- 146C>T (18 of 27 patients [67%]), whereas c.-124C>T was the second-most common (8 of 27 patients [30%]). The 2 observed mutations in the 13 patients with BRAF mutations were V600E and V600K, with almost equal distribution (54% and 46%, respectively). The mean (SD) TMB was 33.2 (39) mut/Mb (range, 1-203 mut/Mb). Ten patients (29%) had a TMB < 10 mut/Mb, whereas 24 (69%) had a TMB > 10 mut/Mb. The TMB could not be determined in 1 case. The frequency of TMB-high tumors in the study population compared with frequency in the reference population is shown in Table 3.12 Only 3 patients (0.64%) in the reference population had MSI-H tumors, and the microsatellite status could not be determined in those tumors (Table 4).13 Table 5 outlines statistically significant findings.




Agent Orange Subgroup
AO was a tactical herbicide used by the US military, named for the orange band around the storage barrels. Possible mutagenic properties of AO have been attributed to its byproduct, dioxin. Among the most common cancers known to be associated with AO exposure are bladder and prostate carcinoma and hematopoietic neoplasms. The association between genetic alterations and AO exposure was studied in veterans with prostate cancer.14 However, to our knowledge, insufficient information is available to determine whether an association exists between exposure to herbicides used in Vietnam or the contaminant dioxin and melanoma. Because a significant proportion of this study population had a well-documented history of AO exposure (37.1%), we were able to analyze them as a subgroup and to separately compare their mutation frequency with the general population.
Results were notable for different distributions of the most frequently mutated genes in the AO subgroup compared with the whole study population. As such, TERT promoter remained the most frequently mutated gene (92%), followed by CDKN2A/B (46%); however, frequency of mutations in NF1 (46%) outnumbered those of BRAF (31%), the fourth-most common mutation. Moreover, when compared with the general melanoma population, a significantly higher frequency of mutations in the NF1 gene was observed in the AO subgroup—not the entire study population.
Discussion
Given that veterans constitute a distinct population, there is reasonable interest in investigating characteristic health issues related to military service. Skin cancer—melanoma in particular—has been researched recently in a veteran population. The differences in demographics, tumor characteristics, and melanoma- specific survival in veterans compared with the general population have already been assessed. According to Chang et al, compared with the general population, veterans are more likely to present with metastatic disease and have lower 5-year survival rates.8
Melanoma is one of the most highly mutated malignancies.15 Fortunately, the most common mutation in melanoma, BRAF V600E, is now considered therapeutically targetable. However, there are still many mutations that are less often discussed and not well understood. Regardless of therapeutic implications, all mutations observed in melanoma are worth investigating because a tumor’s genomic profile also can provide prognostic and etiologic information. Developing comprehensive descriptions of melanoma mutational profiles in specific populations is critical to advancing etiologic understanding and informing prevention strategies.
Our results demonstrate the high prevalence of TERT promoter mutations with characteristic ultraviolet signature (C>T) in the study population. This aligns with general evidence that TERT promoter mutations are common in cutaneous melanomas: 77% of this study sample and up to 86% of all mutations are TERT promoter mutations, according to Davis et al.15 TERT promoter mutations are positively associated with the initiation, invasion, and metastasis of melanoma. In certain subtypes, there is evidence that the presence of TERT promoter mutations is significantly associated with risk for extranodal metastasis and death.16 The second-most common mutated gene in the veteran study population was CDKN2A/B (43%), and the third-most mutated gene was BRAF (37%).
In chronically sun-exposed skin NF1, NRAS, and occasionally BRAF V600K mutations tend to predominate. BRAF V600E mutations, on the other hand, are rare in these melanomas.15 In our study population, the most prevalent melanoma site was the trunk (31%), which is considered a location with an intermittent pattern of sun exposure.17
This study population also had a higher frequency of CDKN2A/B mutations. High frequencies of CDKN2A/B mutations have been reported in familial melanomas, but only 1 patient with CDKN2A/B mutations had a known family history of melanoma.15 Tumors in the study population showed significantly lower frequency of mutations in ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 (P < .05).
In this study the subgroup of veterans with AO exposure differed from the whole study population. As such, CDKN2A/B mutations were observed with the same frequency as NF1 mutations (46% each); however, BRAF mutations constituted only 31% of the mutations. In addition, the frequency of NF1 mutations was significantly higher in the AO subgroup compared with the general population, but not in the whole study population.
Our sample also differed from the reference population by showing a significantly higher frequency of TMB-high (ie, ≥ 10 mut/Mb) tumors (71% vs 49%; P = .01).12 Interestingly, no significant difference in the frequency of TMB-high tumors was observed between the AO subgroup and the reference population (69% vs 49%; P = .16). There also was no statistically significant difference between the frequency of MSI-H tumors in our study population and the reference population (P = .64).13
One patient in the study population had uveal melanoma. Mutations encountered in this patient’s tumor differed from the general mutational profile of tumors. None of the 21 mutations depicted in Table 2 were present in this sample.10,11 On the other hand, those mutations frequently observed in intraocular melanomas, BAP1 and GNA11, were present in this patient.18 Additionally, this particular melanoma possessed mutations in genes RICTOR, RAD21, and PIK3R1.
Limitations
This study population consisted exclusively of male patients, introducing sex as a potential confounder in analyzing differences between the study population and the general population. As noted in a 2020 systematic review, there were no sex-based differences in the frequency of mutations in BRAF, NRAS, and KIT genes.19
Regarding NF1 mutations, only NF1-mutated acral and mucosal melanomas were more frequently observed in female patients, whereas nonacral NF1-mutated melanomas were more frequently observed in male patients.20 However, there is currently no clear evidence of whether the mutational landscapes of cutaneous melanoma differ by sex.21 Among the 11 cases with NF1-mutatation, site of origin was known in 6, 5 of which originated at nonacral sites. Although the AO subgroup also consisted entirely of male patients, this does not explain the observed increased frequency of NF1 mutations relative to the general population. No such difference was observed between the whole study population, which also consisted exclusively of male patients, and the general population. The similar frequencies of nonacral location in the whole study population (3 acral, 18 nonacral, 14 unknown site of origin) and AO subgroup (1 acral, 7 nonacral, 5 unknown site of origin) preclude location as an explanation.
The Cancer Genome Atlas Network proposed a framework for genomic classification of melanoma into 4 subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and triple–wild-type. According to that study, BRAF mutations were indeed associated with younger age, in contrast to the NF1-mutant genomic subtype, which was more prevalent in older individuals with higher TMB.22 This emphasizes the need to interpret the potential association of AO exposure and NF1 mutation in melanoma with caution, although additional studies are required to observe the difference between the veteran population and age-matched general population.
On the other hand, Yu et al reported no significant differences of TMB values between patients aged < 60 and ≥ 60 years with melanoma.23 In short, the observed differences we report in our limited study warrant additional investigation with larger sample sizes, sex-matched controlling, and age-matched controlling. The study was limited by its small sample size and the single location.
Conclusion
The genomic profile of melanomas in the veteran population appears to be similar to that of the general population with a few possible differences. Melanomas in the veteran study population showed a higher frequency of CDKN2A/B mutations; lower frequency of ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 mutations; and higher TMB. In addition, melanomas in the AO subgroup showed higher frequencies of NF1 mutations. The significance of such findings remains to be determined by further investigation.
The veteran population, with its unique and diverse types of exposure and military service experiences, faces distinct health factors compared with the general population. These factors can be categorized into exposures during military service and those occurring postservice. While the latter phase incorporates psychological issues that may arise while transitioning to civilian life, the service period is associated with major physical, chemical, and psychological exposures that can impact veterans’ health. Carcinogenesis related to military exposures is concerning, and different types of malignancies have been associated with military exposures.1 The 2022 introduction of the Cancer Moonshot initiative served as a breeding ground for multiple projects aimed at investigation of exposure-related carcinogenesis, prompting increased attention and efforts to linking specific exposures to specific malignancies.2
Melanoma is the deadliest skin cancer, accounting for 1.3% of all cancer deaths.3 Although it may only account for 1% to 5% of skin cancer diagnoses, its incidence in the United States’ population has been increasing.4,5 There were 97,610 estimated new cases of melanoma in 2023, according to the National Cancer Institute.6
The incidence of melanoma may be higher in the military population compared with the general population.7 Melanoma is the fourth-most common cancer diagnosed in veterans.8
Several demographic characteristics of the US military population are associated with higher melanoma incidence and poorer prognosis, including male sex, older age, and White race. Apart from sun exposure—a known risk factor for melanoma development—other factors, such as service branch, seem to contribute to risk, with the highest melanoma rates noted in the Air Force.9 According to a study by Chang et al, veterans have a higher risk of stage III (18%) or stage IV (13%) melanoma at initial diagnosis.8
Molecular testing of metastatic melanoma is currently the standard of care for guiding the use of US Food and Drug Administration-approved targeted therapies such as BRAF, MEK, and KIT inhibitors. This comparative analysis details the melanoma comprehensive genomic profiles observed at a large US Department of Veterans Affairs (VA) medical center (VAMC) and those reported in reference databases.
Methods
A query to select all metastatic melanomas sent for comprehensive genomic profiling from the Kansas City VAMC (KCVAMC), identified 35 cases from 2019 through 2023 as the study population. The health records of these patients were reviewed to collect demographic information, military service history, melanoma history, other medical, social, and family histories. The comprehensive genomic profiling reports were reviewed to collect the reported pathogenic variants, microsatellite instability (MSI) status, and tumor mutational burden (TMB) for each case.
The Catalogue of Somatic Mutations in Cancer (COSMIC) was used to identify the most commonly mutated genes in melanomas from The Cancer Genome Atlas for the general population.4,5 The literature was consulted to determine the MSI status and TMB in melanomas from The Cancer Genome Atlas for separate reference populations.6,7 The frequency of MSI-high (MSI-H) status, TMB ≥ 10 mutations/megabase (mut/Mb), and mutations in each of the 20 most commonly mutated genes was determined and compared between melanomas from The Cancer Genome Atlas and KCVAMC cases. Corresponding P values were calculated to identify significant differences. Values were calculated for the entire sample as well as a subgroup with Agent Orange (AO) exposure. The study was approved by the KCVAMC Institutional Review Board.
Results
The mean (SD) age of study participants was 72.9 (9.4) years (range, 39-90 years). The mean (SD) duration of military service was 1654 (1421) days (about 4 years, 6 months, and 10 days). Of the 35 patients included, 22 (63%) served during the Vietnam era (November 1, 1965, to April 30, 1975) and 2 (6%) served during the Persian Gulf War era (August 2, 1990, to February 28, 1991). Seventeen veterans (49%) served in the Army, 9 in the Navy (26%), 5 in the Air Force (14%), and 4 in the Marine Corps (11%). Definitive AO exposure was noted in 13 patients (37%) (Table 1).

Of the 35 patients, 24 (69%) had metastatic disease and the primary site of melanoma was unknown in 14 patients (40%). One patient (Patient 32) had an intraocular melanoma. The primary site was the trunk for 11 patients (31%), the face/head for 7 patients (20%) and extremities for 3 patients (9%). Eight patients (23%) were pT3 stage (thickness > 2 mm but < 4 mm), 7 patients (20%) were pT4 stage (thickness > 4 mm), and 5 patients (14%) were pT1 (thickness ≥ 1 mm). One patient had a primary lesion at pT2 stage, and 1 had a Tis stage lesion. Three patients (9%) had a family history of melanoma in a first-degree relative.
The list of genes mutated in melanoma cells in the study population is provided in the eAppendix.10,11 Twenty-seven patients (77%) had mutations in TERT promoter, 15 (43%) in CDKN2A/B, 13 (37%) in BRAF, 11 (31%) in NF1, 9 (26%) in TP53, and 8 (23%) in NRAS (Table 2). The majority of mutations in TERT promoter were c.- 146C>T (18 of 27 patients [67%]), whereas c.-124C>T was the second-most common (8 of 27 patients [30%]). The 2 observed mutations in the 13 patients with BRAF mutations were V600E and V600K, with almost equal distribution (54% and 46%, respectively). The mean (SD) TMB was 33.2 (39) mut/Mb (range, 1-203 mut/Mb). Ten patients (29%) had a TMB < 10 mut/Mb, whereas 24 (69%) had a TMB > 10 mut/Mb. The TMB could not be determined in 1 case. The frequency of TMB-high tumors in the study population compared with frequency in the reference population is shown in Table 3.12 Only 3 patients (0.64%) in the reference population had MSI-H tumors, and the microsatellite status could not be determined in those tumors (Table 4).13 Table 5 outlines statistically significant findings.




Agent Orange Subgroup
AO was a tactical herbicide used by the US military, named for the orange band around the storage barrels. Possible mutagenic properties of AO have been attributed to its byproduct, dioxin. Among the most common cancers known to be associated with AO exposure are bladder and prostate carcinoma and hematopoietic neoplasms. The association between genetic alterations and AO exposure was studied in veterans with prostate cancer.14 However, to our knowledge, insufficient information is available to determine whether an association exists between exposure to herbicides used in Vietnam or the contaminant dioxin and melanoma. Because a significant proportion of this study population had a well-documented history of AO exposure (37.1%), we were able to analyze them as a subgroup and to separately compare their mutation frequency with the general population.
Results were notable for different distributions of the most frequently mutated genes in the AO subgroup compared with the whole study population. As such, TERT promoter remained the most frequently mutated gene (92%), followed by CDKN2A/B (46%); however, frequency of mutations in NF1 (46%) outnumbered those of BRAF (31%), the fourth-most common mutation. Moreover, when compared with the general melanoma population, a significantly higher frequency of mutations in the NF1 gene was observed in the AO subgroup—not the entire study population.
Discussion
Given that veterans constitute a distinct population, there is reasonable interest in investigating characteristic health issues related to military service. Skin cancer—melanoma in particular—has been researched recently in a veteran population. The differences in demographics, tumor characteristics, and melanoma- specific survival in veterans compared with the general population have already been assessed. According to Chang et al, compared with the general population, veterans are more likely to present with metastatic disease and have lower 5-year survival rates.8
Melanoma is one of the most highly mutated malignancies.15 Fortunately, the most common mutation in melanoma, BRAF V600E, is now considered therapeutically targetable. However, there are still many mutations that are less often discussed and not well understood. Regardless of therapeutic implications, all mutations observed in melanoma are worth investigating because a tumor’s genomic profile also can provide prognostic and etiologic information. Developing comprehensive descriptions of melanoma mutational profiles in specific populations is critical to advancing etiologic understanding and informing prevention strategies.
Our results demonstrate the high prevalence of TERT promoter mutations with characteristic ultraviolet signature (C>T) in the study population. This aligns with general evidence that TERT promoter mutations are common in cutaneous melanomas: 77% of this study sample and up to 86% of all mutations are TERT promoter mutations, according to Davis et al.15 TERT promoter mutations are positively associated with the initiation, invasion, and metastasis of melanoma. In certain subtypes, there is evidence that the presence of TERT promoter mutations is significantly associated with risk for extranodal metastasis and death.16 The second-most common mutated gene in the veteran study population was CDKN2A/B (43%), and the third-most mutated gene was BRAF (37%).
In chronically sun-exposed skin NF1, NRAS, and occasionally BRAF V600K mutations tend to predominate. BRAF V600E mutations, on the other hand, are rare in these melanomas.15 In our study population, the most prevalent melanoma site was the trunk (31%), which is considered a location with an intermittent pattern of sun exposure.17
This study population also had a higher frequency of CDKN2A/B mutations. High frequencies of CDKN2A/B mutations have been reported in familial melanomas, but only 1 patient with CDKN2A/B mutations had a known family history of melanoma.15 Tumors in the study population showed significantly lower frequency of mutations in ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 (P < .05).
In this study the subgroup of veterans with AO exposure differed from the whole study population. As such, CDKN2A/B mutations were observed with the same frequency as NF1 mutations (46% each); however, BRAF mutations constituted only 31% of the mutations. In addition, the frequency of NF1 mutations was significantly higher in the AO subgroup compared with the general population, but not in the whole study population.
Our sample also differed from the reference population by showing a significantly higher frequency of TMB-high (ie, ≥ 10 mut/Mb) tumors (71% vs 49%; P = .01).12 Interestingly, no significant difference in the frequency of TMB-high tumors was observed between the AO subgroup and the reference population (69% vs 49%; P = .16). There also was no statistically significant difference between the frequency of MSI-H tumors in our study population and the reference population (P = .64).13
One patient in the study population had uveal melanoma. Mutations encountered in this patient’s tumor differed from the general mutational profile of tumors. None of the 21 mutations depicted in Table 2 were present in this sample.10,11 On the other hand, those mutations frequently observed in intraocular melanomas, BAP1 and GNA11, were present in this patient.18 Additionally, this particular melanoma possessed mutations in genes RICTOR, RAD21, and PIK3R1.
Limitations
This study population consisted exclusively of male patients, introducing sex as a potential confounder in analyzing differences between the study population and the general population. As noted in a 2020 systematic review, there were no sex-based differences in the frequency of mutations in BRAF, NRAS, and KIT genes.19
Regarding NF1 mutations, only NF1-mutated acral and mucosal melanomas were more frequently observed in female patients, whereas nonacral NF1-mutated melanomas were more frequently observed in male patients.20 However, there is currently no clear evidence of whether the mutational landscapes of cutaneous melanoma differ by sex.21 Among the 11 cases with NF1-mutatation, site of origin was known in 6, 5 of which originated at nonacral sites. Although the AO subgroup also consisted entirely of male patients, this does not explain the observed increased frequency of NF1 mutations relative to the general population. No such difference was observed between the whole study population, which also consisted exclusively of male patients, and the general population. The similar frequencies of nonacral location in the whole study population (3 acral, 18 nonacral, 14 unknown site of origin) and AO subgroup (1 acral, 7 nonacral, 5 unknown site of origin) preclude location as an explanation.
