Melanoma

THE DIAGNOSIS: Apocrine Hidrocystoma

Histology for all 3 lesions demonstrated similar cystic structures lined by a dual layer of epithelial cells, with the outermost layer composed of flattened myoepithelial cells and the inner layer composed of cells with apocrine features (Figure 1). Based on these findings, a diagnosis of apocrine hidrocystoma was made. The patient underwent successful surgical excision shortly thereafter without recurrence at follow-up 1 year later. 

Apocrine hidrocystomas are rare benign cystic lesions that are considered to be adenomatous proliferations of apocrine glands. They typically manifest as solitary asymptomatic lesions measuring 3 to 15 mm.¹ They tend to appear on the face, usually in the periorbital region, but also have been described on the neck, scalp, trunk, arms, and legs.^2-4 Multiple apocrine hidrocystomas can be a marker of 2 rare inherited disorders: Gorlin-Goltz syndrome and Schopf-Schulz-Passarge syndrome.⁵ Apocrine hidrocystomas may be flesh colored or may have a blue, black, or brown appearance due to the Tyndall effect, in which light with shorter wavelengths is scattered by the contents of the lesions.² Histologically, apocrine hidrocystomas are cysts lined by a dual layer of epithelial cells. The inner layer is composed of cells with apocrine features, and the outer layer is composed of flattened myoepithelial cells. Due to their range of colors and predilection for sun-exposed surfaces, apocrine hidrocystomas may be mistaken for various malignant neoplasms, including melanoma.^6,7

The differential diagnosis for our patient included agminated blue nevi, melanoma, pigmented basal cell carcinoma (BCC), and seborrheic keratosis. A blue nevus is a dermal melanocytic lesion that manifests as a well-demarcated, blue to blue-black papule that typically appears on the face, scalp, arms, legs, lower back, and buttocks. Although there are several histologic subtypes, the common blue nevus usually manifests as a solitary lesion measuring less than 1 cm, often developing during childhood to young adulthood.⁸ Histologically, common blue nevi are characterized by a dermal proliferation of deeply pigmented bipolar spindled melanocytes embedded in thickened collagen bundles, often with scattered epithelioid melanophages, and no conspicuous mitotic activity (Figure 2).⁹ There are other types of blue nevi, including cellular blue nevi, which tend to be larger and manifest commonly on the buttocks and sacrococcygeal region in early adulthood.⁹ Histologically, cellular blue nevi contain oval to spindled melanocytes with scattered melanophages forming a well-demarcated nodule typically in the reticular dermis. There may be bulbous extension into the subcutaneous adipose tissue. Occasional mitoses may be seen.^9,10 Melanoma can arise from common or cellular blue nevi, though it more frequently occurs with cellular blue nevi. Other subtypes of blue nevi have been described, including the sclerosing, plaque-type, combined, hypomelanotic/amelanotic, and pigmented epithelioid melanocytoma.¹¹ However, they typically have features of the common blue nevus or cellular blue nevus, such as oval/spindle cell morphology, some degree of melanin, and biphasic architecture, but are classified according to their dominant histologic characteristics. 

Given the location of our patient’s lesions on the scalp and his extensive history of sun exposure, malignancy was high in the differential. Multiple synchronous primary melanomas including nodular melanoma, blue nevus–like metastatic melanoma, and metastatic melanoma were considered. The leg and the scalp have the highest reported incidence of cutaneous metastases of melanoma, with many cases presenting as dermal or subcutaneous nodules and eruptive blue nevus–like papules, similar to our patient’s clinical presentation.^12,13 Nodular melanoma (NM) is one of 4 major types of melanoma, accounting for approximately 15% to 30% of cases in the United States.¹⁴ Nodular melanoma typically manifests as a smooth, raised, symmetric, well-circumscribed lesion with variable pigmentation, from very dark to amelanotic. Histologically, NM is defined as a dermal mass, either in isolation or with an epidermal component, not to exceed 3 rete ridges beyond the dermal component.¹⁵ Tumor cells have a high cell density with pleomorphism, usually with atypical epithelioid cells with vesicular nuclei and irregular cytoplasm, and occasionally spindle cells (Figure 2).¹⁶ Mitoses and necrosis are frequent. Scalp location independently is responsible for worse survival, both overall and melanoma specific.¹⁷ Nodular melanoma tends to have greater Breslow thickness at diagnosis than other melanoma subtypes and often carries a worse prognosis. 

Malignant melanomas that develop from or in conjunction with or bear histologic resemblance to blue nevi are termed blue nevus–like melanoma or blue nevus–associated melanoma. These malignancies are exceedingly rare, accounting for only 0.3% of melanomas in one Turkey-based multicenter study.¹⁸ The histologic criteria for diagnosing blue nevus–like melanoma are poorly defined, and terminology of these lesions has led to some debate in naming conventions.¹⁹ Nevertheless, unlike blue nevus, blue nevus–like melanoma demonstrates histologic features of malignancy, including pleomorphism, prominent nucleoli, mitotic activity, vascular invasion, and potential necrosis.¹⁰ The lack of an inflammatory infiltrate, surrounding fibrosis, junctional activity, and pre-existing nevus can help distinguish cutaneous melanoma metastases from primary nodular melanoma. Immunohistochemical stains such as S100, Melan-A/MART1, or SOX-10 can help confirm melanocytic lineage.¹² 

Pigmented BCC is a clinical and histologic variant of BCC characterized by increased melanin pigmentation due to melanocytes admixed with tumor cells. Dermoscopically, the pigment can have a maple leaf–like appearance with spoke-wheel areas, in-focus dots, and concentric structures at the dermoepidermal junction, which is more characteristic of superficial and infiltrating BCC.²⁰ In nodular BCC, the pigment occurs as blue-gray ovoid nests and globules in deeper layers of the dermis.²⁰ 

Seborrheic keratoses (SKs) can vary widely in clinical appearance, with pigmentation ranging from flesh colored to yellow to brown to black. Melanoacanthomas are acanthotic SKs that are highly pigmented due to intermixed epidermal melanocytes and subepidermal melanophages.²¹ Dermoscopy can help distinguish cutaneous malignancies from SKs, which often demonstrate fissures and ridges, comedolike openings, and milialike cysts. Biopsy sometimes is required to assess for malignancy, as was the case in our patient. The classic histologic features of SKs include acanthosis, papillomatosis, and hyperkeratosis.²² 

This case highlights the need to consider apocrine hidrocystoma, along with malignancy, in the differential diagnosis of pigmented cystic masses of the face and scalp. Because apocrine hidrocystomas are benign, they do not need to be treated but often are surgically excised for cosmesis or complete histopathologic examination. Destruction via electrodessication, carbon dioxide ablation, trichloroacetic acid chemical ablation, botulinum toxin injection, and anticholinergic creams sometimes is used, especially for cosmetic treatment of multiple small lesions.⁵ Our patient was treated with surgical excision with no evidence of recurrence on follow-up 1 year later. 