The Cancer Genome Atlas Network proposed a framework for genomic classification of melanoma into 4 subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and triple–wild-type. According to that study, BRAF mutations were indeed associated with younger age, in contrast to the NF1-mutant genomic subtype, which was more prevalent in older individuals with higher TMB.22 This emphasizes the need to interpret the potential association of AO exposure and NF1 mutation in melanoma with caution, although additional studies are required to observe the difference between the veteran population and age-matched general population.
On the other hand, Yu et al reported no significant differences of TMB values between patients aged < 60 and ≥ 60 years with melanoma.23 In short, the observed differences we report in our limited study warrant additional investigation with larger sample sizes, sex-matched controlling, and age-matched controlling. The study was limited by its small sample size and the single location.
Conclusion
The genomic profile of melanomas in the veteran population appears to be similar to that of the general population with a few possible differences. Melanomas in the veteran study population showed a higher frequency of CDKN2A/B mutations; lower frequency of ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 mutations; and higher TMB. In addition, melanomas in the AO subgroup showed higher frequencies of NF1 mutations. The significance of such findings remains to be determined by further investigation.
- Bytnar JA, McGlynn KA, et al. Cancer incidence in the US military: An updated analysis. Cancer. 2024;130(1):96-106. doi:10.1002/cncr.34978
- Singer DS. A new phase of the Cancer Moonshot to end cancer as we know it. Nat Med. 2022;28(7):1345-1347. doi:10.1038/s41591-022-01881-5
- Koczkodaj P, Sulkowska U, Didkowska J, et al. Melanoma mortality trends in 28 European countries: a retrospective analysis for the years 1960-2020. Cancers (Basel). 2023;15(5):1514. Published 2023 Feb 28. doi:10.3390/cancers15051514
- Okobi OE, Abreo E, Sams NP, et al. Trends in melanoma incidence, prevalence, stage at diagnosis, and survival: an analysis of the United States Cancer Statistics (USCS) database. Cureus. 2024;16(10):e70697. doi:10.7759/cureus.70697
- Bartling SJ, Rivard SC, Meyerle JH. Melanoma in an active duty marine. Mil Med. 2017;182:e2034-e2039. doi:10.7205/MILMED-D-17-00127
- American Cancer Society. Cancer facts & figures 2023. American Cancer Society; 2023. Accessed June 20, 2025. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
- Rezaei SJ, Kim J, Onyeka S, et al. Skin cancer and other dermatologic conditions among US veterans. JAMA Dermatol. 2024;160(10):1107-1111. doi:10.1001/jamadermatol.2024.3043
- Chang MS, La J, Trepanowski N, et al. Increased relative proportions of advanced melanoma among veterans: a comparative analysis with the Surveillance, Epidemiology, and End Results registry. J Am Acad Dermatol. 2022;87:72-79. doi:10.1016/j.jaad.2022.02.063
- Riemenschneider K, Liu J, Powers JG. Skin cancer in the military: a systematic review of melanoma and nonmelanoma skin cancer incidence, prevention, and screening among active duty and veteran personnel. J Am Acad Dermatol. 2018;78:1185-1192. doi:10.1016/j.jaad.2017.11.062
- Huang FW, Hodis E, Xu MJ, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339:957-959. doi:10.1126/science.1229259
- Tate JG, Bamford S, Jubb HC, et al. COSMIC: the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2019;47:D941-D947. doi:10.1093/nar/gky1015
- Li M, Gao X, Wang X. Identification of tumor mutation burden-associated molecular and clinical features in cancer by analyzing multi-omics data. Front Immunol. 2023;14:1090838. doi:10.3389/fimmu.2023.1090838
- Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017:PO.17.00073. doi:10.1200/PO.17.00073
- Lui AJ, Pagadala MS, Zhong AY, et al. Agent Orange exposure and prostate cancer risk in the Million Veteran Program. medRxiv [Preprint]. 2023:2023.06.14.23291413. doi:10.1101/2023.06.14.23291413
- Davis EJ, Johnson DB, Sosman JA, et al. Melanoma: what do all the mutations mean? Cancer. 2018;124:3490-3499. doi:10.1002/cncr.31345
- Guo Y, Chen Y, Zhang L, et al. TERT promoter mutations and telomerase in melanoma. J Oncol. 2022;2022:6300329. doi:10.1155/2022/6300329
- Whiteman DC, Stickley M, Watt P, et al. Anatomic site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol. 2006;24:3172-3177. doi:10.1200/JCO.2006.06.1325
- Decatur CL, Ong E, Garg N, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 2016;134:728-733. doi:10.1001/jamaophthalmol.2016.0903
- Gutiérrez-Castañeda LD, Nova JA, Tovar-Parra JD. Frequency of mutations in BRAF, NRAS, and KIT in different populations and histological subtypes of melanoma: a systemic review. Melanoma Res. 2020;30:62- 70. doi:10.1097/CMR.0000000000000628
- Thielmann CM, Chorti E, Matull J, et al. NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors. Eur J Cancer. 2021;159:113-124. doi:10.1016/j.ejca.2021.09.035
- D’Ecclesiis O, Caini S, Martinoli C, et al. Gender-dependent specificities in cutaneous melanoma predisposition, risk factors, somatic mutations, prognostic and predictive factors: a systematic review. Int J Environ Res Public Health. 2021;18:7945. doi:10.3390/ijerph18157945
- Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681-1696. doi:10.1016/j.cell.2015.05.044
- Yu Z, Wang J, Feng L, et al. Association of tumor mutational burden with age in solid tumors. J Clin Oncol. 2020;38:e13590-e13590. doi:10.1200/JCO.2020.38.15_suppl.e13590
- Bytnar JA, McGlynn KA, et al. Cancer incidence in the US military: An updated analysis. Cancer. 2024;130(1):96-106. doi:10.1002/cncr.34978
- Singer DS. A new phase of the Cancer Moonshot to end cancer as we know it. Nat Med. 2022;28(7):1345-1347. doi:10.1038/s41591-022-01881-5
- Koczkodaj P, Sulkowska U, Didkowska J, et al. Melanoma mortality trends in 28 European countries: a retrospective analysis for the years 1960-2020. Cancers (Basel). 2023;15(5):1514. Published 2023 Feb 28. doi:10.3390/cancers15051514
- Okobi OE, Abreo E, Sams NP, et al. Trends in melanoma incidence, prevalence, stage at diagnosis, and survival: an analysis of the United States Cancer Statistics (USCS) database. Cureus. 2024;16(10):e70697. doi:10.7759/cureus.70697
- Bartling SJ, Rivard SC, Meyerle JH. Melanoma in an active duty marine. Mil Med. 2017;182:e2034-e2039. doi:10.7205/MILMED-D-17-00127
- American Cancer Society. Cancer facts & figures 2023. American Cancer Society; 2023. Accessed June 20, 2025. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
- Rezaei SJ, Kim J, Onyeka S, et al. Skin cancer and other dermatologic conditions among US veterans. JAMA Dermatol. 2024;160(10):1107-1111. doi:10.1001/jamadermatol.2024.3043
- Chang MS, La J, Trepanowski N, et al. Increased relative proportions of advanced melanoma among veterans: a comparative analysis with the Surveillance, Epidemiology, and End Results registry. J Am Acad Dermatol. 2022;87:72-79. doi:10.1016/j.jaad.2022.02.063
- Riemenschneider K, Liu J, Powers JG. Skin cancer in the military: a systematic review of melanoma and nonmelanoma skin cancer incidence, prevention, and screening among active duty and veteran personnel. J Am Acad Dermatol. 2018;78:1185-1192. doi:10.1016/j.jaad.2017.11.062
- Huang FW, Hodis E, Xu MJ, et al. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339:957-959. doi:10.1126/science.1229259
- Tate JG, Bamford S, Jubb HC, et al. COSMIC: the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2019;47:D941-D947. doi:10.1093/nar/gky1015
- Li M, Gao X, Wang X. Identification of tumor mutation burden-associated molecular and clinical features in cancer by analyzing multi-omics data. Front Immunol. 2023;14:1090838. doi:10.3389/fimmu.2023.1090838
- Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017:PO.17.00073. doi:10.1200/PO.17.00073
- Lui AJ, Pagadala MS, Zhong AY, et al. Agent Orange exposure and prostate cancer risk in the Million Veteran Program. medRxiv [Preprint]. 2023:2023.06.14.23291413. doi:10.1101/2023.06.14.23291413
- Davis EJ, Johnson DB, Sosman JA, et al. Melanoma: what do all the mutations mean? Cancer. 2018;124:3490-3499. doi:10.1002/cncr.31345
- Guo Y, Chen Y, Zhang L, et al. TERT promoter mutations and telomerase in melanoma. J Oncol. 2022;2022:6300329. doi:10.1155/2022/6300329
- Whiteman DC, Stickley M, Watt P, et al. Anatomic site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol. 2006;24:3172-3177. doi:10.1200/JCO.2006.06.1325
- Decatur CL, Ong E, Garg N, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 2016;134:728-733. doi:10.1001/jamaophthalmol.2016.0903
- Gutiérrez-Castañeda LD, Nova JA, Tovar-Parra JD. Frequency of mutations in BRAF, NRAS, and KIT in different populations and histological subtypes of melanoma: a systemic review. Melanoma Res. 2020;30:62- 70. doi:10.1097/CMR.0000000000000628
- Thielmann CM, Chorti E, Matull J, et al. NF1-mutated melanomas reveal distinct clinical characteristics depending on tumour origin and respond favourably to immune checkpoint inhibitors. Eur J Cancer. 2021;159:113-124. doi:10.1016/j.ejca.2021.09.035
- D’Ecclesiis O, Caini S, Martinoli C, et al. Gender-dependent specificities in cutaneous melanoma predisposition, risk factors, somatic mutations, prognostic and predictive factors: a systematic review. Int J Environ Res Public Health. 2021;18:7945. doi:10.3390/ijerph18157945
- Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681-1696. doi:10.1016/j.cell.2015.05.044
- Yu Z, Wang J, Feng L, et al. Association of tumor mutational burden with age in solid tumors. J Clin Oncol. 2020;38:e13590-e13590. doi:10.1200/JCO.2020.38.15_suppl.e13590
Comprehensive Genomic Profiles of Melanoma in Veterans Compared to Reference Databases
Comprehensive Genomic Profiles of Melanoma in Veterans Compared to Reference Databases
“Noteworthy” Link Between Agent Orange and Acral Melanoma Found
Recent research has revealed potential links between Agent Orange (AO) exposure and risk of acral melanoma (AM) among Vietnam War-era veterans, providing strong evidence of a relationship between the chemical and this type of cancer.
Localized to the palms, soles, and nail units, AM is a melanoma subtype less associated with UV radiation. From 1962 to 1971, the US military sprayed an estimated 18 million gallons of herbicides, including AO, over the fields and forests of Vietnam. Those herbicides have since been connected to numerous health issues, including cancer, though evidence of a relationship between AO and skin cancers has been weak.
Vietnam War-era veterans have a higher melanoma burden than the general population, with the disease being the fourth-most common cancer among those who served. AM, however, is rare, representing about 2% to 3% of all melanomas.
In a nested case-control study, Hwang et al used US Department of Veterans Affairs (VA) health care system data, including the VA Cancer Registry. The authors compared 1292 patients with AM and 2 pair-matched control groups: a group matched 4:1 to nonacral cutaneous melanoma controls, and a group without a melanoma diagnosis.
Hwang et al found AO exposure was associated with increased odds of AM compared with each control group. In an accompanying editorial, Andrew Olshan, PhD, from Department of Epidemiology at the University of North Carolina Gillings School of Global Public Health, wrote, “The magnitude of the effects was modest (about 30%) but noteworthy.”
A limitation of the study was that presumptive AOE status was based on whether the veteran filed a disability claim with evidence of officially recognized service in a period and place where Agent Orange was used—not on an assessment of the veteran’s individual AOE potential, including level of exposure. Because melanoma has never been included on the VA list of cancers presumed to be related to AO exposure, veterans do not automatically gain benefits by filing AOE claims after diagnosis. Even so, Olshan says, the reported study findings may underestimate the true effect of AO exposure on the risk of AM.
Given the rarity of AM, the association (if causal) would translate to 0.4 to 0.8 new annual cases of AM per 1,000,000 veterans, according to the study. Narrowed down to Vietnam War-era veterans—who are dwindling in number—the attributable cases would be scarce.
Nevertheless, the search for a better understanding of a potential link between AOE and melanomas among Vietnam War-era veterans is important, Olshan wrote.
“The Hwang et al study provides a strong impetus to further these research goals and contribute to the investigation of the legacy of the Vietnam War and honor a commitment to the veterans community.”
Recent research has revealed potential links between Agent Orange (AO) exposure and risk of acral melanoma (AM) among Vietnam War-era veterans, providing strong evidence of a relationship between the chemical and this type of cancer.
Localized to the palms, soles, and nail units, AM is a melanoma subtype less associated with UV radiation. From 1962 to 1971, the US military sprayed an estimated 18 million gallons of herbicides, including AO, over the fields and forests of Vietnam. Those herbicides have since been connected to numerous health issues, including cancer, though evidence of a relationship between AO and skin cancers has been weak.
Vietnam War-era veterans have a higher melanoma burden than the general population, with the disease being the fourth-most common cancer among those who served. AM, however, is rare, representing about 2% to 3% of all melanomas.
In a nested case-control study, Hwang et al used US Department of Veterans Affairs (VA) health care system data, including the VA Cancer Registry. The authors compared 1292 patients with AM and 2 pair-matched control groups: a group matched 4:1 to nonacral cutaneous melanoma controls, and a group without a melanoma diagnosis.
Hwang et al found AO exposure was associated with increased odds of AM compared with each control group. In an accompanying editorial, Andrew Olshan, PhD, from Department of Epidemiology at the University of North Carolina Gillings School of Global Public Health, wrote, “The magnitude of the effects was modest (about 30%) but noteworthy.”
A limitation of the study was that presumptive AOE status was based on whether the veteran filed a disability claim with evidence of officially recognized service in a period and place where Agent Orange was used—not on an assessment of the veteran’s individual AOE potential, including level of exposure. Because melanoma has never been included on the VA list of cancers presumed to be related to AO exposure, veterans do not automatically gain benefits by filing AOE claims after diagnosis. Even so, Olshan says, the reported study findings may underestimate the true effect of AO exposure on the risk of AM.
Given the rarity of AM, the association (if causal) would translate to 0.4 to 0.8 new annual cases of AM per 1,000,000 veterans, according to the study. Narrowed down to Vietnam War-era veterans—who are dwindling in number—the attributable cases would be scarce.
Nevertheless, the search for a better understanding of a potential link between AOE and melanomas among Vietnam War-era veterans is important, Olshan wrote.
“The Hwang et al study provides a strong impetus to further these research goals and contribute to the investigation of the legacy of the Vietnam War and honor a commitment to the veterans community.”
Recent research has revealed potential links between Agent Orange (AO) exposure and risk of acral melanoma (AM) among Vietnam War-era veterans, providing strong evidence of a relationship between the chemical and this type of cancer.
Localized to the palms, soles, and nail units, AM is a melanoma subtype less associated with UV radiation. From 1962 to 1971, the US military sprayed an estimated 18 million gallons of herbicides, including AO, over the fields and forests of Vietnam. Those herbicides have since been connected to numerous health issues, including cancer, though evidence of a relationship between AO and skin cancers has been weak.
Vietnam War-era veterans have a higher melanoma burden than the general population, with the disease being the fourth-most common cancer among those who served. AM, however, is rare, representing about 2% to 3% of all melanomas.
In a nested case-control study, Hwang et al used US Department of Veterans Affairs (VA) health care system data, including the VA Cancer Registry. The authors compared 1292 patients with AM and 2 pair-matched control groups: a group matched 4:1 to nonacral cutaneous melanoma controls, and a group without a melanoma diagnosis.
Hwang et al found AO exposure was associated with increased odds of AM compared with each control group. In an accompanying editorial, Andrew Olshan, PhD, from Department of Epidemiology at the University of North Carolina Gillings School of Global Public Health, wrote, “The magnitude of the effects was modest (about 30%) but noteworthy.”
A limitation of the study was that presumptive AOE status was based on whether the veteran filed a disability claim with evidence of officially recognized service in a period and place where Agent Orange was used—not on an assessment of the veteran’s individual AOE potential, including level of exposure. Because melanoma has never been included on the VA list of cancers presumed to be related to AO exposure, veterans do not automatically gain benefits by filing AOE claims after diagnosis. Even so, Olshan says, the reported study findings may underestimate the true effect of AO exposure on the risk of AM.
Given the rarity of AM, the association (if causal) would translate to 0.4 to 0.8 new annual cases of AM per 1,000,000 veterans, according to the study. Narrowed down to Vietnam War-era veterans—who are dwindling in number—the attributable cases would be scarce.
Nevertheless, the search for a better understanding of a potential link between AOE and melanomas among Vietnam War-era veterans is important, Olshan wrote.
“The Hwang et al study provides a strong impetus to further these research goals and contribute to the investigation of the legacy of the Vietnam War and honor a commitment to the veterans community.”
Can Fecal Transplants Enhance Immunotherapy? New Evidence and Cautions
Can Fecal Transplants Enhance Immunotherapy? New Evidence and Cautions
A trio of new studies, published simultaneously in February in Nature Medicine, add to growing evidence that manipulating the gut microbiome may enhance responses to immunotherapy in selected patients with cancer.
In these small, early-phase studies involving patients with metastatic renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and melanoma receiving immune checkpoint inhibitor (ICI) therapy, fecal microbiota transplantation (FMT) was associated with objective response rates that compared favorably with historical or prespecified benchmarks.
The idea that microbiome modulation via FMT “can augment immunotherapy efficacy is probably a good one and these studies certainly support that hypothesis,” said Diwakar Davar, MD, assistant professor of medicine and an oncologist/hematologist at the University of Pittsburgh, Pennsylvania, who wasn’t part of the new work.While “an intriguing approach and certainly worthy of further evaluation,” Davar cautioned that the latest studies are not robust enough to answer the question conclusively.