THE DIAGNOSIS: Apocrine Hidrocystoma

Histology for all 3 lesions demonstrated similar cystic structures lined by a dual layer of epithelial cells, with the outermost layer composed of flattened myoepithelial cells and the inner layer composed of cells with apocrine features (Figure 1). Based on these findings, a diagnosis of apocrine hidrocystoma was made. The patient underwent successful surgical excision shortly thereafter without recurrence at follow-up 1 year later. 

Apocrine hidrocystomas are rare benign cystic lesions that are considered to be adenomatous proliferations of apocrine glands. They typically manifest as solitary asymptomatic lesions measuring 3 to 15 mm.¹ They tend to appear on the face, usually in the periorbital region, but also have been described on the neck, scalp, trunk, arms, and legs.^2-4 Multiple apocrine hidrocystomas can be a marker of 2 rare inherited disorders: Gorlin-Goltz syndrome and Schopf-Schulz-Passarge syndrome.⁵ Apocrine hidrocystomas may be flesh colored or may have a blue, black, or brown appearance due to the Tyndall effect, in which light with shorter wavelengths is scattered by the contents of the lesions.² Histologically, apocrine hidrocystomas are cysts lined by a dual layer of epithelial cells. The inner layer is composed of cells with apocrine features, and the outer layer is composed of flattened myoepithelial cells. Due to their range of colors and predilection for sun-exposed surfaces, apocrine hidrocystomas may be mistaken for various malignant neoplasms, including melanoma.^6,7

The differential diagnosis for our patient included agminated blue nevi, melanoma, pigmented basal cell carcinoma (BCC), and seborrheic keratosis. A blue nevus is a dermal melanocytic lesion that manifests as a well-demarcated, blue to blue-black papule that typically appears on the face, scalp, arms, legs, lower back, and buttocks. Although there are several histologic subtypes, the common blue nevus usually manifests as a solitary lesion measuring less than 1 cm, often developing during childhood to young adulthood.⁸ Histologically, common blue nevi are characterized by a dermal proliferation of deeply pigmented bipolar spindled melanocytes embedded in thickened collagen bundles, often with scattered epithelioid melanophages, and no conspicuous mitotic activity (Figure 2).⁹ There are other types of blue nevi, including cellular blue nevi, which tend to be larger and manifest commonly on the buttocks and sacrococcygeal region in early adulthood.⁹ Histologically, cellular blue nevi contain oval to spindled melanocytes with scattered melanophages forming a well-demarcated nodule typically in the reticular dermis. There may be bulbous extension into the subcutaneous adipose tissue. Occasional mitoses may be seen.^9,10 Melanoma can arise from common or cellular blue nevi, though it more frequently occurs with cellular blue nevi. Other subtypes of blue nevi have been described, including the sclerosing, plaque-type, combined, hypomelanotic/amelanotic, and pigmented epithelioid melanocytoma.¹¹ However, they typically have features of the common blue nevus or cellular blue nevus, such as oval/spindle cell morphology, some degree of melanin, and biphasic architecture, but are classified according to their dominant histologic characteristics. 

Given the location of our patient’s lesions on the scalp and his extensive history of sun exposure, malignancy was high in the differential. Multiple synchronous primary melanomas including nodular melanoma, blue nevus–like metastatic melanoma, and metastatic melanoma were considered. The leg and the scalp have the highest reported incidence of cutaneous metastases of melanoma, with many cases presenting as dermal or subcutaneous nodules and eruptive blue nevus–like papules, similar to our patient’s clinical presentation.^12,13 Nodular melanoma (NM) is one of 4 major types of melanoma, accounting for approximately 15% to 30% of cases in the United States.¹⁴ Nodular melanoma typically manifests as a smooth, raised, symmetric, well-circumscribed lesion with variable pigmentation, from very dark to amelanotic. Histologically, NM is defined as a dermal mass, either in isolation or with an epidermal component, not to exceed 3 rete ridges beyond the dermal component.¹⁵ Tumor cells have a high cell density with pleomorphism, usually with atypical epithelioid cells with vesicular nuclei and irregular cytoplasm, and occasionally spindle cells (Figure 2).¹⁶ Mitoses and necrosis are frequent. Scalp location independently is responsible for worse survival, both overall and melanoma specific.¹⁷ Nodular melanoma tends to have greater Breslow thickness at diagnosis than other melanoma subtypes and often carries a worse prognosis. 

Malignant melanomas that develop from or in conjunction with or bear histologic resemblance to blue nevi are termed blue nevus–like melanoma or blue nevus–associated melanoma. These malignancies are exceedingly rare, accounting for only 0.3% of melanomas in one Turkey-based multicenter study.¹⁸ The histologic criteria for diagnosing blue nevus–like melanoma are poorly defined, and terminology of these lesions has led to some debate in naming conventions.¹⁹ Nevertheless, unlike blue nevus, blue nevus–like melanoma demonstrates histologic features of malignancy, including pleomorphism, prominent nucleoli, mitotic activity, vascular invasion, and potential necrosis.¹⁰ The lack of an inflammatory infiltrate, surrounding fibrosis, junctional activity, and pre-existing nevus can help distinguish cutaneous melanoma metastases from primary nodular melanoma. Immunohistochemical stains such as S100, Melan-A/MART1, or SOX-10 can help confirm melanocytic lineage.¹² 

Pigmented BCC is a clinical and histologic variant of BCC characterized by increased melanin pigmentation due to melanocytes admixed with tumor cells. Dermoscopically, the pigment can have a maple leaf–like appearance with spoke-wheel areas, in-focus dots, and concentric structures at the dermoepidermal junction, which is more characteristic of superficial and infiltrating BCC.²⁰ In nodular BCC, the pigment occurs as blue-gray ovoid nests and globules in deeper layers of the dermis.²⁰ 

Seborrheic keratoses (SKs) can vary widely in clinical appearance, with pigmentation ranging from flesh colored to yellow to brown to black. Melanoacanthomas are acanthotic SKs that are highly pigmented due to intermixed epidermal melanocytes and subepidermal melanophages.²¹ Dermoscopy can help distinguish cutaneous malignancies from SKs, which often demonstrate fissures and ridges, comedolike openings, and milialike cysts. Biopsy sometimes is required to assess for malignancy, as was the case in our patient. The classic histologic features of SKs include acanthosis, papillomatosis, and hyperkeratosis.²² 

This case highlights the need to consider apocrine hidrocystoma, along with malignancy, in the differential diagnosis of pigmented cystic masses of the face and scalp. Because apocrine hidrocystomas are benign, they do not need to be treated but often are surgically excised for cosmesis or complete histopathologic examination. Destruction via electrodessication, carbon dioxide ablation, trichloroacetic acid chemical ablation, botulinum toxin injection, and anticholinergic creams sometimes is used, especially for cosmetic treatment of multiple small lesions.⁵ Our patient was treated with surgical excision with no evidence of recurrence on follow-up 1 year later. 

THE DIAGNOSIS: Apocrine Hidrocystoma

Histology for all 3 lesions demonstrated similar cystic structures lined by a dual layer of epithelial cells, with the outermost layer composed of flattened myoepithelial cells and the inner layer composed of cells with apocrine features (Figure 1). Based on these findings, a diagnosis of apocrine hidrocystoma was made. The patient underwent successful surgical excision shortly thereafter without recurrence at follow-up 1 year later. 

Apocrine hidrocystomas are rare benign cystic lesions that are considered to be adenomatous proliferations of apocrine glands. They typically manifest as solitary asymptomatic lesions measuring 3 to 15 mm.¹ They tend to appear on the face, usually in the periorbital region, but also have been described on the neck, scalp, trunk, arms, and legs.^2-4 Multiple apocrine hidrocystomas can be a marker of 2 rare inherited disorders: Gorlin-Goltz syndrome and Schopf-Schulz-Passarge syndrome.⁵ Apocrine hidrocystomas may be flesh colored or may have a blue, black, or brown appearance due to the Tyndall effect, in which light with shorter wavelengths is scattered by the contents of the lesions.² Histologically, apocrine hidrocystomas are cysts lined by a dual layer of epithelial cells. The inner layer is composed of cells with apocrine features, and the outer layer is composed of flattened myoepithelial cells. Due to their range of colors and predilection for sun-exposed surfaces, apocrine hidrocystomas may be mistaken for various malignant neoplasms, including melanoma.^6,7

The differential diagnosis for our patient included agminated blue nevi, melanoma, pigmented basal cell carcinoma (BCC), and seborrheic keratosis. A blue nevus is a dermal melanocytic lesion that manifests as a well-demarcated, blue to blue-black papule that typically appears on the face, scalp, arms, legs, lower back, and buttocks. Although there are several histologic subtypes, the common blue nevus usually manifests as a solitary lesion measuring less than 1 cm, often developing during childhood to young adulthood.⁸ Histologically, common blue nevi are characterized by a dermal proliferation of deeply pigmented bipolar spindled melanocytes embedded in thickened collagen bundles, often with scattered epithelioid melanophages, and no conspicuous mitotic activity (Figure 2).⁹ There are other types of blue nevi, including cellular blue nevi, which tend to be larger and manifest commonly on the buttocks and sacrococcygeal region in early adulthood.⁹ Histologically, cellular blue nevi contain oval to spindled melanocytes with scattered melanophages forming a well-demarcated nodule typically in the reticular dermis. There may be bulbous extension into the subcutaneous adipose tissue. Occasional mitoses may be seen.^9,10 Melanoma can arise from common or cellular blue nevi, though it more frequently occurs with cellular blue nevi. Other subtypes of blue nevi have been described, including the sclerosing, plaque-type, combined, hypomelanotic/amelanotic, and pigmented epithelioid melanocytoma.¹¹ However, they typically have features of the common blue nevus or cellular blue nevus, such as oval/spindle cell morphology, some degree of melanin, and biphasic architecture, but are classified according to their dominant histologic characteristics. 

Given the location of our patient’s lesions on the scalp and his extensive history of sun exposure, malignancy was high in the differential. Multiple synchronous primary melanomas including nodular melanoma, blue nevus–like metastatic melanoma, and metastatic melanoma were considered. The leg and the scalp have the highest reported incidence of cutaneous metastases of melanoma, with many cases presenting as dermal or subcutaneous nodules and eruptive blue nevus–like papules, similar to our patient’s clinical presentation.^12,13 Nodular melanoma (NM) is one of 4 major types of melanoma, accounting for approximately 15% to 30% of cases in the United States.¹⁴ Nodular melanoma typically manifests as a smooth, raised, symmetric, well-circumscribed lesion with variable pigmentation, from very dark to amelanotic. Histologically, NM is defined as a dermal mass, either in isolation or with an epidermal component, not to exceed 3 rete ridges beyond the dermal component.¹⁵ Tumor cells have a high cell density with pleomorphism, usually with atypical epithelioid cells with vesicular nuclei and irregular cytoplasm, and occasionally spindle cells (Figure 2).¹⁶ Mitoses and necrosis are frequent. Scalp location independently is responsible for worse survival, both overall and melanoma specific.¹⁷ Nodular melanoma tends to have greater Breslow thickness at diagnosis than other melanoma subtypes and often carries a worse prognosis. 