Although ICIs have improved outcomes for patients with melanoma, NSCLC, and RCC, many patients still do not respond or eventually develop resistance. A growing body of evidence suggests that the gut microbiome can influence the effectiveness of ICI therapy. However, much of this evidence comes from preclinical studies showing that modulating the microbiome via FMT can alter responses to immunotherapy, along with small proof-of-concept human studies — predominantly in melanoma — suggesting this approach may help overcome primary or acquired resistance to anti-PD-1 therapy.
The new studies aimed to build on this foundation by exploring whether FMT could improve ICI responses and clinical outcomes in patients with NSCLC, melanoma, and RCC.
In the phase 2, open-label FMT-LUMINate trial, researchers tested a healthy-donor FMT delivered as oral capsules before patients began immunotherapy. FMT capsules were produced using 80-100 g of feces per dose from screened healthy donors, and patients consumed 30-40 capsules while under supervision. The study included 20 patients with NSCLC and high PD-L1 tumor expression receiving FMT before standard first-line pembrolizumab monotherapy and 20 patients with cutaneous melanoma receiving FMT before ipilimumab plus nivolumab.
In the NSCLC cohort, 16 patients (80%) achieved an objective response. The 80% objective response rate exceeded the prespecified efficacy threshold of 64% and was higher than previously described historical data, which ranged from 39% to 46%, the study team noted.
In the melanoma cohort, FMT before nivolumab and ipilimumab yielded an objective response rate of 75%, also exceeding the historical expected response rates of 50% to 58% among patients receiving this ICI combination.
In patients with NSCLC, no grade 3 or higher adverse events were reported. However, grade 3 or higher adverse events were reported in 13 (65%) patients in the melanoma group, suggesting a potentially accelerated onset of immune-related adverse events. Researchers also observed a higher-than-expected frequency of myocarditis in melanoma patients (15%). These toxicities clustered among patients who had FMT donors enriched in Prevotella spp, highlighting the importance of donor selection for future trials, the researchers explained.
The team plans to assess the potential of FMT to overcome primary resistance to ICI as part of the phase 2 CanBiome2 randomized trial, which aims to enroll 128 patients.
The RCC Data
The other two studies focused on FMT in patients with metastatic RCC. In the phase 1 PERFORM study, 20 treatment-naive patients with metastatic RCC added encapsulated healthy-donor FMT to standard ICI-based regimens — most commonly ipilimumab plus nivolumab, with some patients receiving pembrolizumab plus axitinib or pembrolizumab plus lenvatinib.
The primary endpoint was safety defined by the incidence and severity of immune-related adverse events. The safety endpoint was met; 50% of patients (10 of 20) experienced grade 3 immune-related adverse events, and there were no serious FMT-related toxicities and no grade 4 or 5 events.
Among 18 evaluable patients, nine (50%) achieved an objective response, including two who had complete responses (11%). Notably, most treatment responders did not develop any grade 3 or higher immune-related adverse events, the researchers reported.
Finally, in the phase 2a TACITO trial, 45 patients with treatment-naive metastatic RCC were randomly allocated to receive donor FMT or placebo FMT. Patients received three administrations over 6 months — first via colonoscopy then as capsulized doses, alongside pembrolizumab plus axitinib.
The primary endpoint of 12-month progression-free survival narrowly missed statistical significance — 70% vs 41% (P = .053) — but suggested a benefit in the donor FMT group.
“We need more than 1 year to appreciate statistical significance in terms of progression-free survival,” study investigator Gianluca Ianiro, MD, PhD, with Catholic University of the Sacred Heart, Rome, told Medscape Medical News.
As for secondary endpoints, median progression-free survival was significantly longer with donor FMT (24.0 vs 9.0 months; hazard ratio, 0.50; P = .035) and the objective response rate was higher with donor FMT (52% vs 32%).
Why Might FMT Boost ICI Response?
Conceptually, FMT is intended to reshape the gut ecosystem in ways that favor antitumor immunity, and possibly reduce immune dysregulation.
Across these new studies, the mechanistic story is moving beyond the idea that more diversity is good and toward a model that suggests a benefit to removing or suppressing taxa associated with resistance or inflammatory toxicity.
For example, in the TACITO trial, microbiome analysis confirmed that acquisition or loss of specific bacterial strains was associated with 12-month progression-free survival.
Additionally, results of the FMT-LUMINate trial hinted that the therapeutic benefit of FMT may be driven by eliminating harmful bacteria present at baseline, most notably Enterocloster, Clostridium and Streptococcus spp.
“This bacterial depletion was associated with a favorable immunometabolic milieu,” the FMT-LUMINate researchers wrote. Additionally, the results suggest that “failure to eliminate baseline deleterious taxa may sustain an immunosuppressive metabolic and systemic immune milieu that compromises ICI responses.”
Is FMT Ready for Prime Time?
Ianiro told Medscape Medical News he “definitely” thinks microbiome modulation could eventually become part of standard immunotherapy regimens.
Although the “signal” of benefit is clearly there, Davar cautioned that it’s too early to justify routine, off-trial use of FMT specifically to improve ICI response.
“These remain small, proof-of-concept studies. They are not adequately powered trials of fecal transplants and multiple different covariates haven’t been considered,” Davar said.
The study researchers noted that issues around donor selection and availability, dosing schedules, product standardization, and safety risk stratification need to be resolved.
For example, TACITO’s real-world experience shows logistics can matter. Delays occurred due to capsule unavailability and other scheduling barriers, which led to late dosing and missed or shifted treatments in some patients.
That’s a reminder that scaling FMT for oncology would require robust manufacturing, distribution, and time-sensitive coordination with ICI start dates.
More broadly, “whether FMT is the most suitable method of essentially changing the gut microbiome remains unclear,” explained Davar, who suggested that engineered microbiome therapeutics or tailored therapies may be a preferable, more scalable and tailored long-term solution.
Overall, does this new research provide impetus to develop stool banks? “Probably not,” Davar said.
But is it a call for interested parties to think about clinical trials and experimental products that could influence the gut microbiome? “Those are all probably good ideas,” he said.
The PERFORM, TACITO and FMT-LUMINate trials had no commercial funding. Saman Maleki Vareki, PhD, of the PERFORM trial, is a cofounder of LND Therapeutics Inc and has submitted a US patent application related to FMT donor screening. Ianiro has received personal fees for acting as a speaker for Biocodex and Illumina and for acting as a consultant/advisor for Ferring Therapeutics. Arielle Elkrief, MD, of the FMT-LUMINate trial, has received honoraria from AstraZeneca, Merck, Bristol Myers Squibb, and EMD Serono; consulting fees from EverImmune, NECBio, and Sanofi-Pasteur; and is an inventor on a patent regarding the microbiome and immunotherapy response. Davar had no relevant disclosures.
A version of this article first appeared on Medscape.com.
A trio of new studies, published simultaneously in February in Nature Medicine, add to growing evidence that manipulating the gut microbiome may enhance responses to immunotherapy in selected patients with cancer.
In these small, early-phase studies involving patients with metastatic renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and melanoma receiving immune checkpoint inhibitor (ICI) therapy, fecal microbiota transplantation (FMT) was associated with objective response rates that compared favorably with historical or prespecified benchmarks.
The idea that microbiome modulation via FMT “can augment immunotherapy efficacy is probably a good one and these studies certainly support that hypothesis,” said Diwakar Davar, MD, assistant professor of medicine and an oncologist/hematologist at the University of Pittsburgh, Pennsylvania, who wasn’t part of the new work.While “an intriguing approach and certainly worthy of further evaluation,” Davar cautioned that the latest studies are not robust enough to answer the question conclusively.
Although ICIs have improved outcomes for patients with melanoma, NSCLC, and RCC, many patients still do not respond or eventually develop resistance. A growing body of evidence suggests that the gut microbiome can influence the effectiveness of ICI therapy. However, much of this evidence comes from preclinical studies showing that modulating the microbiome via FMT can alter responses to immunotherapy, along with small proof-of-concept human studies — predominantly in melanoma — suggesting this approach may help overcome primary or acquired resistance to anti-PD-1 therapy.
The new studies aimed to build on this foundation by exploring whether FMT could improve ICI responses and clinical outcomes in patients with NSCLC, melanoma, and RCC.
In the phase 2, open-label FMT-LUMINate trial, researchers tested a healthy-donor FMT delivered as oral capsules before patients began immunotherapy. FMT capsules were produced using 80-100 g of feces per dose from screened healthy donors, and patients consumed 30-40 capsules while under supervision. The study included 20 patients with NSCLC and high PD-L1 tumor expression receiving FMT before standard first-line pembrolizumab monotherapy and 20 patients with cutaneous melanoma receiving FMT before ipilimumab plus nivolumab.
In the NSCLC cohort, 16 patients (80%) achieved an objective response. The 80% objective response rate exceeded the prespecified efficacy threshold of 64% and was higher than previously described historical data, which ranged from 39% to 46%, the study team noted.
In the melanoma cohort, FMT before nivolumab and ipilimumab yielded an objective response rate of 75%, also exceeding the historical expected response rates of 50% to 58% among patients receiving this ICI combination.
In patients with NSCLC, no grade 3 or higher adverse events were reported. However, grade 3 or higher adverse events were reported in 13 (65%) patients in the melanoma group, suggesting a potentially accelerated onset of immune-related adverse events. Researchers also observed a higher-than-expected frequency of myocarditis in melanoma patients (15%). These toxicities clustered among patients who had FMT donors enriched in Prevotella spp, highlighting the importance of donor selection for future trials, the researchers explained.
The team plans to assess the potential of FMT to overcome primary resistance to ICI as part of the phase 2 CanBiome2 randomized trial, which aims to enroll 128 patients.
The RCC Data
The other two studies focused on FMT in patients with metastatic RCC. In the phase 1 PERFORM study, 20 treatment-naive patients with metastatic RCC added encapsulated healthy-donor FMT to standard ICI-based regimens — most commonly ipilimumab plus nivolumab, with some patients receiving pembrolizumab plus axitinib or pembrolizumab plus lenvatinib.
The primary endpoint was safety defined by the incidence and severity of immune-related adverse events. The safety endpoint was met; 50% of patients (10 of 20) experienced grade 3 immune-related adverse events, and there were no serious FMT-related toxicities and no grade 4 or 5 events.
Among 18 evaluable patients, nine (50%) achieved an objective response, including two who had complete responses (11%). Notably, most treatment responders did not develop any grade 3 or higher immune-related adverse events, the researchers reported.
Finally, in the phase 2a TACITO trial, 45 patients with treatment-naive metastatic RCC were randomly allocated to receive donor FMT or placebo FMT. Patients received three administrations over 6 months — first via colonoscopy then as capsulized doses, alongside pembrolizumab plus axitinib.
The primary endpoint of 12-month progression-free survival narrowly missed statistical significance — 70% vs 41% (P = .053) — but suggested a benefit in the donor FMT group.
“We need more than 1 year to appreciate statistical significance in terms of progression-free survival,” study investigator Gianluca Ianiro, MD, PhD, with Catholic University of the Sacred Heart, Rome, told Medscape Medical News.
As for secondary endpoints, median progression-free survival was significantly longer with donor FMT (24.0 vs 9.0 months; hazard ratio, 0.50; P = .035) and the objective response rate was higher with donor FMT (52% vs 32%).
Why Might FMT Boost ICI Response?
Conceptually, FMT is intended to reshape the gut ecosystem in ways that favor antitumor immunity, and possibly reduce immune dysregulation.
Across these new studies, the mechanistic story is moving beyond the idea that more diversity is good and toward a model that suggests a benefit to removing or suppressing taxa associated with resistance or inflammatory toxicity.
For example, in the TACITO trial, microbiome analysis confirmed that acquisition or loss of specific bacterial strains was associated with 12-month progression-free survival.
Additionally, results of the FMT-LUMINate trial hinted that the therapeutic benefit of FMT may be driven by eliminating harmful bacteria present at baseline, most notably Enterocloster, Clostridium and Streptococcus spp.
“This bacterial depletion was associated with a favorable immunometabolic milieu,” the FMT-LUMINate researchers wrote. Additionally, the results suggest that “failure to eliminate baseline deleterious taxa may sustain an immunosuppressive metabolic and systemic immune milieu that compromises ICI responses.”
Is FMT Ready for Prime Time?
Ianiro told Medscape Medical News he “definitely” thinks microbiome modulation could eventually become part of standard immunotherapy regimens.
Although the “signal” of benefit is clearly there, Davar cautioned that it’s too early to justify routine, off-trial use of FMT specifically to improve ICI response.
“These remain small, proof-of-concept studies. They are not adequately powered trials of fecal transplants and multiple different covariates haven’t been considered,” Davar said.
The study researchers noted that issues around donor selection and availability, dosing schedules, product standardization, and safety risk stratification need to be resolved.
For example, TACITO’s real-world experience shows logistics can matter. Delays occurred due to capsule unavailability and other scheduling barriers, which led to late dosing and missed or shifted treatments in some patients.
That’s a reminder that scaling FMT for oncology would require robust manufacturing, distribution, and time-sensitive coordination with ICI start dates.
More broadly, “whether FMT is the most suitable method of essentially changing the gut microbiome remains unclear,” explained Davar, who suggested that engineered microbiome therapeutics or tailored therapies may be a preferable, more scalable and tailored long-term solution.
Overall, does this new research provide impetus to develop stool banks? “Probably not,” Davar said.
But is it a call for interested parties to think about clinical trials and experimental products that could influence the gut microbiome? “Those are all probably good ideas,” he said.
The PERFORM, TACITO and FMT-LUMINate trials had no commercial funding. Saman Maleki Vareki, PhD, of the PERFORM trial, is a cofounder of LND Therapeutics Inc and has submitted a US patent application related to FMT donor screening. Ianiro has received personal fees for acting as a speaker for Biocodex and Illumina and for acting as a consultant/advisor for Ferring Therapeutics. Arielle Elkrief, MD, of the FMT-LUMINate trial, has received honoraria from AstraZeneca, Merck, Bristol Myers Squibb, and EMD Serono; consulting fees from EverImmune, NECBio, and Sanofi-Pasteur; and is an inventor on a patent regarding the microbiome and immunotherapy response. Davar had no relevant disclosures.
A version of this article first appeared on Medscape.com.
A trio of new studies, published simultaneously in February in Nature Medicine, add to growing evidence that manipulating the gut microbiome may enhance responses to immunotherapy in selected patients with cancer.
In these small, early-phase studies involving patients with metastatic renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and melanoma receiving immune checkpoint inhibitor (ICI) therapy, fecal microbiota transplantation (FMT) was associated with objective response rates that compared favorably with historical or prespecified benchmarks.
The idea that microbiome modulation via FMT “can augment immunotherapy efficacy is probably a good one and these studies certainly support that hypothesis,” said Diwakar Davar, MD, assistant professor of medicine and an oncologist/hematologist at the University of Pittsburgh, Pennsylvania, who wasn’t part of the new work.While “an intriguing approach and certainly worthy of further evaluation,” Davar cautioned that the latest studies are not robust enough to answer the question conclusively.
Although ICIs have improved outcomes for patients with melanoma, NSCLC, and RCC, many patients still do not respond or eventually develop resistance. A growing body of evidence suggests that the gut microbiome can influence the effectiveness of ICI therapy. However, much of this evidence comes from preclinical studies showing that modulating the microbiome via FMT can alter responses to immunotherapy, along with small proof-of-concept human studies — predominantly in melanoma — suggesting this approach may help overcome primary or acquired resistance to anti-PD-1 therapy.
The new studies aimed to build on this foundation by exploring whether FMT could improve ICI responses and clinical outcomes in patients with NSCLC, melanoma, and RCC.
In the phase 2, open-label FMT-LUMINate trial, researchers tested a healthy-donor FMT delivered as oral capsules before patients began immunotherapy. FMT capsules were produced using 80-100 g of feces per dose from screened healthy donors, and patients consumed 30-40 capsules while under supervision. The study included 20 patients with NSCLC and high PD-L1 tumor expression receiving FMT before standard first-line pembrolizumab monotherapy and 20 patients with cutaneous melanoma receiving FMT before ipilimumab plus nivolumab.
In the NSCLC cohort, 16 patients (80%) achieved an objective response. The 80% objective response rate exceeded the prespecified efficacy threshold of 64% and was higher than previously described historical data, which ranged from 39% to 46%, the study team noted.
In the melanoma cohort, FMT before nivolumab and ipilimumab yielded an objective response rate of 75%, also exceeding the historical expected response rates of 50% to 58% among patients receiving this ICI combination.
In patients with NSCLC, no grade 3 or higher adverse events were reported. However, grade 3 or higher adverse events were reported in 13 (65%) patients in the melanoma group, suggesting a potentially accelerated onset of immune-related adverse events. Researchers also observed a higher-than-expected frequency of myocarditis in melanoma patients (15%). These toxicities clustered among patients who had FMT donors enriched in Prevotella spp, highlighting the importance of donor selection for future trials, the researchers explained.
The team plans to assess the potential of FMT to overcome primary resistance to ICI as part of the phase 2 CanBiome2 randomized trial, which aims to enroll 128 patients.
The RCC Data
The other two studies focused on FMT in patients with metastatic RCC. In the phase 1 PERFORM study, 20 treatment-naive patients with metastatic RCC added encapsulated healthy-donor FMT to standard ICI-based regimens — most commonly ipilimumab plus nivolumab, with some patients receiving pembrolizumab plus axitinib or pembrolizumab plus lenvatinib.
The primary endpoint was safety defined by the incidence and severity of immune-related adverse events. The safety endpoint was met; 50% of patients (10 of 20) experienced grade 3 immune-related adverse events, and there were no serious FMT-related toxicities and no grade 4 or 5 events.
Among 18 evaluable patients, nine (50%) achieved an objective response, including two who had complete responses (11%). Notably, most treatment responders did not develop any grade 3 or higher immune-related adverse events, the researchers reported.
Finally, in the phase 2a TACITO trial, 45 patients with treatment-naive metastatic RCC were randomly allocated to receive donor FMT or placebo FMT. Patients received three administrations over 6 months — first via colonoscopy then as capsulized doses, alongside pembrolizumab plus axitinib.
The primary endpoint of 12-month progression-free survival narrowly missed statistical significance — 70% vs 41% (P = .053) — but suggested a benefit in the donor FMT group.
“We need more than 1 year to appreciate statistical significance in terms of progression-free survival,” study investigator Gianluca Ianiro, MD, PhD, with Catholic University of the Sacred Heart, Rome, told Medscape Medical News.
As for secondary endpoints, median progression-free survival was significantly longer with donor FMT (24.0 vs 9.0 months; hazard ratio, 0.50; P = .035) and the objective response rate was higher with donor FMT (52% vs 32%).
Why Might FMT Boost ICI Response?
Conceptually, FMT is intended to reshape the gut ecosystem in ways that favor antitumor immunity, and possibly reduce immune dysregulation.
Across these new studies, the mechanistic story is moving beyond the idea that more diversity is good and toward a model that suggests a benefit to removing or suppressing taxa associated with resistance or inflammatory toxicity.
For example, in the TACITO trial, microbiome analysis confirmed that acquisition or loss of specific bacterial strains was associated with 12-month progression-free survival.
Additionally, results of the FMT-LUMINate trial hinted that the therapeutic benefit of FMT may be driven by eliminating harmful bacteria present at baseline, most notably Enterocloster, Clostridium and Streptococcus spp.
“This bacterial depletion was associated with a favorable immunometabolic milieu,” the FMT-LUMINate researchers wrote. Additionally, the results suggest that “failure to eliminate baseline deleterious taxa may sustain an immunosuppressive metabolic and systemic immune milieu that compromises ICI responses.”
Is FMT Ready for Prime Time?
Ianiro told Medscape Medical News he “definitely” thinks microbiome modulation could eventually become part of standard immunotherapy regimens.
Although the “signal” of benefit is clearly there, Davar cautioned that it’s too early to justify routine, off-trial use of FMT specifically to improve ICI response.
“These remain small, proof-of-concept studies. They are not adequately powered trials of fecal transplants and multiple different covariates haven’t been considered,” Davar said.
The study researchers noted that issues around donor selection and availability, dosing schedules, product standardization, and safety risk stratification need to be resolved.
For example, TACITO’s real-world experience shows logistics can matter. Delays occurred due to capsule unavailability and other scheduling barriers, which led to late dosing and missed or shifted treatments in some patients.
That’s a reminder that scaling FMT for oncology would require robust manufacturing, distribution, and time-sensitive coordination with ICI start dates.
More broadly, “whether FMT is the most suitable method of essentially changing the gut microbiome remains unclear,” explained Davar, who suggested that engineered microbiome therapeutics or tailored therapies may be a preferable, more scalable and tailored long-term solution.
Overall, does this new research provide impetus to develop stool banks? “Probably not,” Davar said.
But is it a call for interested parties to think about clinical trials and experimental products that could influence the gut microbiome? “Those are all probably good ideas,” he said.
The PERFORM, TACITO and FMT-LUMINate trials had no commercial funding. Saman Maleki Vareki, PhD, of the PERFORM trial, is a cofounder of LND Therapeutics Inc and has submitted a US patent application related to FMT donor screening. Ianiro has received personal fees for acting as a speaker for Biocodex and Illumina and for acting as a consultant/advisor for Ferring Therapeutics. Arielle Elkrief, MD, of the FMT-LUMINate trial, has received honoraria from AstraZeneca, Merck, Bristol Myers Squibb, and EMD Serono; consulting fees from EverImmune, NECBio, and Sanofi-Pasteur; and is an inventor on a patent regarding the microbiome and immunotherapy response. Davar had no relevant disclosures.
A version of this article first appeared on Medscape.com.
Can Fecal Transplants Enhance Immunotherapy? New Evidence and Cautions
Can Fecal Transplants Enhance Immunotherapy? New Evidence and Cautions
Melanoma Leads Skin Cancer Malpractice Cases Over 95 Years
Melanoma Leads Skin Cancer Malpractice Cases Over 95 Years
TOPLINE:
In a review of physician-related malpractice cases from 1930 to 2025, melanoma was the most frequently litigated skin cancer, and failure or delay in diagnosis was the most common allegation, with documented death in nearly one third of cases.
METHODOLOGY:
Researchers conducted a review of physician-related medicolegal cases involving skin cancer using the LexisNexis legal database and identified 188 unique cases from 1930 through May 2025.
Cases were included if physicians were named as defendants and the litigation centered on diagnosis or management of a cutaneous malignancy.
Study outcomes examined case characteristics including cancer type, practice setting, defendant specialty, primary allegations, clinical outcomes, and case verdicts across the US.
TAKEAWAY:
Melanoma accounted for 49.5% of litigated cases, followed by squamous cell carcinoma (21.6%), basal cell carcinoma (14.2%), unspecified skin cancer (11.6%), and other rare tumors (3.1%). Death was reported in 29.8% of cases and metastatic disease in 39.9%.
Failure or delay in diagnosis was the leading allegation (38.1%), followed by treatment or management errors (24.2%), misdiagnosis (11.4%), “deliberate indifference” (8.3%), inadequate informed consent (7.5%), and pathology-related errors (7.2%).
Family physicians were the most common defendants (27.5%), followed by dermatologists, including Mohs surgeons (20.1%), and pathologists or dermatopathologists (14.4%), followed by general or plastic surgeons (7.9%), and internists (4.4%). Most cases originated in private practices (59.7%), and New York (16.0%) and California (13.3%) were the states with the most cases.
Among 109 closed cases, 5.5% resulted in plaintiff verdicts, whereas defense verdicts predominated in 55.0%. Plaintiff awards ranged from $10,000 to $4.25 million.
IN PRACTICE:
“This comprehensive review demonstrates that melanoma is the most frequently litigated skin cancer, particularly in cases involving metastatic disease or death, and that family physicians are the most commonly named defendants overall,” the authors wrote. “By examining both allegations and outcomes,” they added, “this analysis provides a pragmatic assessment of real-world litigation exposure and the clinical scenarios that expose physicians to legal proceedings, financial cost, reputational harm, and psychological burden, regardless of case disposition.”
SOURCE:
The study was led by Ghassan Barnawi, MD, Division of Dermatology, McGill University in Montreal, Quebec, Canada, and was published online on February 20, 2026, in the Journal of the American Academy of Dermatology.
LIMITATIONS:
The study relied on published court decisions, which likely underestimated malpractice burden by excluding settlements and unreported claims.
DISCLOSURES:
The study did not receive any funding. The authors reported having no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
The study had no commercial funding. The authors had no relevant disclosures.
A version of this article first appeared on Medscape.com
TOPLINE:
In a review of physician-related malpractice cases from 1930 to 2025, melanoma was the most frequently litigated skin cancer, and failure or delay in diagnosis was the most common allegation, with documented death in nearly one third of cases.
METHODOLOGY:
Researchers conducted a review of physician-related medicolegal cases involving skin cancer using the LexisNexis legal database and identified 188 unique cases from 1930 through May 2025.
Cases were included if physicians were named as defendants and the litigation centered on diagnosis or management of a cutaneous malignancy.
Study outcomes examined case characteristics including cancer type, practice setting, defendant specialty, primary allegations, clinical outcomes, and case verdicts across the US.
TAKEAWAY:
Melanoma accounted for 49.5% of litigated cases, followed by squamous cell carcinoma (21.6%), basal cell carcinoma (14.2%), unspecified skin cancer (11.6%), and other rare tumors (3.1%). Death was reported in 29.8% of cases and metastatic disease in 39.9%.
Failure or delay in diagnosis was the leading allegation (38.1%), followed by treatment or management errors (24.2%), misdiagnosis (11.4%), “deliberate indifference” (8.3%), inadequate informed consent (7.5%), and pathology-related errors (7.2%).
Family physicians were the most common defendants (27.5%), followed by dermatologists, including Mohs surgeons (20.1%), and pathologists or dermatopathologists (14.4%), followed by general or plastic surgeons (7.9%), and internists (4.4%). Most cases originated in private practices (59.7%), and New York (16.0%) and California (13.3%) were the states with the most cases.
Among 109 closed cases, 5.5% resulted in plaintiff verdicts, whereas defense verdicts predominated in 55.0%. Plaintiff awards ranged from $10,000 to $4.25 million.
IN PRACTICE:
“This comprehensive review demonstrates that melanoma is the most frequently litigated skin cancer, particularly in cases involving metastatic disease or death, and that family physicians are the most commonly named defendants overall,” the authors wrote. “By examining both allegations and outcomes,” they added, “this analysis provides a pragmatic assessment of real-world litigation exposure and the clinical scenarios that expose physicians to legal proceedings, financial cost, reputational harm, and psychological burden, regardless of case disposition.”
SOURCE:
The study was led by Ghassan Barnawi, MD, Division of Dermatology, McGill University in Montreal, Quebec, Canada, and was published online on February 20, 2026, in the Journal of the American Academy of Dermatology.
LIMITATIONS:
The study relied on published court decisions, which likely underestimated malpractice burden by excluding settlements and unreported claims.
DISCLOSURES:
The study did not receive any funding. The authors reported having no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
The study had no commercial funding. The authors had no relevant disclosures.
A version of this article first appeared on Medscape.com
TOPLINE:
In a review of physician-related malpractice cases from 1930 to 2025, melanoma was the most frequently litigated skin cancer, and failure or delay in diagnosis was the most common allegation, with documented death in nearly one third of cases.
METHODOLOGY:
Researchers conducted a review of physician-related medicolegal cases involving skin cancer using the LexisNexis legal database and identified 188 unique cases from 1930 through May 2025.
Cases were included if physicians were named as defendants and the litigation centered on diagnosis or management of a cutaneous malignancy.
Study outcomes examined case characteristics including cancer type, practice setting, defendant specialty, primary allegations, clinical outcomes, and case verdicts across the US.
TAKEAWAY:
Melanoma accounted for 49.5% of litigated cases, followed by squamous cell carcinoma (21.6%), basal cell carcinoma (14.2%), unspecified skin cancer (11.6%), and other rare tumors (3.1%). Death was reported in 29.8% of cases and metastatic disease in 39.9%.
Failure or delay in diagnosis was the leading allegation (38.1%), followed by treatment or management errors (24.2%), misdiagnosis (11.4%), “deliberate indifference” (8.3%), inadequate informed consent (7.5%), and pathology-related errors (7.2%).
Family physicians were the most common defendants (27.5%), followed by dermatologists, including Mohs surgeons (20.1%), and pathologists or dermatopathologists (14.4%), followed by general or plastic surgeons (7.9%), and internists (4.4%). Most cases originated in private practices (59.7%), and New York (16.0%) and California (13.3%) were the states with the most cases.
Among 109 closed cases, 5.5% resulted in plaintiff verdicts, whereas defense verdicts predominated in 55.0%. Plaintiff awards ranged from $10,000 to $4.25 million.
IN PRACTICE:
“This comprehensive review demonstrates that melanoma is the most frequently litigated skin cancer, particularly in cases involving metastatic disease or death, and that family physicians are the most commonly named defendants overall,” the authors wrote. “By examining both allegations and outcomes,” they added, “this analysis provides a pragmatic assessment of real-world litigation exposure and the clinical scenarios that expose physicians to legal proceedings, financial cost, reputational harm, and psychological burden, regardless of case disposition.”
SOURCE:
The study was led by Ghassan Barnawi, MD, Division of Dermatology, McGill University in Montreal, Quebec, Canada, and was published online on February 20, 2026, in the Journal of the American Academy of Dermatology.
LIMITATIONS:
The study relied on published court decisions, which likely underestimated malpractice burden by excluding settlements and unreported claims.
DISCLOSURES:
The study did not receive any funding. The authors reported having no relevant conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
The study had no commercial funding. The authors had no relevant disclosures.
A version of this article first appeared on Medscape.com
Melanoma Leads Skin Cancer Malpractice Cases Over 95 Years
Melanoma Leads Skin Cancer Malpractice Cases Over 95 Years
Flu Shot May Boost Survival in Patients With Cancer on ICIs
Flu Shot May Boost Survival in Patients With Cancer on ICIs
Patients with advanced cancer treated with immune checkpoint inhibitors appear to have a survival benefit if they receive influenza vaccination, a new retrospective analysis found. The results also suggest no increase in the risk for immune-related adverse events (IRAEs) in these patients and that the improvement in survival outcomes may be stronger among those with cutaneous malignant melanoma.
“Our findings align with a growing body of evidence, mainly from retrospective studies, that suggest a potential association between influenza vaccination during immune checkpoint inhibitor treatment and improved survival among patients with cancer,” wrote senior author Antonis Valachis, MD, PhD, and colleagues in an article published in JCO Clinical Practice on February 9. “An additional clinically relevant observation is that the association between influenza vaccination and survival may vary by tumor type.”
The new research supports “current recommendations to offer influenza vaccination to all patients undergoing cancer therapy, including those receiving the drugs,” Valachis, of the Department of Oncology, Örebro University in Örebro, Sweden, and his coauthors wrote.
“What we observed is that influenza vaccination is safe for patients under immunotherapy treatment,” Valachis told Medscape Medical News. But “whether influenza vaccination can be used to boost immunotherapy effectiveness should be tested in a study with a different design,” such as a prospective interventional trial.
Discussing potential explanations for why influenza vaccination could affect immunotherapy outcomes without affecting rates of IRAEs, Valachis said that this “cannot be answered within the constraints of our study design, since all patients were treated with immunotherapy.”
It may nevertheless be hypothesized that “immune activation triggered by vaccination preferentially stimulates immune mechanisms that enhance immunotherapy efficacy, while sparing those that contribute to IRAEs.”
Steady Was 'Relatively Modestly Sized'
Question marks were raised over the study itself and, as a result, its findings.
Justin Jee, MD, PhD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News that there are “a lot of challenges when looking at retrospective data.”
“The authors did a very reasonable job of trying to control for confounders and certain time dependent issues, like immortality bias,” he said. “That said, it’s a relatively modestly sized retrospective study for looking at something that has enormous potential for confounding bias that really can’t be captured with any standard statistical method.”
Jee pointed to factors such as providers potentially being more likely to refer people for vaccination if they’re healthier “vs if the patient is in hospice care,” or individuals simply not getting vaccinated because it is not uppermost in their mind.
“Those things are very, very difficult to control for.”
Jee also said he believes the benefit with influenza vaccination being stronger in cutaneous malignant melanoma could be a study artifact, while the lack of difference in rates of IRAEs could be the result of selection bias, but “it’s just impossible to say with a study like this.”
“I’ve seen several studies looking at both COVID and flu vaccines and whether or not they improve immune checkpoint blockade efficacy,” he added, explaining that “some of them say COVID vaccine good, flu vaccine not as good; others say both flu and COVID vaccines good; others say flu vaccine good, COVID vaccine not as good.”
All Patients With Cancer Should Be Vaccinated
What is clear is that “patients with cancer are [at] especially high risk of developing complications from viral illnesses, including flu, including COVID, and vaccines are a very important part of reducing morbidity, mortality, and spread,” Jee said. The “big picture” is that everyone should get the influenza vaccine, especially patients with cancer, “so in that sense I agree with that part of the conclusion of the paper” and that’s “an important message.”
Mini Kamboj, MD, chief medical epidemiologist at Memorial Sloan Kettering Cancer Center, agreed, saying that the results are “consistent with other research showing that vaccines are safe and beneficial for patients on checkpoint inhibitors.”
“While vaccinated patients with melanoma showed the greatest survival benefit, the authors note small sample size and unrecognized differences between the groups as a potential explanation for their findings. This does not change vaccine recommendations as evidence already supports flu vaccine safety and effectiveness in people with lung cancer on checkpoint inhibitors.”
Nearly 600 Patients With Advanced Cancer
The researchers performed a retrospective cohort study of patients from three regions in Sweden who had advanced solid tumors and were treated with PD-1 or PD-L1 inhibitor monotherapy, or PD-1 combination therapy with a cytotoxic T-lymphocyte-associated protein 4 inhibitor, between January 1, 2016, until December 31, 2021. Treatment was given either routinely or as part of a clinical trial.
Electronic medical records were examined to gather data on a range of variables, including age at diagnosis, sex, Charlson Comorbidity Index, type of cancer, primary treatment at diagnosis, number of previous lines of treatment, best treatment response, IRAEs, influenza vaccination status, and date and cause of death.
In all, 587 patients were treated with immune checkpoint inhibition over the study period. They had a median age of 66 years, and 58.1% were men. The most common malignancies were nonsmall cell lung cancer (NSCLC), cutaneous malignant melanoma (32.5%), and renal cell carcinoma (14.7%).
The most commonly used immune checkpoint inhibitor was nivolumab, which was administered to 47.9% of patients, followed by pembrolizumab (34.6%), atezolizumab (9.4%), and nivolumab plus ipilimumab (6.8%).
Only Patients With Malignant Melanoma Benefit
Over the study period, 17.7% of patients underwent influenza vaccination, at a median time between initiation of immune checkpoint inhibition and vaccination of 2 months. Ninety per cent of patients received the vaccine within 9 months of starting treatment.
Time-dependent Cox regression analysis revealed that real-world progression-free survival (rwPFS) was significantly longer with vaccinated patients than unvaccinated patients at a hazard ratio of 0.59 (95% CI, 0.44-0.79), as was overall survival, at a hazard ratio of 0.56 (95% CI, 0.42-0.75).
There was no significant difference in rwPFS and overall survival between vaccinated and unvaccinated patients among those with NSCLC, but significant differences were seen in those with cutaneous malignant melanoma, at hazard ratios of 0.58 (95% CI, 0.36-0.96) and 0.58 (95% CI, 0.36-0.96), respectively.
Restricting the analysis to immune checkpoint inhibitor monotherapy indicated that vaccinated patients had significantly longer rwPFS and overall survival than unvaccinated patients, at hazard ratios of 0.58 (95% CI, 0.43-0.79) and 0.50 (95% CI, 0.38-0.76), respectively.