Malignant melanomas that develop from or in conjunction with or bear histologic resemblance to blue nevi are termed blue nevus–like melanoma or blue nevus–associated melanoma. These malignancies are exceedingly rare, accounting for only 0.3% of melanomas in one Turkey-based multicenter study.¹⁸ The histologic criteria for diagnosing blue nevus–like melanoma are poorly defined, and terminology of these lesions has led to some debate in naming conventions.¹⁹ Nevertheless, unlike blue nevus, blue nevus–like melanoma demonstrates histologic features of malignancy, including pleomorphism, prominent nucleoli, mitotic activity, vascular invasion, and potential necrosis.¹⁰ The lack of an inflammatory infiltrate, surrounding fibrosis, junctional activity, and pre-existing nevus can help distinguish cutaneous melanoma metastases from primary nodular melanoma. Immunohistochemical stains such as S100, Melan-A/MART1, or SOX-10 can help confirm melanocytic lineage.¹² 

Pigmented BCC is a clinical and histologic variant of BCC characterized by increased melanin pigmentation due to melanocytes admixed with tumor cells. Dermoscopically, the pigment can have a maple leaf–like appearance with spoke-wheel areas, in-focus dots, and concentric structures at the dermoepidermal junction, which is more characteristic of superficial and infiltrating BCC.²⁰ In nodular BCC, the pigment occurs as blue-gray ovoid nests and globules in deeper layers of the dermis.²⁰ 

Seborrheic keratoses (SKs) can vary widely in clinical appearance, with pigmentation ranging from flesh colored to yellow to brown to black. Melanoacanthomas are acanthotic SKs that are highly pigmented due to intermixed epidermal melanocytes and subepidermal melanophages.²¹ Dermoscopy can help distinguish cutaneous malignancies from SKs, which often demonstrate fissures and ridges, comedolike openings, and milialike cysts. Biopsy sometimes is required to assess for malignancy, as was the case in our patient. The classic histologic features of SKs include acanthosis, papillomatosis, and hyperkeratosis.²² 

This case highlights the need to consider apocrine hidrocystoma, along with malignancy, in the differential diagnosis of pigmented cystic masses of the face and scalp. Because apocrine hidrocystomas are benign, they do not need to be treated but often are surgically excised for cosmesis or complete histopathologic examination. Destruction via electrodessication, carbon dioxide ablation, trichloroacetic acid chemical ablation, botulinum toxin injection, and anticholinergic creams sometimes is used, especially for cosmetic treatment of multiple small lesions.⁵ Our patient was treated with surgical excision with no evidence of recurrence on follow-up 1 year later. 

Store-and-forward teledermatology (SFT) allows clinical images and information to be sent to a dermatologist for evaluation. In fiscal year (FY) 2018, 117,780 SFT consultations were completed in the Veterans Health Administration. Continued growth is expected since SFT has proven to be an effective method for improving access to face-to-face (FTF) dermatology care.¹ In the same period, the US Department of Veterans Affairs (VA) Puget Sound Health Care System (VAPSHCS) completed 12,563 consultations in a mean 1.1 days from entry into episode of care (EEC), according to data reported by VA Teledermatology Program Administrator Chris Foster.

Obtaining a prompt consultation is reported to be an overwhelming advantage of using SFT.^2-5 Rapid turnaround may appear to make SFT specialist care more accessible to veterans, yet this is an oversimplification. The process of delivering care (rather than consultation) through SFT is more complex than reading the images and reporting the findings. When a skin condition is identified by a primary care clinician and that person decides to request an SFT consultation, a complex set of tasks and handoffs is set into motion. A swim-lane diagram illustrates the numerous steps and handoffs that go into delivering care to a patient with a malignant melanoma on the SFT platform compared to FTF care, which requires fewer handoffs (Figure).

This process improvement project examined whether handoffs necessitated by SFT care lengthened the timeline of care for biopsy-proven primary cutaneous malignant melanoma. The stakes of delay in care are high. A 2018 study using the National Cancer Database found that a delay of > 30 days from biopsy to definitive excision (the date definitive surgical procedure for the condition is performed) resulted in a measurable increase in melanoma-related mortality. ⁶ This study sought to identify areas where the SFT timeline of care could be shortened.

Methods

This retrospective cohort study was approved by the VAPSHCS Institutional Review Board. The study drew from secondary data obtained from VistA, the VA Corporate Data Warehouse, the Veterans Integrated Service Network (VISN) 20 database, the American Academy of Dermatology Teledermatology Program database, and the VA Computerized Patient Record System.

Patients registered for ≥ 1 year at VAPSHCS with a diagnosis of primary cutaneous malignant melanoma by the Pathology service between January 1, 2006, and December 31, 2013, were included. Patients with metastatic or recurrent melanoma were excluded.

Cases were randomly selected from a melanoma database previously validated and used for another quality improvement project.⁷ There were initially 115 patient cases extracted from this database for both the FTF and SFT groups. Eighty-seven SFT and 107 FTF cases met inclusion criteria. To further analyze these groups, we split the FTF group into 2 subgroups: FTF dermatology (patients whose melanomas were entered into care in a dermatology clinic) and FTF primary care (patients whose melanomas were entered into care in primary care or a nondermatology setting).

The timeline of care was divided into 2 major time intervals: (1) entry into episode of care (EEC; the date a lesion was first documented in the electronic health record) to biopsy; and (2) biopsy to definitive excision. The SFT process was divided into the following intervals: EEC to imaging request (the date a clinician requested imaging); imaging request to imaging completion (the date an imager photographed a patient’s lesion); imaging completion to SFT consultation request (the date the SFT consultation was requested); SFT consultation request to consultation completion (the date an SFT reader completed the consultation request for a patient); and SFT consultation completion to biopsy. Mean and median interval lengths were compared between groups and additional analyses identified steps that may have contributed to delays in care.

To address potential bias based on access to care for rural veterans, SFT and FTF primary care cases were categorized into groups based on their location: (1) EEC and biopsy conducted at the same facility; (2) EEC and biopsy conducted at different facilities within the same health care system (main health care facility and its community-based outpatient clinics); and (3) EEC and biopsy conducted at different health care systems.

Statistics

Means, medians, and SDs were calculated in Excel. The Mann-Whitney U test was used to compare SFT medians to the FTF data and X² test was used to compare proportions for secondary analyses.

Results

The median (mean) interval from EEC to definitive excision was 73 days (85) for SFT and 58 days (73) for FTF (P = .004) (Table). To understand this difference, the distribution of intervals from EEC to biopsy and biopsy to definitive excision were calculated. Only 38% of SFT cases were biopsied within 20 days compared to 65% of FTF cases (P < .001). The difference in time from biopsy to definitive excision distributions were not statistically significant, suggesting that the difference is actually a reflection of the differences seen in the period between EEC and biopsy.

EEC and biopsy occurred at the same facility in 85% and 82% of FTF primary care and SFT cases, respectively. EEC and biopsy occurred at different facilities within the same health care system in 15% and 16% of FTF primary care and SFT cases, respectively. EEC and biopsy occurred at different health care systems in 0% and 2% of FTF primary care and SFT cases, respectively. Geographic bias did not impact results for either group of veterans.

The interval between EEC and biopsy was shorter for FTF dermatology cases than for FTF primary care cases. For FTF dermatology cases, 96% were biopsied within 20 days compared with 34% of FTF primary care cases (P < .001).

To further analyze the difference in the EEC to biopsy interval duration between SFT and FTF primary care the timeline was divided into smaller steps: EEC to imaging completion, imaging completion to SFT consult completion, and SFT consult completion to biopsy. From EEC to SFT consult completion, SFT cases took a median of 6.0 days and a mean of 12.3 days, reflecting the administrative handoffs that must occur in SFT. A total of 82% of FTF primary care cases were entered into care and consultation was requested on the same day, while this was true for only 1% of SFT cases.

Since mortality data were not collected, the frequency of in situ melanomas and invasive melanomas (pathologic stage pT1a or greater) was used as a proxy for comparing outcomes. No significant difference was found in the frequency of in situ vs invasive melanomas in the SFT and FTF dermatology groups; however, there was a much higher frequency of invasive melanomas in the FTF primary care group (P = .007).

Discussion

This study compared the time to treatment for SFT vs FTF and identified important differences. The episode of care for melanomas diagnosed by SFT was statistically significantly longer (15 days) than those diagnosed by FTF. The interval between biopsy and definitive excision was a median of 34 and 38 days, and a mean of 48 and 44 days for SFT and FTF, respectively, which were not statistically significant. The difference in the total duration of the interval between EEC and definitive excision was accounted for by the duration of the interval from EEC to biopsy. When excluding dermatology clinic cases from the FTF group, there was no difference in the interval between EEC and biopsy for SFT and FTF primary care. The handoffs in SFT accounted for a median of 6 days and mean of 12 days, a significant portion of the timeline, and is a target for process improvement. The delay necessitated by handoffs did not significantly affect the distribution of in situ and invasive melanomas in the SFT and FTF dermatology groups. This suggests that SFT may have better outcomes than FTF primary care.

There has been extensive research on the timeline from the patient initially noticing a lesion to the EEC.^8-11 There is also a body of research on the timeline from biopsy to definitive excision. ^6,12-16 However, there has been little research on the timeline between EEC and biopsy, which comprises a large portion of the overall timeline of both SFT care and FTF care. This study analyzed the delays that can occur in this interval. When patients first enter FTF dermatology care, this timeline is quite short because lesions are often biopsied on the same day. When patients enter into care with their primary or nondermatology clinician, there can be significant delays.

Since the stakes are high when it comes to treating melanoma, it is important to minimize the overall timeline. A 6-day median and 12-day mean were established as targets for teledermatology handoffs. Ideally, a lesion should be entered into an episode of care, imaged, and sent for consultation on the same day. To help further understand delays in administrative handoffs, we stratified the SFT cases by VISN 20 sites and spoke with an administrator at a top performing site. Between 2006 and 2013, this site had a dedicated full-time imager as well as a backup imager that ensured images were taken quickly, usually on the same day the lesion was entered into care. Unfortunately, this is not the standard at all VISN 20 sites and certainly contributes to the overall delay in care in SFT

Minimizing the timeline of care is possible, as shown by the Danish health system, which developed a fast-track referral system after recognizing the need to minimize delays between the presentation, diagnosis, and treatment of cutaneous melanomas. In Denmark, a patient who presents to a general practitioner with a suspicious lesion is referred to secondary care for excision biopsy within 6 days. Diagnosis is made within 2 weeks, and, if necessary, definitive excision is offered within 9 days of the diagnosis. This translates into a maximum 20-day EEC to biopsy timeline and maximum 29-day EEC to definitive excision timeline. Although an intervention such as this may be difficult to implement in the United States due to its size and decentralized health care system, it would, however, be more realistic within the VA due to its centralized structure. The Danish system shows that with appropriate resource allocation and strict timeframes for treatment referrals, the timeline can be minimized.¹⁷

Despite the delay in the SFT timeline, this study found no significant difference between the distribution of in situ vs invasive melanomas in FTF dermatology and SFT groups. One possible explanation for this is that SFT increases access to dermatologist care, meaning clinicians may be more willing to consult SFT for less advanced– appearing lesions.

The finding that SFT diagnosed a larger proportion of in situ melanomas than FTF primary care is consistent with the findings of Ferrándiz et al, who reported that the mean Breslow thickness was significantly lower among patients in an SFT group compared to patients in an FTF group consisting of general practitioners. ¹⁸ However, the study population was not randomized and the results may have been impacted by ascertainment bias. Ferrándiz et al hypothesized that clinicians may have a lower threshold for consulting teledermatology, resulting in lower mean Breslow thicknesses.¹⁸ Karavan et al found the opposite results, with a higher mean Breslow thickness in SFT compared to a primary care FTF group.¹⁹ The data presented here suggest that SFT has room for process improvement yet is essentially equivalent to FTF dermatology in terms of outcomes.

Limitations

The majority of patients in this study were aged > 50 years, White, and male. The results may not be representative for other populations. The study was relatively small compared to studies that looked at other aspects of the melanoma care timeline. The study was not powered to ascertain mortality, the most important metric for melanoma.

Conclusions

The episode of care was significantly longer for melanomas diagnosed by SFT than those diagnosed by FTF; however, timelines were not statistically different when FTF lesions entered into care in dermatology were excluded. A median 6-day and mean 12.3-day delay in administrative handoffs occurred at the beginning of the SFT process and is a target for process improvement. Considering the high stakes of melanoma, the SFT timeline could be reduced if EEC, imaging, and SFT consultation all happened in the same day.