Finally, the team found that there were no significant differences in the rates of any grade IRAEs between vaccinated and unvaccinated patients, at 48.4% vs 51.2% (P = .455), or in rates of multiple IRAEs, at 15.1% vs 19.2% (P = .297). The therapeutic management and outcomes of IRAEs were also comparable.
No funding or relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
Patients with advanced cancer treated with immune checkpoint inhibitors appear to have a survival benefit if they receive influenza vaccination, a new retrospective analysis found. The results also suggest no increase in the risk for immune-related adverse events (IRAEs) in these patients and that the improvement in survival outcomes may be stronger among those with cutaneous malignant melanoma.
“Our findings align with a growing body of evidence, mainly from retrospective studies, that suggest a potential association between influenza vaccination during immune checkpoint inhibitor treatment and improved survival among patients with cancer,” wrote senior author Antonis Valachis, MD, PhD, and colleagues in an article published in JCO Clinical Practice on February 9. “An additional clinically relevant observation is that the association between influenza vaccination and survival may vary by tumor type.”
The new research supports “current recommendations to offer influenza vaccination to all patients undergoing cancer therapy, including those receiving the drugs,” Valachis, of the Department of Oncology, Örebro University in Örebro, Sweden, and his coauthors wrote.
“What we observed is that influenza vaccination is safe for patients under immunotherapy treatment,” Valachis told Medscape Medical News. But “whether influenza vaccination can be used to boost immunotherapy effectiveness should be tested in a study with a different design,” such as a prospective interventional trial.
Discussing potential explanations for why influenza vaccination could affect immunotherapy outcomes without affecting rates of IRAEs, Valachis said that this “cannot be answered within the constraints of our study design, since all patients were treated with immunotherapy.”
It may nevertheless be hypothesized that “immune activation triggered by vaccination preferentially stimulates immune mechanisms that enhance immunotherapy efficacy, while sparing those that contribute to IRAEs.”
Steady Was 'Relatively Modestly Sized'
Question marks were raised over the study itself and, as a result, its findings.
Justin Jee, MD, PhD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News that there are “a lot of challenges when looking at retrospective data.”
“The authors did a very reasonable job of trying to control for confounders and certain time dependent issues, like immortality bias,” he said. “That said, it’s a relatively modestly sized retrospective study for looking at something that has enormous potential for confounding bias that really can’t be captured with any standard statistical method.”
Jee pointed to factors such as providers potentially being more likely to refer people for vaccination if they’re healthier “vs if the patient is in hospice care,” or individuals simply not getting vaccinated because it is not uppermost in their mind.
“Those things are very, very difficult to control for.”
Jee also said he believes the benefit with influenza vaccination being stronger in cutaneous malignant melanoma could be a study artifact, while the lack of difference in rates of IRAEs could be the result of selection bias, but “it’s just impossible to say with a study like this.”
“I’ve seen several studies looking at both COVID and flu vaccines and whether or not they improve immune checkpoint blockade efficacy,” he added, explaining that “some of them say COVID vaccine good, flu vaccine not as good; others say both flu and COVID vaccines good; others say flu vaccine good, COVID vaccine not as good.”
All Patients With Cancer Should Be Vaccinated
What is clear is that “patients with cancer are [at] especially high risk of developing complications from viral illnesses, including flu, including COVID, and vaccines are a very important part of reducing morbidity, mortality, and spread,” Jee said. The “big picture” is that everyone should get the influenza vaccine, especially patients with cancer, “so in that sense I agree with that part of the conclusion of the paper” and that’s “an important message.”
Mini Kamboj, MD, chief medical epidemiologist at Memorial Sloan Kettering Cancer Center, agreed, saying that the results are “consistent with other research showing that vaccines are safe and beneficial for patients on checkpoint inhibitors.”
“While vaccinated patients with melanoma showed the greatest survival benefit, the authors note small sample size and unrecognized differences between the groups as a potential explanation for their findings. This does not change vaccine recommendations as evidence already supports flu vaccine safety and effectiveness in people with lung cancer on checkpoint inhibitors.”
Nearly 600 Patients With Advanced Cancer
The researchers performed a retrospective cohort study of patients from three regions in Sweden who had advanced solid tumors and were treated with PD-1 or PD-L1 inhibitor monotherapy, or PD-1 combination therapy with a cytotoxic T-lymphocyte-associated protein 4 inhibitor, between January 1, 2016, until December 31, 2021. Treatment was given either routinely or as part of a clinical trial.
Electronic medical records were examined to gather data on a range of variables, including age at diagnosis, sex, Charlson Comorbidity Index, type of cancer, primary treatment at diagnosis, number of previous lines of treatment, best treatment response, IRAEs, influenza vaccination status, and date and cause of death.
In all, 587 patients were treated with immune checkpoint inhibition over the study period. They had a median age of 66 years, and 58.1% were men. The most common malignancies were nonsmall cell lung cancer (NSCLC), cutaneous malignant melanoma (32.5%), and renal cell carcinoma (14.7%).
The most commonly used immune checkpoint inhibitor was nivolumab, which was administered to 47.9% of patients, followed by pembrolizumab (34.6%), atezolizumab (9.4%), and nivolumab plus ipilimumab (6.8%).
Only Patients With Malignant Melanoma Benefit
Over the study period, 17.7% of patients underwent influenza vaccination, at a median time between initiation of immune checkpoint inhibition and vaccination of 2 months. Ninety per cent of patients received the vaccine within 9 months of starting treatment.
Time-dependent Cox regression analysis revealed that real-world progression-free survival (rwPFS) was significantly longer with vaccinated patients than unvaccinated patients at a hazard ratio of 0.59 (95% CI, 0.44-0.79), as was overall survival, at a hazard ratio of 0.56 (95% CI, 0.42-0.75).
There was no significant difference in rwPFS and overall survival between vaccinated and unvaccinated patients among those with NSCLC, but significant differences were seen in those with cutaneous malignant melanoma, at hazard ratios of 0.58 (95% CI, 0.36-0.96) and 0.58 (95% CI, 0.36-0.96), respectively.
Restricting the analysis to immune checkpoint inhibitor monotherapy indicated that vaccinated patients had significantly longer rwPFS and overall survival than unvaccinated patients, at hazard ratios of 0.58 (95% CI, 0.43-0.79) and 0.50 (95% CI, 0.38-0.76), respectively.
Finally, the team found that there were no significant differences in the rates of any grade IRAEs between vaccinated and unvaccinated patients, at 48.4% vs 51.2% (P = .455), or in rates of multiple IRAEs, at 15.1% vs 19.2% (P = .297). The therapeutic management and outcomes of IRAEs were also comparable.
No funding or relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
Patients with advanced cancer treated with immune checkpoint inhibitors appear to have a survival benefit if they receive influenza vaccination, a new retrospective analysis found. The results also suggest no increase in the risk for immune-related adverse events (IRAEs) in these patients and that the improvement in survival outcomes may be stronger among those with cutaneous malignant melanoma.
“Our findings align with a growing body of evidence, mainly from retrospective studies, that suggest a potential association between influenza vaccination during immune checkpoint inhibitor treatment and improved survival among patients with cancer,” wrote senior author Antonis Valachis, MD, PhD, and colleagues in an article published in JCO Clinical Practice on February 9. “An additional clinically relevant observation is that the association between influenza vaccination and survival may vary by tumor type.”
The new research supports “current recommendations to offer influenza vaccination to all patients undergoing cancer therapy, including those receiving the drugs,” Valachis, of the Department of Oncology, Örebro University in Örebro, Sweden, and his coauthors wrote.
“What we observed is that influenza vaccination is safe for patients under immunotherapy treatment,” Valachis told Medscape Medical News. But “whether influenza vaccination can be used to boost immunotherapy effectiveness should be tested in a study with a different design,” such as a prospective interventional trial.
Discussing potential explanations for why influenza vaccination could affect immunotherapy outcomes without affecting rates of IRAEs, Valachis said that this “cannot be answered within the constraints of our study design, since all patients were treated with immunotherapy.”
It may nevertheless be hypothesized that “immune activation triggered by vaccination preferentially stimulates immune mechanisms that enhance immunotherapy efficacy, while sparing those that contribute to IRAEs.”
Steady Was 'Relatively Modestly Sized'
Question marks were raised over the study itself and, as a result, its findings.
Justin Jee, MD, PhD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News that there are “a lot of challenges when looking at retrospective data.”
“The authors did a very reasonable job of trying to control for confounders and certain time dependent issues, like immortality bias,” he said. “That said, it’s a relatively modestly sized retrospective study for looking at something that has enormous potential for confounding bias that really can’t be captured with any standard statistical method.”
Jee pointed to factors such as providers potentially being more likely to refer people for vaccination if they’re healthier “vs if the patient is in hospice care,” or individuals simply not getting vaccinated because it is not uppermost in their mind.
“Those things are very, very difficult to control for.”
Jee also said he believes the benefit with influenza vaccination being stronger in cutaneous malignant melanoma could be a study artifact, while the lack of difference in rates of IRAEs could be the result of selection bias, but “it’s just impossible to say with a study like this.”
“I’ve seen several studies looking at both COVID and flu vaccines and whether or not they improve immune checkpoint blockade efficacy,” he added, explaining that “some of them say COVID vaccine good, flu vaccine not as good; others say both flu and COVID vaccines good; others say flu vaccine good, COVID vaccine not as good.”
All Patients With Cancer Should Be Vaccinated
What is clear is that “patients with cancer are [at] especially high risk of developing complications from viral illnesses, including flu, including COVID, and vaccines are a very important part of reducing morbidity, mortality, and spread,” Jee said. The “big picture” is that everyone should get the influenza vaccine, especially patients with cancer, “so in that sense I agree with that part of the conclusion of the paper” and that’s “an important message.”
Mini Kamboj, MD, chief medical epidemiologist at Memorial Sloan Kettering Cancer Center, agreed, saying that the results are “consistent with other research showing that vaccines are safe and beneficial for patients on checkpoint inhibitors.”
“While vaccinated patients with melanoma showed the greatest survival benefit, the authors note small sample size and unrecognized differences between the groups as a potential explanation for their findings. This does not change vaccine recommendations as evidence already supports flu vaccine safety and effectiveness in people with lung cancer on checkpoint inhibitors.”
Nearly 600 Patients With Advanced Cancer
The researchers performed a retrospective cohort study of patients from three regions in Sweden who had advanced solid tumors and were treated with PD-1 or PD-L1 inhibitor monotherapy, or PD-1 combination therapy with a cytotoxic T-lymphocyte-associated protein 4 inhibitor, between January 1, 2016, until December 31, 2021. Treatment was given either routinely or as part of a clinical trial.
Electronic medical records were examined to gather data on a range of variables, including age at diagnosis, sex, Charlson Comorbidity Index, type of cancer, primary treatment at diagnosis, number of previous lines of treatment, best treatment response, IRAEs, influenza vaccination status, and date and cause of death.
In all, 587 patients were treated with immune checkpoint inhibition over the study period. They had a median age of 66 years, and 58.1% were men. The most common malignancies were nonsmall cell lung cancer (NSCLC), cutaneous malignant melanoma (32.5%), and renal cell carcinoma (14.7%).
The most commonly used immune checkpoint inhibitor was nivolumab, which was administered to 47.9% of patients, followed by pembrolizumab (34.6%), atezolizumab (9.4%), and nivolumab plus ipilimumab (6.8%).
Only Patients With Malignant Melanoma Benefit
Over the study period, 17.7% of patients underwent influenza vaccination, at a median time between initiation of immune checkpoint inhibition and vaccination of 2 months. Ninety per cent of patients received the vaccine within 9 months of starting treatment.
Time-dependent Cox regression analysis revealed that real-world progression-free survival (rwPFS) was significantly longer with vaccinated patients than unvaccinated patients at a hazard ratio of 0.59 (95% CI, 0.44-0.79), as was overall survival, at a hazard ratio of 0.56 (95% CI, 0.42-0.75).
There was no significant difference in rwPFS and overall survival between vaccinated and unvaccinated patients among those with NSCLC, but significant differences were seen in those with cutaneous malignant melanoma, at hazard ratios of 0.58 (95% CI, 0.36-0.96) and 0.58 (95% CI, 0.36-0.96), respectively.
Restricting the analysis to immune checkpoint inhibitor monotherapy indicated that vaccinated patients had significantly longer rwPFS and overall survival than unvaccinated patients, at hazard ratios of 0.58 (95% CI, 0.43-0.79) and 0.50 (95% CI, 0.38-0.76), respectively.
Finally, the team found that there were no significant differences in the rates of any grade IRAEs between vaccinated and unvaccinated patients, at 48.4% vs 51.2% (P = .455), or in rates of multiple IRAEs, at 15.1% vs 19.2% (P = .297). The therapeutic management and outcomes of IRAEs were also comparable.
No funding or relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
Flu Shot May Boost Survival in Patients With Cancer on ICIs
Flu Shot May Boost Survival in Patients With Cancer on ICIs
US Vet Study Identifies Risk Factors for Acral Melanoma
US Vet Study Identifies Risk Factors for Acral Melanoma
TOPLINE:
Exposure to Agent Orange, the defoliant used by the US Air Force during the Vietnam War, was one of the factors associated with increased odds of acral melanoma (AM), a rare melanoma subtype affecting palms, soles, and nail units.
METHODOLOGY:
- Researchers conducted a nested case-control study in the Veterans Affairs healthcare system, and identified 1292 veterans (median age, 70.13 years; 94.0% men; 73.4% White, 14.6% Black) with AM through the Veterans Affairs Cancer Registry and a validated natural language processing pipeline from 2000 to 2024.
- Researchers matched each case of AM to 4 individuals with nonacral cutaneous melanoma (CM) and 4 control individuals without melanoma diagnoses, based on diagnosis year and outpatient visit frequency.
- Exposures included age, sex, race, ethnicity, rurality, region, military branch, comorbidities, smoking status, alcohol use, BMI, Agent Orange exposure, prior photosensitizing medications, nevi, and keratinocyte carcinoma.
TAKEAWAY:
- Veterans exposed to Agent Orange had higher odds of AM than individuals with CM (adjusted odds ratio [AOR], 1.31; 95% CI, 1.06-1.62) and control individuals without melanoma (AOR, 1.27; 95% CI, 1.04-1.56).
- Individuals with current smoking habit had lower odds of AM than those with CM (AOR, 0.65; 95% CI, 0.52-0.81) and control individuals without melanoma (AOR, 0.50; 95% CI, 0.40-0.62).
- Patients with prior keratinocyte carcinoma and actinic keratosis had higher odds of AM than control individuals without melanoma but lower odds than those with CM.
- History of nevus was associated with higher odds of acral melanoma compared with individuals without melanoma (AOR, 2.11; 95% CI, 1.49-2.98).
IN PRACTICE:
“Our results support the need for continued investigation of AM as a distinct entity from CM and may inform future evaluations of the associations between [Agent Orange exposure] in veteran populations, as well as those between other environmental exposures in different populations," the study authors wrote. Referring to the “continued search for a better understanding of a potential link” between Agent Orange and melanoma, as well as AM, and other possible etiologic factors for AM, this study “provides a strong impetus to further these research goals and contribute to the investigation of the legacy of the Vietnam War and honor a commitment to the veterans community,” Andrew F. Olshan, PhD, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
SOURCE:
The study was led by Jonathan C. Hwang, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and was published online on February 4 in JAMA Dermatology.
LIMITATIONS:
The case-control design limits causal inference and the findings might not be generalized outside US veterans. Exposure misclassification could be present.
DISCLOSURES:
The study was supported by the Department of Defense and the Department of Veterans Affairs. Several authors reported receiving grants from CU Anschutz Medical Center, Department of Defense, CDMRP Melanoma Research Program, and Merck, Bayer, and Department of Veteran Affairs. They also reported receiving royalty from UpToDate, and being shareholder in many companies, including Apple. NVIDIA, Amazon, Gilead, AstraZeneca, BioNTech, and Moderna. Olshan declared being a member of the National Academies of Sciences, Engineering, and Medicine Veterans and Agent Orange review committee.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
Exposure to Agent Orange, the defoliant used by the US Air Force during the Vietnam War, was one of the factors associated with increased odds of acral melanoma (AM), a rare melanoma subtype affecting palms, soles, and nail units.
METHODOLOGY:
- Researchers conducted a nested case-control study in the Veterans Affairs healthcare system, and identified 1292 veterans (median age, 70.13 years; 94.0% men; 73.4% White, 14.6% Black) with AM through the Veterans Affairs Cancer Registry and a validated natural language processing pipeline from 2000 to 2024.
- Researchers matched each case of AM to 4 individuals with nonacral cutaneous melanoma (CM) and 4 control individuals without melanoma diagnoses, based on diagnosis year and outpatient visit frequency.
- Exposures included age, sex, race, ethnicity, rurality, region, military branch, comorbidities, smoking status, alcohol use, BMI, Agent Orange exposure, prior photosensitizing medications, nevi, and keratinocyte carcinoma.
TAKEAWAY:
- Veterans exposed to Agent Orange had higher odds of AM than individuals with CM (adjusted odds ratio [AOR], 1.31; 95% CI, 1.06-1.62) and control individuals without melanoma (AOR, 1.27; 95% CI, 1.04-1.56).
- Individuals with current smoking habit had lower odds of AM than those with CM (AOR, 0.65; 95% CI, 0.52-0.81) and control individuals without melanoma (AOR, 0.50; 95% CI, 0.40-0.62).
- Patients with prior keratinocyte carcinoma and actinic keratosis had higher odds of AM than control individuals without melanoma but lower odds than those with CM.
- History of nevus was associated with higher odds of acral melanoma compared with individuals without melanoma (AOR, 2.11; 95% CI, 1.49-2.98).