Store-and-forward teledermatology (SFT) allows clinical images and information to be sent to a dermatologist for evaluation. In fiscal year (FY) 2018, 117,780 SFT consultations were completed in the Veterans Health Administration. Continued growth is expected since SFT has proven to be an effective method for improving access to face-to-face (FTF) dermatology care.¹ In the same period, the US Department of Veterans Affairs (VA) Puget Sound Health Care System (VAPSHCS) completed 12,563 consultations in a mean 1.1 days from entry into episode of care (EEC), according to data reported by VA Teledermatology Program Administrator Chris Foster.

Obtaining a prompt consultation is reported to be an overwhelming advantage of using SFT.^2-5 Rapid turnaround may appear to make SFT specialist care more accessible to veterans, yet this is an oversimplification. The process of delivering care (rather than consultation) through SFT is more complex than reading the images and reporting the findings. When a skin condition is identified by a primary care clinician and that person decides to request an SFT consultation, a complex set of tasks and handoffs is set into motion. A swim-lane diagram illustrates the numerous steps and handoffs that go into delivering care to a patient with a malignant melanoma on the SFT platform compared to FTF care, which requires fewer handoffs (Figure).

This process improvement project examined whether handoffs necessitated by SFT care lengthened the timeline of care for biopsy-proven primary cutaneous malignant melanoma. The stakes of delay in care are high. A 2018 study using the National Cancer Database found that a delay of > 30 days from biopsy to definitive excision (the date definitive surgical procedure for the condition is performed) resulted in a measurable increase in melanoma-related mortality. ⁶ This study sought to identify areas where the SFT timeline of care could be shortened.

Methods

This retrospective cohort study was approved by the VAPSHCS Institutional Review Board. The study drew from secondary data obtained from VistA, the VA Corporate Data Warehouse, the Veterans Integrated Service Network (VISN) 20 database, the American Academy of Dermatology Teledermatology Program database, and the VA Computerized Patient Record System.

Patients registered for ≥ 1 year at VAPSHCS with a diagnosis of primary cutaneous malignant melanoma by the Pathology service between January 1, 2006, and December 31, 2013, were included. Patients with metastatic or recurrent melanoma were excluded.

Cases were randomly selected from a melanoma database previously validated and used for another quality improvement project.⁷ There were initially 115 patient cases extracted from this database for both the FTF and SFT groups. Eighty-seven SFT and 107 FTF cases met inclusion criteria. To further analyze these groups, we split the FTF group into 2 subgroups: FTF dermatology (patients whose melanomas were entered into care in a dermatology clinic) and FTF primary care (patients whose melanomas were entered into care in primary care or a nondermatology setting).

The timeline of care was divided into 2 major time intervals: (1) entry into episode of care (EEC; the date a lesion was first documented in the electronic health record) to biopsy; and (2) biopsy to definitive excision. The SFT process was divided into the following intervals: EEC to imaging request (the date a clinician requested imaging); imaging request to imaging completion (the date an imager photographed a patient’s lesion); imaging completion to SFT consultation request (the date the SFT consultation was requested); SFT consultation request to consultation completion (the date an SFT reader completed the consultation request for a patient); and SFT consultation completion to biopsy. Mean and median interval lengths were compared between groups and additional analyses identified steps that may have contributed to delays in care.

To address potential bias based on access to care for rural veterans, SFT and FTF primary care cases were categorized into groups based on their location: (1) EEC and biopsy conducted at the same facility; (2) EEC and biopsy conducted at different facilities within the same health care system (main health care facility and its community-based outpatient clinics); and (3) EEC and biopsy conducted at different health care systems.

Statistics

Means, medians, and SDs were calculated in Excel. The Mann-Whitney U test was used to compare SFT medians to the FTF data and X² test was used to compare proportions for secondary analyses.

Results

The median (mean) interval from EEC to definitive excision was 73 days (85) for SFT and 58 days (73) for FTF (P = .004) (Table). To understand this difference, the distribution of intervals from EEC to biopsy and biopsy to definitive excision were calculated. Only 38% of SFT cases were biopsied within 20 days compared to 65% of FTF cases (P < .001). The difference in time from biopsy to definitive excision distributions were not statistically significant, suggesting that the difference is actually a reflection of the differences seen in the period between EEC and biopsy.

EEC and biopsy occurred at the same facility in 85% and 82% of FTF primary care and SFT cases, respectively. EEC and biopsy occurred at different facilities within the same health care system in 15% and 16% of FTF primary care and SFT cases, respectively. EEC and biopsy occurred at different health care systems in 0% and 2% of FTF primary care and SFT cases, respectively. Geographic bias did not impact results for either group of veterans.

The interval between EEC and biopsy was shorter for FTF dermatology cases than for FTF primary care cases. For FTF dermatology cases, 96% were biopsied within 20 days compared with 34% of FTF primary care cases (P < .001).

To further analyze the difference in the EEC to biopsy interval duration between SFT and FTF primary care the timeline was divided into smaller steps: EEC to imaging completion, imaging completion to SFT consult completion, and SFT consult completion to biopsy. From EEC to SFT consult completion, SFT cases took a median of 6.0 days and a mean of 12.3 days, reflecting the administrative handoffs that must occur in SFT. A total of 82% of FTF primary care cases were entered into care and consultation was requested on the same day, while this was true for only 1% of SFT cases.

Since mortality data were not collected, the frequency of in situ melanomas and invasive melanomas (pathologic stage pT1a or greater) was used as a proxy for comparing outcomes. No significant difference was found in the frequency of in situ vs invasive melanomas in the SFT and FTF dermatology groups; however, there was a much higher frequency of invasive melanomas in the FTF primary care group (P = .007).