IN PRACTICE:
“Our results support the need for continued investigation of AM as a distinct entity from CM and may inform future evaluations of the associations between [Agent Orange exposure] in veteran populations, as well as those between other environmental exposures in different populations," the study authors wrote. Referring to the “continued search for a better understanding of a potential link” between Agent Orange and melanoma, as well as AM, and other possible etiologic factors for AM, this study “provides a strong impetus to further these research goals and contribute to the investigation of the legacy of the Vietnam War and honor a commitment to the veterans community,” Andrew F. Olshan, PhD, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
SOURCE:
The study was led by Jonathan C. Hwang, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and was published online on February 4 in JAMA Dermatology.
LIMITATIONS:
The case-control design limits causal inference and the findings might not be generalized outside US veterans. Exposure misclassification could be present.
DISCLOSURES:
The study was supported by the Department of Defense and the Department of Veterans Affairs. Several authors reported receiving grants from CU Anschutz Medical Center, Department of Defense, CDMRP Melanoma Research Program, and Merck, Bayer, and Department of Veteran Affairs. They also reported receiving royalty from UpToDate, and being shareholder in many companies, including Apple. NVIDIA, Amazon, Gilead, AstraZeneca, BioNTech, and Moderna. Olshan declared being a member of the National Academies of Sciences, Engineering, and Medicine Veterans and Agent Orange review committee.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
Exposure to Agent Orange, the defoliant used by the US Air Force during the Vietnam War, was one of the factors associated with increased odds of acral melanoma (AM), a rare melanoma subtype affecting palms, soles, and nail units.
METHODOLOGY:
- Researchers conducted a nested case-control study in the Veterans Affairs healthcare system, and identified 1292 veterans (median age, 70.13 years; 94.0% men; 73.4% White, 14.6% Black) with AM through the Veterans Affairs Cancer Registry and a validated natural language processing pipeline from 2000 to 2024.
- Researchers matched each case of AM to 4 individuals with nonacral cutaneous melanoma (CM) and 4 control individuals without melanoma diagnoses, based on diagnosis year and outpatient visit frequency.
- Exposures included age, sex, race, ethnicity, rurality, region, military branch, comorbidities, smoking status, alcohol use, BMI, Agent Orange exposure, prior photosensitizing medications, nevi, and keratinocyte carcinoma.
TAKEAWAY:
- Veterans exposed to Agent Orange had higher odds of AM than individuals with CM (adjusted odds ratio [AOR], 1.31; 95% CI, 1.06-1.62) and control individuals without melanoma (AOR, 1.27; 95% CI, 1.04-1.56).
- Individuals with current smoking habit had lower odds of AM than those with CM (AOR, 0.65; 95% CI, 0.52-0.81) and control individuals without melanoma (AOR, 0.50; 95% CI, 0.40-0.62).
- Patients with prior keratinocyte carcinoma and actinic keratosis had higher odds of AM than control individuals without melanoma but lower odds than those with CM.
- History of nevus was associated with higher odds of acral melanoma compared with individuals without melanoma (AOR, 2.11; 95% CI, 1.49-2.98).
IN PRACTICE:
“Our results support the need for continued investigation of AM as a distinct entity from CM and may inform future evaluations of the associations between [Agent Orange exposure] in veteran populations, as well as those between other environmental exposures in different populations," the study authors wrote. Referring to the “continued search for a better understanding of a potential link” between Agent Orange and melanoma, as well as AM, and other possible etiologic factors for AM, this study “provides a strong impetus to further these research goals and contribute to the investigation of the legacy of the Vietnam War and honor a commitment to the veterans community,” Andrew F. Olshan, PhD, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
SOURCE:
The study was led by Jonathan C. Hwang, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and was published online on February 4 in JAMA Dermatology.
LIMITATIONS:
The case-control design limits causal inference and the findings might not be generalized outside US veterans. Exposure misclassification could be present.
DISCLOSURES:
The study was supported by the Department of Defense and the Department of Veterans Affairs. Several authors reported receiving grants from CU Anschutz Medical Center, Department of Defense, CDMRP Melanoma Research Program, and Merck, Bayer, and Department of Veteran Affairs. They also reported receiving royalty from UpToDate, and being shareholder in many companies, including Apple. NVIDIA, Amazon, Gilead, AstraZeneca, BioNTech, and Moderna. Olshan declared being a member of the National Academies of Sciences, Engineering, and Medicine Veterans and Agent Orange review committee.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
US Vet Study Identifies Risk Factors for Acral Melanoma
US Vet Study Identifies Risk Factors for Acral Melanoma
Screening for Meaning: Do Skin Cancer Screening Events Accomplish Anything?
Screening for Meaning: Do Skin Cancer Screening Events Accomplish Anything?
When Skin Cancer Awareness Month rolls around every May, my social media feed is inundated with posts extolling the benefits of total body skin examinations and the life-saving potential of skin cancer screenings; however, time and again the US Preventive Services Task Force (USPSTF)—the leading authority on evidence-based public health recommendations in the United States—has found the evidence supporting skin cancer screenings to be insufficient. The USPSTF has cited a lack of high-quality studies and inadequate data to recommend screening for the general population, excluding those at elevated risk due to personal, family, or occupational history.1 A 2019 Cochrane review went further, concluding that current evidence refutes the utility of population-based screening for melanoma.2
Despite these findings, skin cancer screenings and total body skin examinations remain popular among patients both with and without a personal or family history of cutaneous malignancy. Indeed, the anecdotal experience of dermatologists worldwide suggests an intangible benefit to screening that persists, even if robust data to support it remain elusive.
Putting aside studies that suggest these screenings help identify melanomas at earlier stages and with reduced Breslow thicknesses,3 there is a crucial benefit from face-to-face interaction between medical professionals and the public during skin cancer screening events or health fairs. This interaction has become especially important in an era when misinformation thrives online and so-called skin care “experts” with no formal training can amass tens of thousands—or even millions—of followers on social media.
So, what are the intangible benefits of the face-to-face interactions that occur naturally during skin cancer screenings? The most obvious is education. While the USPSTF may not recommend routine screening for skin cancer in the general population, it does endorse education for children, adolescents, and adults on the importance of minimizing exposure to UV radiation, particularly those with lighter skin tones.4 Publicly advertised skin cancer screenings at health fairs or other community events may offer an opportunity to raise awareness about sun safety and protection, including the value of peak UV avoidance, sun-protective clothing, and proper sunscreen use; these settings also serve as platforms for health care providers to counter misinformation, including concerns about sunscreen safety both for the patient and the environment, overhyped risks for vitamin D deficiency from sun avoidance, and myths about low skin cancer risk in patients with skin of color.
While the benefits of skin self-examination (SSE) remain uncertain, especially in low-risk populations, screening events provide an opportunity to educate patients on who is most likely to benefit from SSE and in whom the practice may cause more harm than good.5 For higher-risk individuals such as melanoma survivors or those with a strong family history, screening fairs can serve as meaningful touchpoints that reinforce the importance of sun protection and regular examinations with a health care provider. For those eager to perform SSEs, these events offer the chance to teach best practices—how to conduct SSEs effectively, what features to look for (eg, the ABCDE method or the ugly duckling sign), and when to seek professional care.
Finally (and importantly), skin cancer screening events provide peace of mind for patients. Reassurance from a professional about a benign skin lesion can alleviate anxiety that might otherwise lead to emergency or urgent care visits. While cellulitis and other skin infections are the most common dermatologic conditions seen in emergency settings, benign neoplasms and similar nonurgent conditions still contribute a substantial burden to urgent care systems in the United States.6 Outside emergency care, systems-level data support what many of us observe in practice: two of the most common reasons for referral to dermatology are benign neoplasms and epidermoid cysts, accounting for millions of visits annually.7 In fact, recent claims data suggest that the most common diagnosis made in US dermatology clinics in 2023 was (you guessed it!) seborrheic keratosis.8
What if instead of requiring a patient to wait weeks for a primary care appointment and months for a dermatology referral—all while worrying about a rapidly growing pigmented lesion and incurring costs in copays, travel, lost wages, and time away from work—we offered a fast, trustworthy, and free evaluation that meets the patient where they live, work, or socialize? An evaluation that not only eases their fears but also provides meaningful education about skin cancer prevention and screening guidelines? While precautions must of course be taken to ensure that the quality and completeness of such an examination equals that of an in-clinic evaluation, if services of this quality can be provided, public screening events may offer a simple, accessible, and valuable solution that delivers peace of mind and helps reduce unnecessary strain on emergency, primary, and specialty care networks.
- US Preventive Services Task Force; Mangione CM, Barry MJ, Nicholson WK, et al. Screening for skin cancer: US Preventive Services Task Force recommendation statement. JAMA. 2023;329:1290-1295. doi:10.1001/jama.2023.4342
- Johansson M, Brodersen J, Gøtzsche PC. Screening for reducing morbidity and mortality in malignant melanoma. Cochrane Database Syst Rev. 2019;6:CD012352. doi:10.1002/14651858.CD012352.pub2
- Matsumoto M, Wack S, Weinstock MA, et al. Five-year outcomes of a melanoma screening initiative in a large health care system. JAMA Dermatol. 2022;158:504-512. doi:10.1001/jamadermatol.2022.0253
- Grossman DC, Curry SJ, Owens DK, et al. Behavioral counseling to prevent skin cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:1134-1142.
- Ersser SJ, Effah A, Dyson J, et al. Effectiveness of interventions to support the early detection of skin cancer through skin self‐examination: a systematic review and meta‐analysis. Br J Dermatol. 2019;180:1339-1347. doi:10.1111/bjd.17529
- Nadkarni A, Domeisen N, Hill D, et al. The most common dermatology diagnoses in the emergency department. J Am Acad Dermatol. 2016;75:1261-1266. doi:10.1016/j.jaad.2016.07.054
- Grada A, Muddasani S, Fleischer AB Jr. Trends in office visits for the five most common skin diseases in the United States. J Clin Aesthet Dermatol. 2022;15:E82-E86.
- Definitive Healthcare. What are the most common diagnoses by dermatologists? Published January 31, 2024. Accessed May 5, 2025. https://www.definitivehc.com/resources/healthcare-insights/top-dermatologist-diagnoses
When Skin Cancer Awareness Month rolls around every May, my social media feed is inundated with posts extolling the benefits of total body skin examinations and the life-saving potential of skin cancer screenings; however, time and again the US Preventive Services Task Force (USPSTF)—the leading authority on evidence-based public health recommendations in the United States—has found the evidence supporting skin cancer screenings to be insufficient. The USPSTF has cited a lack of high-quality studies and inadequate data to recommend screening for the general population, excluding those at elevated risk due to personal, family, or occupational history.1 A 2019 Cochrane review went further, concluding that current evidence refutes the utility of population-based screening for melanoma.2
Despite these findings, skin cancer screenings and total body skin examinations remain popular among patients both with and without a personal or family history of cutaneous malignancy. Indeed, the anecdotal experience of dermatologists worldwide suggests an intangible benefit to screening that persists, even if robust data to support it remain elusive.
Putting aside studies that suggest these screenings help identify melanomas at earlier stages and with reduced Breslow thicknesses,3 there is a crucial benefit from face-to-face interaction between medical professionals and the public during skin cancer screening events or health fairs. This interaction has become especially important in an era when misinformation thrives online and so-called skin care “experts” with no formal training can amass tens of thousands—or even millions—of followers on social media.
So, what are the intangible benefits of the face-to-face interactions that occur naturally during skin cancer screenings? The most obvious is education. While the USPSTF may not recommend routine screening for skin cancer in the general population, it does endorse education for children, adolescents, and adults on the importance of minimizing exposure to UV radiation, particularly those with lighter skin tones.4 Publicly advertised skin cancer screenings at health fairs or other community events may offer an opportunity to raise awareness about sun safety and protection, including the value of peak UV avoidance, sun-protective clothing, and proper sunscreen use; these settings also serve as platforms for health care providers to counter misinformation, including concerns about sunscreen safety both for the patient and the environment, overhyped risks for vitamin D deficiency from sun avoidance, and myths about low skin cancer risk in patients with skin of color.
While the benefits of skin self-examination (SSE) remain uncertain, especially in low-risk populations, screening events provide an opportunity to educate patients on who is most likely to benefit from SSE and in whom the practice may cause more harm than good.5 For higher-risk individuals such as melanoma survivors or those with a strong family history, screening fairs can serve as meaningful touchpoints that reinforce the importance of sun protection and regular examinations with a health care provider. For those eager to perform SSEs, these events offer the chance to teach best practices—how to conduct SSEs effectively, what features to look for (eg, the ABCDE method or the ugly duckling sign), and when to seek professional care.
Finally (and importantly), skin cancer screening events provide peace of mind for patients. Reassurance from a professional about a benign skin lesion can alleviate anxiety that might otherwise lead to emergency or urgent care visits. While cellulitis and other skin infections are the most common dermatologic conditions seen in emergency settings, benign neoplasms and similar nonurgent conditions still contribute a substantial burden to urgent care systems in the United States.6 Outside emergency care, systems-level data support what many of us observe in practice: two of the most common reasons for referral to dermatology are benign neoplasms and epidermoid cysts, accounting for millions of visits annually.7 In fact, recent claims data suggest that the most common diagnosis made in US dermatology clinics in 2023 was (you guessed it!) seborrheic keratosis.8
What if instead of requiring a patient to wait weeks for a primary care appointment and months for a dermatology referral—all while worrying about a rapidly growing pigmented lesion and incurring costs in copays, travel, lost wages, and time away from work—we offered a fast, trustworthy, and free evaluation that meets the patient where they live, work, or socialize? An evaluation that not only eases their fears but also provides meaningful education about skin cancer prevention and screening guidelines? While precautions must of course be taken to ensure that the quality and completeness of such an examination equals that of an in-clinic evaluation, if services of this quality can be provided, public screening events may offer a simple, accessible, and valuable solution that delivers peace of mind and helps reduce unnecessary strain on emergency, primary, and specialty care networks.
When Skin Cancer Awareness Month rolls around every May, my social media feed is inundated with posts extolling the benefits of total body skin examinations and the life-saving potential of skin cancer screenings; however, time and again the US Preventive Services Task Force (USPSTF)—the leading authority on evidence-based public health recommendations in the United States—has found the evidence supporting skin cancer screenings to be insufficient. The USPSTF has cited a lack of high-quality studies and inadequate data to recommend screening for the general population, excluding those at elevated risk due to personal, family, or occupational history.1 A 2019 Cochrane review went further, concluding that current evidence refutes the utility of population-based screening for melanoma.2
Despite these findings, skin cancer screenings and total body skin examinations remain popular among patients both with and without a personal or family history of cutaneous malignancy. Indeed, the anecdotal experience of dermatologists worldwide suggests an intangible benefit to screening that persists, even if robust data to support it remain elusive.
Putting aside studies that suggest these screenings help identify melanomas at earlier stages and with reduced Breslow thicknesses,3 there is a crucial benefit from face-to-face interaction between medical professionals and the public during skin cancer screening events or health fairs. This interaction has become especially important in an era when misinformation thrives online and so-called skin care “experts” with no formal training can amass tens of thousands—or even millions—of followers on social media.
So, what are the intangible benefits of the face-to-face interactions that occur naturally during skin cancer screenings? The most obvious is education. While the USPSTF may not recommend routine screening for skin cancer in the general population, it does endorse education for children, adolescents, and adults on the importance of minimizing exposure to UV radiation, particularly those with lighter skin tones.4 Publicly advertised skin cancer screenings at health fairs or other community events may offer an opportunity to raise awareness about sun safety and protection, including the value of peak UV avoidance, sun-protective clothing, and proper sunscreen use; these settings also serve as platforms for health care providers to counter misinformation, including concerns about sunscreen safety both for the patient and the environment, overhyped risks for vitamin D deficiency from sun avoidance, and myths about low skin cancer risk in patients with skin of color.
While the benefits of skin self-examination (SSE) remain uncertain, especially in low-risk populations, screening events provide an opportunity to educate patients on who is most likely to benefit from SSE and in whom the practice may cause more harm than good.5 For higher-risk individuals such as melanoma survivors or those with a strong family history, screening fairs can serve as meaningful touchpoints that reinforce the importance of sun protection and regular examinations with a health care provider. For those eager to perform SSEs, these events offer the chance to teach best practices—how to conduct SSEs effectively, what features to look for (eg, the ABCDE method or the ugly duckling sign), and when to seek professional care.
Finally (and importantly), skin cancer screening events provide peace of mind for patients. Reassurance from a professional about a benign skin lesion can alleviate anxiety that might otherwise lead to emergency or urgent care visits. While cellulitis and other skin infections are the most common dermatologic conditions seen in emergency settings, benign neoplasms and similar nonurgent conditions still contribute a substantial burden to urgent care systems in the United States.6 Outside emergency care, systems-level data support what many of us observe in practice: two of the most common reasons for referral to dermatology are benign neoplasms and epidermoid cysts, accounting for millions of visits annually.7 In fact, recent claims data suggest that the most common diagnosis made in US dermatology clinics in 2023 was (you guessed it!) seborrheic keratosis.8
What if instead of requiring a patient to wait weeks for a primary care appointment and months for a dermatology referral—all while worrying about a rapidly growing pigmented lesion and incurring costs in copays, travel, lost wages, and time away from work—we offered a fast, trustworthy, and free evaluation that meets the patient where they live, work, or socialize? An evaluation that not only eases their fears but also provides meaningful education about skin cancer prevention and screening guidelines? While precautions must of course be taken to ensure that the quality and completeness of such an examination equals that of an in-clinic evaluation, if services of this quality can be provided, public screening events may offer a simple, accessible, and valuable solution that delivers peace of mind and helps reduce unnecessary strain on emergency, primary, and specialty care networks.
- US Preventive Services Task Force; Mangione CM, Barry MJ, Nicholson WK, et al. Screening for skin cancer: US Preventive Services Task Force recommendation statement. JAMA. 2023;329:1290-1295. doi:10.1001/jama.2023.4342
- Johansson M, Brodersen J, Gøtzsche PC. Screening for reducing morbidity and mortality in malignant melanoma. Cochrane Database Syst Rev. 2019;6:CD012352. doi:10.1002/14651858.CD012352.pub2
- Matsumoto M, Wack S, Weinstock MA, et al. Five-year outcomes of a melanoma screening initiative in a large health care system. JAMA Dermatol. 2022;158:504-512. doi:10.1001/jamadermatol.2022.0253
- Grossman DC, Curry SJ, Owens DK, et al. Behavioral counseling to prevent skin cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:1134-1142.
- Ersser SJ, Effah A, Dyson J, et al. Effectiveness of interventions to support the early detection of skin cancer through skin self‐examination: a systematic review and meta‐analysis. Br J Dermatol. 2019;180:1339-1347. doi:10.1111/bjd.17529
- Nadkarni A, Domeisen N, Hill D, et al. The most common dermatology diagnoses in the emergency department. J Am Acad Dermatol. 2016;75:1261-1266. doi:10.1016/j.jaad.2016.07.054
- Grada A, Muddasani S, Fleischer AB Jr. Trends in office visits for the five most common skin diseases in the United States. J Clin Aesthet Dermatol. 2022;15:E82-E86.
- Definitive Healthcare. What are the most common diagnoses by dermatologists? Published January 31, 2024. Accessed May 5, 2025. https://www.definitivehc.com/resources/healthcare-insights/top-dermatologist-diagnoses
- US Preventive Services Task Force; Mangione CM, Barry MJ, Nicholson WK, et al. Screening for skin cancer: US Preventive Services Task Force recommendation statement. JAMA. 2023;329:1290-1295. doi:10.1001/jama.2023.4342
- Johansson M, Brodersen J, Gøtzsche PC. Screening for reducing morbidity and mortality in malignant melanoma. Cochrane Database Syst Rev. 2019;6:CD012352. doi:10.1002/14651858.CD012352.pub2
- Matsumoto M, Wack S, Weinstock MA, et al. Five-year outcomes of a melanoma screening initiative in a large health care system. JAMA Dermatol. 2022;158:504-512. doi:10.1001/jamadermatol.2022.0253
- Grossman DC, Curry SJ, Owens DK, et al. Behavioral counseling to prevent skin cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:1134-1142.
- Ersser SJ, Effah A, Dyson J, et al. Effectiveness of interventions to support the early detection of skin cancer through skin self‐examination: a systematic review and meta‐analysis. Br J Dermatol. 2019;180:1339-1347. doi:10.1111/bjd.17529
- Nadkarni A, Domeisen N, Hill D, et al. The most common dermatology diagnoses in the emergency department. J Am Acad Dermatol. 2016;75:1261-1266. doi:10.1016/j.jaad.2016.07.054
- Grada A, Muddasani S, Fleischer AB Jr. Trends in office visits for the five most common skin diseases in the United States. J Clin Aesthet Dermatol. 2022;15:E82-E86.
- Definitive Healthcare. What are the most common diagnoses by dermatologists? Published January 31, 2024. Accessed May 5, 2025. https://www.definitivehc.com/resources/healthcare-insights/top-dermatologist-diagnoses
Screening for Meaning: Do Skin Cancer Screening Events Accomplish Anything?
Screening for Meaning: Do Skin Cancer Screening Events Accomplish Anything?
Interactive Approach to Teaching Mohs Micrographic Surgery to Dermatology Residents
Interactive Approach to Teaching Mohs Micrographic Surgery to Dermatology Residents
Practice Gap
Tissue processing and complete margin assessment in Mohs micrographic surgery (MMS) are challenging concepts for residents, yet they are essential components of the dermatology residency curriculum. We propose a hands-on active teaching method using craft foam blocks to help residents master these techniques. Prior educational tools have included instructional videos1 as well as the peanut butter–cup and cantaloupe analogies.2,3 Specifically, our method utilizes inexpensive, readily available supplies that allow for repeated practice in a low-stakes environment without limitation of resources. This method provides an immersive, hands-on experience that allows residents to perform multiple practice excisions and simulate positive peripheral or deep margins, unlike tools that offer only fixed-depth or purely visual representations. Additionally, our learning model uniquely enables residents to flatten the simulated tissue, providing a clearer understanding of how a 3-dimensional specimen is transformed on a slide during histologic preparation. This step is particularly important, as tissue architecture can shift during processing, making it one of the most difficult concepts to grasp without hands-on experience. Having a multitude of teaching methods is crucial to accommodate various learning styles, and active learning has been shown to enhance retention for dermatology residents.4
The Technique
Residents use simple art supplies (including craft foam blocks and ink) and inexpensive, readily available surgical tools to simulate MMS (Table)(Figure 1). If desired, the resident can follow along with the comprehensive, stepwise textbook description of MMS, outlined by Benedetto et al5 to contextualize this hands-on exercise within a standardized didactic framework.

The foam block, which represents patient tissue, serves as the specimen. The resident begins by freehand drawing a simulated cutaneous tumor directly onto the foam using a surgical marking pen. At this point, the instructor discusses the advantages and limitations of tumor debulking with a sharp blade or curette. Residents then mark appropriate margins (1-3 mm) of normal-appearing “epidermis” on the foam block and add hash marks for orientation. This is another opportunity for the instructor to discuss common methods for marking tissue in vivo and to review situations when larger or smaller margins might be appropriate.
Next, the resident removes the first layer of simulated tissue using a disposable #15 blade scalpel at a 45° angle circumferentially and deep around the representative tumor. The resident also may use scissors and tissue forceps to remove the representative tumor. Next, the excised foam layer (the simulated “specimen”) is transferred to gauze. To demonstrate a positive margin, the resident or instructor marks the deep or peripheral foam block with a surgical marking pen, indicating residual tumor (Figure 2). This allows for multiple sequential layers of foam to be removed, demonstrating successive stages of MMS.
An inkwell holds different colors of washable paint to simulate tissue inking. After excision, the resident uses cotton-tipped applicators to apply different paint colors to the edges of the excised foam specimen at designated orientation points (eg, 3 o'clock and 12 o'clock). The resident then records the location of the excised sample by hand-drawing it on a printable Mohs map, labeling the corresponding paint colors to indicate orientation (Figure 3).
The resident then places the specimen between 2 plastic page protectors mimicking a glass slide and cover slip. Clear tape can be used to help flatten the specimen (Figure 4). The tissue is compressed between the page protector so that the simulated epidermis, dermis, and subcutaneous fat are all in the same plane. At this stage, the instructor may discuss the use of relaxing incisions, especially for deeper tissue specimens or when excision at a 45° bevel is not achieved.5 The view from the underside of the page protector reveals 100% of the specimen’s margin and mimics the first cut off the tissue block. The resident can visualize the complete circumferential, peripheral, and deep margins and can easily identify any positive margins. At this point, the exercise can conclude, or the resident can explore further stages for positive margins, bisected specimens, or other tissue preparation variations.
Practice Implications
By individually designing and removing a representative tumor with margins, creating hash marks, and preparing a tissue specimen for histologic analysis, our interactive teaching method provides dermatology residents with a relatively simple, effective, and active learning experience for MMS outside the surgical setting. Using a piece of craft foam allows the representative tissue to be manipulated and flattened, similar to cutaneous tissue. This method was implemented and refined across 3 separate teaching sessions held by teaching faculty (E.I.P and E.B.W.) at the San Antonio Uniformed Services Health Education Consortium Dermatology Residency Program (San Antonio, Texas). This method has consistently generated strong resident engagement and prompted insightful questions and discussions. Program directors at other residency programs can readily incorporate this method in their surgical curriculum by allocating a brief didactic period to the exercise and facilitating the discussion with a dermatologic surgeon. Its simplicity, low cost, and effectiveness make the foam block model an easily adoptable teaching tool for dermatology residency programs seeking to provide a comprehensive, hands-on understanding of MMS.
- McNeil E, Reich H, Hurliman E. Educational video improves dermatology residents’ understanding of Mohs micrographic surgery: a surveybased matched cohort study. J Am Acad Dermatol. 2020;83:926-927. doi:10.1016/j.jaad.2020.01.013
- Lee E, Wolverton JE, Somani AK. A simple, effective analogy to elucidate the Mohs micrographic surgery procedure—the peanut butter cup. JAMA Dermatol. 2017;153:743-744. doi:10.1001 /jamadermatol.2017.0614
- Vassantachart JM, Guccione J, Seeburger J. Clinical pearl: Mohs cantaloupe analogy for the dermatology resident. Cutis. 2018; 102:65-66.
- Stratman EJ, Vogel CA, Reck SJ, et al. Analysis of dermatology resident self-reported successful learning styles and implications for core competency curriculum development. Med Teach. 2008;30:420-425. doi:10.1080/01421590801946988
- Benedetto PX, Poblete-Lopez C. Mohs micrographic surgery technique. Dermatol Clinics. 2011;29:141-151. doi:10.1016/j.det.2011.02.002
Practice Gap
Tissue processing and complete margin assessment in Mohs micrographic surgery (MMS) are challenging concepts for residents, yet they are essential components of the dermatology residency curriculum. We propose a hands-on active teaching method using craft foam blocks to help residents master these techniques. Prior educational tools have included instructional videos1 as well as the peanut butter–cup and cantaloupe analogies.2,3 Specifically, our method utilizes inexpensive, readily available supplies that allow for repeated practice in a low-stakes environment without limitation of resources. This method provides an immersive, hands-on experience that allows residents to perform multiple practice excisions and simulate positive peripheral or deep margins, unlike tools that offer only fixed-depth or purely visual representations. Additionally, our learning model uniquely enables residents to flatten the simulated tissue, providing a clearer understanding of how a 3-dimensional specimen is transformed on a slide during histologic preparation. This step is particularly important, as tissue architecture can shift during processing, making it one of the most difficult concepts to grasp without hands-on experience. Having a multitude of teaching methods is crucial to accommodate various learning styles, and active learning has been shown to enhance retention for dermatology residents.4
The Technique
Residents use simple art supplies (including craft foam blocks and ink) and inexpensive, readily available surgical tools to simulate MMS (Table)(Figure 1). If desired, the resident can follow along with the comprehensive, stepwise textbook description of MMS, outlined by Benedetto et al5 to contextualize this hands-on exercise within a standardized didactic framework.

The foam block, which represents patient tissue, serves as the specimen. The resident begins by freehand drawing a simulated cutaneous tumor directly onto the foam using a surgical marking pen. At this point, the instructor discusses the advantages and limitations of tumor debulking with a sharp blade or curette. Residents then mark appropriate margins (1-3 mm) of normal-appearing “epidermis” on the foam block and add hash marks for orientation. This is another opportunity for the instructor to discuss common methods for marking tissue in vivo and to review situations when larger or smaller margins might be appropriate.
Next, the resident removes the first layer of simulated tissue using a disposable #15 blade scalpel at a 45° angle circumferentially and deep around the representative tumor. The resident also may use scissors and tissue forceps to remove the representative tumor. Next, the excised foam layer (the simulated “specimen”) is transferred to gauze. To demonstrate a positive margin, the resident or instructor marks the deep or peripheral foam block with a surgical marking pen, indicating residual tumor (Figure 2). This allows for multiple sequential layers of foam to be removed, demonstrating successive stages of MMS.
An inkwell holds different colors of washable paint to simulate tissue inking. After excision, the resident uses cotton-tipped applicators to apply different paint colors to the edges of the excised foam specimen at designated orientation points (eg, 3 o'clock and 12 o'clock). The resident then records the location of the excised sample by hand-drawing it on a printable Mohs map, labeling the corresponding paint colors to indicate orientation (Figure 3).
The resident then places the specimen between 2 plastic page protectors mimicking a glass slide and cover slip. Clear tape can be used to help flatten the specimen (Figure 4). The tissue is compressed between the page protector so that the simulated epidermis, dermis, and subcutaneous fat are all in the same plane. At this stage, the instructor may discuss the use of relaxing incisions, especially for deeper tissue specimens or when excision at a 45° bevel is not achieved.5 The view from the underside of the page protector reveals 100% of the specimen’s margin and mimics the first cut off the tissue block. The resident can visualize the complete circumferential, peripheral, and deep margins and can easily identify any positive margins. At this point, the exercise can conclude, or the resident can explore further stages for positive margins, bisected specimens, or other tissue preparation variations.
Practice Implications
By individually designing and removing a representative tumor with margins, creating hash marks, and preparing a tissue specimen for histologic analysis, our interactive teaching method provides dermatology residents with a relatively simple, effective, and active learning experience for MMS outside the surgical setting. Using a piece of craft foam allows the representative tissue to be manipulated and flattened, similar to cutaneous tissue. This method was implemented and refined across 3 separate teaching sessions held by teaching faculty (E.I.P and E.B.W.) at the San Antonio Uniformed Services Health Education Consortium Dermatology Residency Program (San Antonio, Texas). This method has consistently generated strong resident engagement and prompted insightful questions and discussions. Program directors at other residency programs can readily incorporate this method in their surgical curriculum by allocating a brief didactic period to the exercise and facilitating the discussion with a dermatologic surgeon. Its simplicity, low cost, and effectiveness make the foam block model an easily adoptable teaching tool for dermatology residency programs seeking to provide a comprehensive, hands-on understanding of MMS.
Practice Gap
Tissue processing and complete margin assessment in Mohs micrographic surgery (MMS) are challenging concepts for residents, yet they are essential components of the dermatology residency curriculum. We propose a hands-on active teaching method using craft foam blocks to help residents master these techniques. Prior educational tools have included instructional videos1 as well as the peanut butter–cup and cantaloupe analogies.2,3 Specifically, our method utilizes inexpensive, readily available supplies that allow for repeated practice in a low-stakes environment without limitation of resources. This method provides an immersive, hands-on experience that allows residents to perform multiple practice excisions and simulate positive peripheral or deep margins, unlike tools that offer only fixed-depth or purely visual representations. Additionally, our learning model uniquely enables residents to flatten the simulated tissue, providing a clearer understanding of how a 3-dimensional specimen is transformed on a slide during histologic preparation. This step is particularly important, as tissue architecture can shift during processing, making it one of the most difficult concepts to grasp without hands-on experience. Having a multitude of teaching methods is crucial to accommodate various learning styles, and active learning has been shown to enhance retention for dermatology residents.4
The Technique
Residents use simple art supplies (including craft foam blocks and ink) and inexpensive, readily available surgical tools to simulate MMS (Table)(Figure 1). If desired, the resident can follow along with the comprehensive, stepwise textbook description of MMS, outlined by Benedetto et al5 to contextualize this hands-on exercise within a standardized didactic framework.

The foam block, which represents patient tissue, serves as the specimen. The resident begins by freehand drawing a simulated cutaneous tumor directly onto the foam using a surgical marking pen. At this point, the instructor discusses the advantages and limitations of tumor debulking with a sharp blade or curette. Residents then mark appropriate margins (1-3 mm) of normal-appearing “epidermis” on the foam block and add hash marks for orientation. This is another opportunity for the instructor to discuss common methods for marking tissue in vivo and to review situations when larger or smaller margins might be appropriate.
Next, the resident removes the first layer of simulated tissue using a disposable #15 blade scalpel at a 45° angle circumferentially and deep around the representative tumor. The resident also may use scissors and tissue forceps to remove the representative tumor. Next, the excised foam layer (the simulated “specimen”) is transferred to gauze. To demonstrate a positive margin, the resident or instructor marks the deep or peripheral foam block with a surgical marking pen, indicating residual tumor (Figure 2). This allows for multiple sequential layers of foam to be removed, demonstrating successive stages of MMS.
An inkwell holds different colors of washable paint to simulate tissue inking. After excision, the resident uses cotton-tipped applicators to apply different paint colors to the edges of the excised foam specimen at designated orientation points (eg, 3 o'clock and 12 o'clock). The resident then records the location of the excised sample by hand-drawing it on a printable Mohs map, labeling the corresponding paint colors to indicate orientation (Figure 3).
The resident then places the specimen between 2 plastic page protectors mimicking a glass slide and cover slip. Clear tape can be used to help flatten the specimen (Figure 4). The tissue is compressed between the page protector so that the simulated epidermis, dermis, and subcutaneous fat are all in the same plane. At this stage, the instructor may discuss the use of relaxing incisions, especially for deeper tissue specimens or when excision at a 45° bevel is not achieved.5 The view from the underside of the page protector reveals 100% of the specimen’s margin and mimics the first cut off the tissue block. The resident can visualize the complete circumferential, peripheral, and deep margins and can easily identify any positive margins. At this point, the exercise can conclude, or the resident can explore further stages for positive margins, bisected specimens, or other tissue preparation variations.
Practice Implications
By individually designing and removing a representative tumor with margins, creating hash marks, and preparing a tissue specimen for histologic analysis, our interactive teaching method provides dermatology residents with a relatively simple, effective, and active learning experience for MMS outside the surgical setting. Using a piece of craft foam allows the representative tissue to be manipulated and flattened, similar to cutaneous tissue. This method was implemented and refined across 3 separate teaching sessions held by teaching faculty (E.I.P and E.B.W.) at the San Antonio Uniformed Services Health Education Consortium Dermatology Residency Program (San Antonio, Texas). This method has consistently generated strong resident engagement and prompted insightful questions and discussions. Program directors at other residency programs can readily incorporate this method in their surgical curriculum by allocating a brief didactic period to the exercise and facilitating the discussion with a dermatologic surgeon. Its simplicity, low cost, and effectiveness make the foam block model an easily adoptable teaching tool for dermatology residency programs seeking to provide a comprehensive, hands-on understanding of MMS.
- McNeil E, Reich H, Hurliman E. Educational video improves dermatology residents’ understanding of Mohs micrographic surgery: a surveybased matched cohort study. J Am Acad Dermatol. 2020;83:926-927. doi:10.1016/j.jaad.2020.01.013
- Lee E, Wolverton JE, Somani AK. A simple, effective analogy to elucidate the Mohs micrographic surgery procedure—the peanut butter cup. JAMA Dermatol. 2017;153:743-744. doi:10.1001 /jamadermatol.2017.0614
- Vassantachart JM, Guccione J, Seeburger J. Clinical pearl: Mohs cantaloupe analogy for the dermatology resident. Cutis. 2018; 102:65-66.