Discussion

This study compared the time to treatment for SFT vs FTF and identified important differences. The episode of care for melanomas diagnosed by SFT was statistically significantly longer (15 days) than those diagnosed by FTF. The interval between biopsy and definitive excision was a median of 34 and 38 days, and a mean of 48 and 44 days for SFT and FTF, respectively, which were not statistically significant. The difference in the total duration of the interval between EEC and definitive excision was accounted for by the duration of the interval from EEC to biopsy. When excluding dermatology clinic cases from the FTF group, there was no difference in the interval between EEC and biopsy for SFT and FTF primary care. The handoffs in SFT accounted for a median of 6 days and mean of 12 days, a significant portion of the timeline, and is a target for process improvement. The delay necessitated by handoffs did not significantly affect the distribution of in situ and invasive melanomas in the SFT and FTF dermatology groups. This suggests that SFT may have better outcomes than FTF primary care.

There has been extensive research on the timeline from the patient initially noticing a lesion to the EEC.^8-11 There is also a body of research on the timeline from biopsy to definitive excision. ^6,12-16 However, there has been little research on the timeline between EEC and biopsy, which comprises a large portion of the overall timeline of both SFT care and FTF care. This study analyzed the delays that can occur in this interval. When patients first enter FTF dermatology care, this timeline is quite short because lesions are often biopsied on the same day. When patients enter into care with their primary or nondermatology clinician, there can be significant delays.

Since the stakes are high when it comes to treating melanoma, it is important to minimize the overall timeline. A 6-day median and 12-day mean were established as targets for teledermatology handoffs. Ideally, a lesion should be entered into an episode of care, imaged, and sent for consultation on the same day. To help further understand delays in administrative handoffs, we stratified the SFT cases by VISN 20 sites and spoke with an administrator at a top performing site. Between 2006 and 2013, this site had a dedicated full-time imager as well as a backup imager that ensured images were taken quickly, usually on the same day the lesion was entered into care. Unfortunately, this is not the standard at all VISN 20 sites and certainly contributes to the overall delay in care in SFT

Minimizing the timeline of care is possible, as shown by the Danish health system, which developed a fast-track referral system after recognizing the need to minimize delays between the presentation, diagnosis, and treatment of cutaneous melanomas. In Denmark, a patient who presents to a general practitioner with a suspicious lesion is referred to secondary care for excision biopsy within 6 days. Diagnosis is made within 2 weeks, and, if necessary, definitive excision is offered within 9 days of the diagnosis. This translates into a maximum 20-day EEC to biopsy timeline and maximum 29-day EEC to definitive excision timeline. Although an intervention such as this may be difficult to implement in the United States due to its size and decentralized health care system, it would, however, be more realistic within the VA due to its centralized structure. The Danish system shows that with appropriate resource allocation and strict timeframes for treatment referrals, the timeline can be minimized.¹⁷

Despite the delay in the SFT timeline, this study found no significant difference between the distribution of in situ vs invasive melanomas in FTF dermatology and SFT groups. One possible explanation for this is that SFT increases access to dermatologist care, meaning clinicians may be more willing to consult SFT for less advanced– appearing lesions.

The finding that SFT diagnosed a larger proportion of in situ melanomas than FTF primary care is consistent with the findings of Ferrándiz et al, who reported that the mean Breslow thickness was significantly lower among patients in an SFT group compared to patients in an FTF group consisting of general practitioners. ¹⁸ However, the study population was not randomized and the results may have been impacted by ascertainment bias. Ferrándiz et al hypothesized that clinicians may have a lower threshold for consulting teledermatology, resulting in lower mean Breslow thicknesses.¹⁸ Karavan et al found the opposite results, with a higher mean Breslow thickness in SFT compared to a primary care FTF group.¹⁹ The data presented here suggest that SFT has room for process improvement yet is essentially equivalent to FTF dermatology in terms of outcomes.

Limitations

The majority of patients in this study were aged > 50 years, White, and male. The results may not be representative for other populations. The study was relatively small compared to studies that looked at other aspects of the melanoma care timeline. The study was not powered to ascertain mortality, the most important metric for melanoma.

Conclusions

The episode of care was significantly longer for melanomas diagnosed by SFT than those diagnosed by FTF; however, timelines were not statistically different when FTF lesions entered into care in dermatology were excluded. A median 6-day and mean 12.3-day delay in administrative handoffs occurred at the beginning of the SFT process and is a target for process improvement. Considering the high stakes of melanoma, the SFT timeline could be reduced if EEC, imaging, and SFT consultation all happened in the same day.

Store-and-forward teledermatology (SFT) allows clinical images and information to be sent to a dermatologist for evaluation. In fiscal year (FY) 2018, 117,780 SFT consultations were completed in the Veterans Health Administration. Continued growth is expected since SFT has proven to be an effective method for improving access to face-to-face (FTF) dermatology care.¹ In the same period, the US Department of Veterans Affairs (VA) Puget Sound Health Care System (VAPSHCS) completed 12,563 consultations in a mean 1.1 days from entry into episode of care (EEC), according to data reported by VA Teledermatology Program Administrator Chris Foster.

Obtaining a prompt consultation is reported to be an overwhelming advantage of using SFT.^2-5 Rapid turnaround may appear to make SFT specialist care more accessible to veterans, yet this is an oversimplification. The process of delivering care (rather than consultation) through SFT is more complex than reading the images and reporting the findings. When a skin condition is identified by a primary care clinician and that person decides to request an SFT consultation, a complex set of tasks and handoffs is set into motion. A swim-lane diagram illustrates the numerous steps and handoffs that go into delivering care to a patient with a malignant melanoma on the SFT platform compared to FTF care, which requires fewer handoffs (Figure).

This process improvement project examined whether handoffs necessitated by SFT care lengthened the timeline of care for biopsy-proven primary cutaneous malignant melanoma. The stakes of delay in care are high. A 2018 study using the National Cancer Database found that a delay of > 30 days from biopsy to definitive excision (the date definitive surgical procedure for the condition is performed) resulted in a measurable increase in melanoma-related mortality. ⁶ This study sought to identify areas where the SFT timeline of care could be shortened.

Methods

This retrospective cohort study was approved by the VAPSHCS Institutional Review Board. The study drew from secondary data obtained from VistA, the VA Corporate Data Warehouse, the Veterans Integrated Service Network (VISN) 20 database, the American Academy of Dermatology Teledermatology Program database, and the VA Computerized Patient Record System.

Patients registered for ≥ 1 year at VAPSHCS with a diagnosis of primary cutaneous malignant melanoma by the Pathology service between January 1, 2006, and December 31, 2013, were included. Patients with metastatic or recurrent melanoma were excluded.