- Stratman EJ, Vogel CA, Reck SJ, et al. Analysis of dermatology resident self-reported successful learning styles and implications for core competency curriculum development. Med Teach. 2008;30:420-425. doi:10.1080/01421590801946988
- Benedetto PX, Poblete-Lopez C. Mohs micrographic surgery technique. Dermatol Clinics. 2011;29:141-151. doi:10.1016/j.det.2011.02.002
- McNeil E, Reich H, Hurliman E. Educational video improves dermatology residents’ understanding of Mohs micrographic surgery: a surveybased matched cohort study. J Am Acad Dermatol. 2020;83:926-927. doi:10.1016/j.jaad.2020.01.013
- Lee E, Wolverton JE, Somani AK. A simple, effective analogy to elucidate the Mohs micrographic surgery procedure—the peanut butter cup. JAMA Dermatol. 2017;153:743-744. doi:10.1001 /jamadermatol.2017.0614
- Vassantachart JM, Guccione J, Seeburger J. Clinical pearl: Mohs cantaloupe analogy for the dermatology resident. Cutis. 2018; 102:65-66.
- Stratman EJ, Vogel CA, Reck SJ, et al. Analysis of dermatology resident self-reported successful learning styles and implications for core competency curriculum development. Med Teach. 2008;30:420-425. doi:10.1080/01421590801946988
- Benedetto PX, Poblete-Lopez C. Mohs micrographic surgery technique. Dermatol Clinics. 2011;29:141-151. doi:10.1016/j.det.2011.02.002
Interactive Approach to Teaching Mohs Micrographic Surgery to Dermatology Residents
Interactive Approach to Teaching Mohs Micrographic Surgery to Dermatology Residents
Does Ethnicity Affect Skin Cancer Risk?
Does Ethnicity Affect Skin Cancer Risk?
TOPLINE:
The incidence of skin cancer in England varied by ethnicity: White individuals had higher rates of melanoma, cutaneous squamous cell carcinoma, and basal cell carcinoma than Asian or Black individuals. In contrast, acral lentiginous melanoma was most common among Black individuals, whereas cutaneous T-cell lymphoma and Kaposi sarcoma were highest among those in the "Other" ethnic group.
METHODOLOGY:
- Researchers analysed all cases of cutaneous melanoma (melanoma and acral lentiginous melanoma), basal cell carcinoma, cutaneous squamous cell carcinoma, cutaneous T-cell lymphoma, and Kaposi sarcoma using data from the NHS National Disease Registration Service cancer registry between 2013 and 2020.
- Data collection incorporated ethnicity information from multiple health care datasets, including Clinical Outcomes and Services Dataset, Patient Administration System, Radiotherapy Dataset, Diagnostic Imaging Dataset, and Hospital Episode Statistics.
- A population analysis categorised patients into 7 standardised ethnic groups (on the basis of Office for National Statistics classifications): White, Asian, Chinese, Black, mixed, other, and unknown groups, with ethnicity data being self-reported by patients.
- Outcomes included European age-standardised rates calculated using the 2013 European Standard Population and reported per 100,000 person-years (PYs).
TAKEAWAY:
- White Individuals had 13-fold higher rates of cutaneous squamous cell carcinoma (61.75 per 100,000 PYs), 26-fold and 27-fold higher rates of basal cell carcinoma (153.69 per 100,000 PYs), and 33-fold and 16-fold higher rates of cutaneous melanoma (27.29 per 100,000 PYs) than Asian and Black individuals, respectively.
- Black individuals had the highest incidence of acral lentiginous melanoma (0.85 per 100,000 PYs), and those in the other ethnic group had the highest incidence of cutaneous T-cell lymphoma (1.74 per 100,000 PYs) and Kaposi sarcoma (1.57 per 100,000 PYs).
- The presentation of early-stage melanoma was low among Asian (53.5%), Black (62.4%), mixed (62.5%), and other (76.4%) ethnic groups compared to that among White ethnicities (79.8%).
- Acral lentiginous melanomas were less likely to get urgent suspected cancer pathway referrals than overall melanoma (40.1% vs 44.6%; P < .001) and more likely to be diagnosed late than overall melanoma (stage I/II at diagnosis; 72% vs 80%; P < .0001).
IN PRACTICE:
"The findings emphasise the need for better, targeted ethnicity data collection strategies to address incidence, outcomes and health care equity for not just skin cancer but all health conditions in underserved populations," the authors wrote. "While projects like the Global Burden of Disease have improved global health care reporting, continuous audit and improvement of collected data are essential to provide better care across people of all ethnicities."
SOURCE:
This study was led by Shehnaz Ahmed, British Association of Dermatologists, London, England. It was published online on September 10, 2025, in the British Journal of Dermatology.
LIMITATIONS:
Census data collection after every 10 years could have contributed to inaccurate population estimates and incidence rates. Small sample sizes in certain ethnic groups could have led to potential confounders, requiring a cautious interpretation of relative incidence. The NHS data included only self-reported ethnicity data with no available details of skin phototypes, skin tones, or racial ancestry. This study lacked granular ethnicity census data and stage data for basal cell carcinoma, cutaneous small cell carcinoma, and Kaposi sarcoma.
DISCLOSURES:
This research was supported through a partnership between the British Association of Dermatologists and NHS England's National Disease Registration Service. Two authors reported being employees of the British Association of Dermatologists.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
The incidence of skin cancer in England varied by ethnicity: White individuals had higher rates of melanoma, cutaneous squamous cell carcinoma, and basal cell carcinoma than Asian or Black individuals. In contrast, acral lentiginous melanoma was most common among Black individuals, whereas cutaneous T-cell lymphoma and Kaposi sarcoma were highest among those in the "Other" ethnic group.
METHODOLOGY:
- Researchers analysed all cases of cutaneous melanoma (melanoma and acral lentiginous melanoma), basal cell carcinoma, cutaneous squamous cell carcinoma, cutaneous T-cell lymphoma, and Kaposi sarcoma using data from the NHS National Disease Registration Service cancer registry between 2013 and 2020.
- Data collection incorporated ethnicity information from multiple health care datasets, including Clinical Outcomes and Services Dataset, Patient Administration System, Radiotherapy Dataset, Diagnostic Imaging Dataset, and Hospital Episode Statistics.
- A population analysis categorised patients into 7 standardised ethnic groups (on the basis of Office for National Statistics classifications): White, Asian, Chinese, Black, mixed, other, and unknown groups, with ethnicity data being self-reported by patients.
- Outcomes included European age-standardised rates calculated using the 2013 European Standard Population and reported per 100,000 person-years (PYs).
TAKEAWAY:
- White Individuals had 13-fold higher rates of cutaneous squamous cell carcinoma (61.75 per 100,000 PYs), 26-fold and 27-fold higher rates of basal cell carcinoma (153.69 per 100,000 PYs), and 33-fold and 16-fold higher rates of cutaneous melanoma (27.29 per 100,000 PYs) than Asian and Black individuals, respectively.
- Black individuals had the highest incidence of acral lentiginous melanoma (0.85 per 100,000 PYs), and those in the other ethnic group had the highest incidence of cutaneous T-cell lymphoma (1.74 per 100,000 PYs) and Kaposi sarcoma (1.57 per 100,000 PYs).
- The presentation of early-stage melanoma was low among Asian (53.5%), Black (62.4%), mixed (62.5%), and other (76.4%) ethnic groups compared to that among White ethnicities (79.8%).
- Acral lentiginous melanomas were less likely to get urgent suspected cancer pathway referrals than overall melanoma (40.1% vs 44.6%; P < .001) and more likely to be diagnosed late than overall melanoma (stage I/II at diagnosis; 72% vs 80%; P < .0001).
IN PRACTICE:
"The findings emphasise the need for better, targeted ethnicity data collection strategies to address incidence, outcomes and health care equity for not just skin cancer but all health conditions in underserved populations," the authors wrote. "While projects like the Global Burden of Disease have improved global health care reporting, continuous audit and improvement of collected data are essential to provide better care across people of all ethnicities."
SOURCE:
This study was led by Shehnaz Ahmed, British Association of Dermatologists, London, England. It was published online on September 10, 2025, in the British Journal of Dermatology.
LIMITATIONS:
Census data collection after every 10 years could have contributed to inaccurate population estimates and incidence rates. Small sample sizes in certain ethnic groups could have led to potential confounders, requiring a cautious interpretation of relative incidence. The NHS data included only self-reported ethnicity data with no available details of skin phototypes, skin tones, or racial ancestry. This study lacked granular ethnicity census data and stage data for basal cell carcinoma, cutaneous small cell carcinoma, and Kaposi sarcoma.
DISCLOSURES:
This research was supported through a partnership between the British Association of Dermatologists and NHS England's National Disease Registration Service. Two authors reported being employees of the British Association of Dermatologists.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
The incidence of skin cancer in England varied by ethnicity: White individuals had higher rates of melanoma, cutaneous squamous cell carcinoma, and basal cell carcinoma than Asian or Black individuals. In contrast, acral lentiginous melanoma was most common among Black individuals, whereas cutaneous T-cell lymphoma and Kaposi sarcoma were highest among those in the "Other" ethnic group.
METHODOLOGY:
- Researchers analysed all cases of cutaneous melanoma (melanoma and acral lentiginous melanoma), basal cell carcinoma, cutaneous squamous cell carcinoma, cutaneous T-cell lymphoma, and Kaposi sarcoma using data from the NHS National Disease Registration Service cancer registry between 2013 and 2020.
- Data collection incorporated ethnicity information from multiple health care datasets, including Clinical Outcomes and Services Dataset, Patient Administration System, Radiotherapy Dataset, Diagnostic Imaging Dataset, and Hospital Episode Statistics.
- A population analysis categorised patients into 7 standardised ethnic groups (on the basis of Office for National Statistics classifications): White, Asian, Chinese, Black, mixed, other, and unknown groups, with ethnicity data being self-reported by patients.
- Outcomes included European age-standardised rates calculated using the 2013 European Standard Population and reported per 100,000 person-years (PYs).
TAKEAWAY:
- White Individuals had 13-fold higher rates of cutaneous squamous cell carcinoma (61.75 per 100,000 PYs), 26-fold and 27-fold higher rates of basal cell carcinoma (153.69 per 100,000 PYs), and 33-fold and 16-fold higher rates of cutaneous melanoma (27.29 per 100,000 PYs) than Asian and Black individuals, respectively.
- Black individuals had the highest incidence of acral lentiginous melanoma (0.85 per 100,000 PYs), and those in the other ethnic group had the highest incidence of cutaneous T-cell lymphoma (1.74 per 100,000 PYs) and Kaposi sarcoma (1.57 per 100,000 PYs).
- The presentation of early-stage melanoma was low among Asian (53.5%), Black (62.4%), mixed (62.5%), and other (76.4%) ethnic groups compared to that among White ethnicities (79.8%).
- Acral lentiginous melanomas were less likely to get urgent suspected cancer pathway referrals than overall melanoma (40.1% vs 44.6%; P < .001) and more likely to be diagnosed late than overall melanoma (stage I/II at diagnosis; 72% vs 80%; P < .0001).
IN PRACTICE:
"The findings emphasise the need for better, targeted ethnicity data collection strategies to address incidence, outcomes and health care equity for not just skin cancer but all health conditions in underserved populations," the authors wrote. "While projects like the Global Burden of Disease have improved global health care reporting, continuous audit and improvement of collected data are essential to provide better care across people of all ethnicities."
SOURCE:
This study was led by Shehnaz Ahmed, British Association of Dermatologists, London, England. It was published online on September 10, 2025, in the British Journal of Dermatology.
LIMITATIONS:
Census data collection after every 10 years could have contributed to inaccurate population estimates and incidence rates. Small sample sizes in certain ethnic groups could have led to potential confounders, requiring a cautious interpretation of relative incidence. The NHS data included only self-reported ethnicity data with no available details of skin phototypes, skin tones, or racial ancestry. This study lacked granular ethnicity census data and stage data for basal cell carcinoma, cutaneous small cell carcinoma, and Kaposi sarcoma.
DISCLOSURES:
This research was supported through a partnership between the British Association of Dermatologists and NHS England's National Disease Registration Service. Two authors reported being employees of the British Association of Dermatologists.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
Does Ethnicity Affect Skin Cancer Risk?
Does Ethnicity Affect Skin Cancer Risk?
Don’t Miss Those Blind Spots
Background
Choroidal malignant melanoma is a relatively rare condition, yet it remains the most common primary intraocular malignancy in adults, affecting approximately 5 individuals per million each year in the United States. Associated risk factors include fair skin, light-colored eyes, ocular melanocytosis, and BAP1 genetic mutations. While 13% of patients presenting with choroidal melanoma are asymptomatic, some symptoms can include photopsia, floaters, blurred vision, and progressive visual field loss.
Case Presentation
We present a case of choroidal melanoma in a 57-year-old male with a past medical history of hypertension, hyperlipidemia, major depressive disorder, and alcohol use disorder. This patient presented to the clinic following a detoxification admission, reporting one week of progressive vision loss in the left eye. Upon initial physical examination, the patient exhibited left superior quadrantanopia, with a visual acuity of 20/40 measured in the left eye. Initial imaging with CT head identified an intraocular hyperdensity within the left globe, raising concerns for potential retinal detachment. Urgent ophthalmologic evaluation revealed an afferent pupillary defect and a large choroidal lesion adjacent to the optic nerve head. Ultrasonography showed a low internal reflectivity mass (5.36 mm by 9.05 mm), and a subsequent dilated fundus examination confirmed a classic dome-shaped choroidal melanoma (11.5 mm by 16.5 mm). Gene expression profiling demonstrated a class 1b uveal melanoma with PRAME positivity and mutations in GNAQ and SF3B1. Comprehensive staging scans were negative for metastatic disease. The patient received four treatment sessions of proton beam therapy, which resulted in rapid improvements in his visual fields. For long-term management, he was scheduled for close ophthalmologic follow-up and regular imaging of the chest and abdomen every six months to monitor for recurrence.
Conclusions
This case highlights the challenges of diagnosing choroidal melanoma in the primary care setting and the importance of multidisciplinary involvement, multimodal imaging, and gene expression profiling in facilitating early diagnosis and treatment.
Background
Choroidal malignant melanoma is a relatively rare condition, yet it remains the most common primary intraocular malignancy in adults, affecting approximately 5 individuals per million each year in the United States. Associated risk factors include fair skin, light-colored eyes, ocular melanocytosis, and BAP1 genetic mutations. While 13% of patients presenting with choroidal melanoma are asymptomatic, some symptoms can include photopsia, floaters, blurred vision, and progressive visual field loss.
Case Presentation
We present a case of choroidal melanoma in a 57-year-old male with a past medical history of hypertension, hyperlipidemia, major depressive disorder, and alcohol use disorder. This patient presented to the clinic following a detoxification admission, reporting one week of progressive vision loss in the left eye. Upon initial physical examination, the patient exhibited left superior quadrantanopia, with a visual acuity of 20/40 measured in the left eye. Initial imaging with CT head identified an intraocular hyperdensity within the left globe, raising concerns for potential retinal detachment. Urgent ophthalmologic evaluation revealed an afferent pupillary defect and a large choroidal lesion adjacent to the optic nerve head. Ultrasonography showed a low internal reflectivity mass (5.36 mm by 9.05 mm), and a subsequent dilated fundus examination confirmed a classic dome-shaped choroidal melanoma (11.5 mm by 16.5 mm). Gene expression profiling demonstrated a class 1b uveal melanoma with PRAME positivity and mutations in GNAQ and SF3B1. Comprehensive staging scans were negative for metastatic disease. The patient received four treatment sessions of proton beam therapy, which resulted in rapid improvements in his visual fields. For long-term management, he was scheduled for close ophthalmologic follow-up and regular imaging of the chest and abdomen every six months to monitor for recurrence.
Conclusions
This case highlights the challenges of diagnosing choroidal melanoma in the primary care setting and the importance of multidisciplinary involvement, multimodal imaging, and gene expression profiling in facilitating early diagnosis and treatment.
Background
Choroidal malignant melanoma is a relatively rare condition, yet it remains the most common primary intraocular malignancy in adults, affecting approximately 5 individuals per million each year in the United States. Associated risk factors include fair skin, light-colored eyes, ocular melanocytosis, and BAP1 genetic mutations. While 13% of patients presenting with choroidal melanoma are asymptomatic, some symptoms can include photopsia, floaters, blurred vision, and progressive visual field loss.
Case Presentation
We present a case of choroidal melanoma in a 57-year-old male with a past medical history of hypertension, hyperlipidemia, major depressive disorder, and alcohol use disorder. This patient presented to the clinic following a detoxification admission, reporting one week of progressive vision loss in the left eye. Upon initial physical examination, the patient exhibited left superior quadrantanopia, with a visual acuity of 20/40 measured in the left eye. Initial imaging with CT head identified an intraocular hyperdensity within the left globe, raising concerns for potential retinal detachment. Urgent ophthalmologic evaluation revealed an afferent pupillary defect and a large choroidal lesion adjacent to the optic nerve head. Ultrasonography showed a low internal reflectivity mass (5.36 mm by 9.05 mm), and a subsequent dilated fundus examination confirmed a classic dome-shaped choroidal melanoma (11.5 mm by 16.5 mm). Gene expression profiling demonstrated a class 1b uveal melanoma with PRAME positivity and mutations in GNAQ and SF3B1. Comprehensive staging scans were negative for metastatic disease. The patient received four treatment sessions of proton beam therapy, which resulted in rapid improvements in his visual fields. For long-term management, he was scheduled for close ophthalmologic follow-up and regular imaging of the chest and abdomen every six months to monitor for recurrence.
Conclusions
This case highlights the challenges of diagnosing choroidal melanoma in the primary care setting and the importance of multidisciplinary involvement, multimodal imaging, and gene expression profiling in facilitating early diagnosis and treatment.