Cases were randomly selected from a melanoma database previously validated and used for another quality improvement project.⁷ There were initially 115 patient cases extracted from this database for both the FTF and SFT groups. Eighty-seven SFT and 107 FTF cases met inclusion criteria. To further analyze these groups, we split the FTF group into 2 subgroups: FTF dermatology (patients whose melanomas were entered into care in a dermatology clinic) and FTF primary care (patients whose melanomas were entered into care in primary care or a nondermatology setting).

The timeline of care was divided into 2 major time intervals: (1) entry into episode of care (EEC; the date a lesion was first documented in the electronic health record) to biopsy; and (2) biopsy to definitive excision. The SFT process was divided into the following intervals: EEC to imaging request (the date a clinician requested imaging); imaging request to imaging completion (the date an imager photographed a patient’s lesion); imaging completion to SFT consultation request (the date the SFT consultation was requested); SFT consultation request to consultation completion (the date an SFT reader completed the consultation request for a patient); and SFT consultation completion to biopsy. Mean and median interval lengths were compared between groups and additional analyses identified steps that may have contributed to delays in care.

To address potential bias based on access to care for rural veterans, SFT and FTF primary care cases were categorized into groups based on their location: (1) EEC and biopsy conducted at the same facility; (2) EEC and biopsy conducted at different facilities within the same health care system (main health care facility and its community-based outpatient clinics); and (3) EEC and biopsy conducted at different health care systems.

Statistics

Means, medians, and SDs were calculated in Excel. The Mann-Whitney U test was used to compare SFT medians to the FTF data and X² test was used to compare proportions for secondary analyses.

Results

The median (mean) interval from EEC to definitive excision was 73 days (85) for SFT and 58 days (73) for FTF (P = .004) (Table). To understand this difference, the distribution of intervals from EEC to biopsy and biopsy to definitive excision were calculated. Only 38% of SFT cases were biopsied within 20 days compared to 65% of FTF cases (P < .001). The difference in time from biopsy to definitive excision distributions were not statistically significant, suggesting that the difference is actually a reflection of the differences seen in the period between EEC and biopsy.

EEC and biopsy occurred at the same facility in 85% and 82% of FTF primary care and SFT cases, respectively. EEC and biopsy occurred at different facilities within the same health care system in 15% and 16% of FTF primary care and SFT cases, respectively. EEC and biopsy occurred at different health care systems in 0% and 2% of FTF primary care and SFT cases, respectively. Geographic bias did not impact results for either group of veterans.

The interval between EEC and biopsy was shorter for FTF dermatology cases than for FTF primary care cases. For FTF dermatology cases, 96% were biopsied within 20 days compared with 34% of FTF primary care cases (P < .001).

To further analyze the difference in the EEC to biopsy interval duration between SFT and FTF primary care the timeline was divided into smaller steps: EEC to imaging completion, imaging completion to SFT consult completion, and SFT consult completion to biopsy. From EEC to SFT consult completion, SFT cases took a median of 6.0 days and a mean of 12.3 days, reflecting the administrative handoffs that must occur in SFT. A total of 82% of FTF primary care cases were entered into care and consultation was requested on the same day, while this was true for only 1% of SFT cases.

Since mortality data were not collected, the frequency of in situ melanomas and invasive melanomas (pathologic stage pT1a or greater) was used as a proxy for comparing outcomes. No significant difference was found in the frequency of in situ vs invasive melanomas in the SFT and FTF dermatology groups; however, there was a much higher frequency of invasive melanomas in the FTF primary care group (P = .007).

Discussion

This study compared the time to treatment for SFT vs FTF and identified important differences. The episode of care for melanomas diagnosed by SFT was statistically significantly longer (15 days) than those diagnosed by FTF. The interval between biopsy and definitive excision was a median of 34 and 38 days, and a mean of 48 and 44 days for SFT and FTF, respectively, which were not statistically significant. The difference in the total duration of the interval between EEC and definitive excision was accounted for by the duration of the interval from EEC to biopsy. When excluding dermatology clinic cases from the FTF group, there was no difference in the interval between EEC and biopsy for SFT and FTF primary care. The handoffs in SFT accounted for a median of 6 days and mean of 12 days, a significant portion of the timeline, and is a target for process improvement. The delay necessitated by handoffs did not significantly affect the distribution of in situ and invasive melanomas in the SFT and FTF dermatology groups. This suggests that SFT may have better outcomes than FTF primary care.

There has been extensive research on the timeline from the patient initially noticing a lesion to the EEC.^8-11 There is also a body of research on the timeline from biopsy to definitive excision. ^6,12-16 However, there has been little research on the timeline between EEC and biopsy, which comprises a large portion of the overall timeline of both SFT care and FTF care. This study analyzed the delays that can occur in this interval. When patients first enter FTF dermatology care, this timeline is quite short because lesions are often biopsied on the same day. When patients enter into care with their primary or nondermatology clinician, there can be significant delays.

Since the stakes are high when it comes to treating melanoma, it is important to minimize the overall timeline. A 6-day median and 12-day mean were established as targets for teledermatology handoffs. Ideally, a lesion should be entered into an episode of care, imaged, and sent for consultation on the same day. To help further understand delays in administrative handoffs, we stratified the SFT cases by VISN 20 sites and spoke with an administrator at a top performing site. Between 2006 and 2013, this site had a dedicated full-time imager as well as a backup imager that ensured images were taken quickly, usually on the same day the lesion was entered into care. Unfortunately, this is not the standard at all VISN 20 sites and certainly contributes to the overall delay in care in SFT

Minimizing the timeline of care is possible, as shown by the Danish health system, which developed a fast-track referral system after recognizing the need to minimize delays between the presentation, diagnosis, and treatment of cutaneous melanomas. In Denmark, a patient who presents to a general practitioner with a suspicious lesion is referred to secondary care for excision biopsy within 6 days. Diagnosis is made within 2 weeks, and, if necessary, definitive excision is offered within 9 days of the diagnosis. This translates into a maximum 20-day EEC to biopsy timeline and maximum 29-day EEC to definitive excision timeline. Although an intervention such as this may be difficult to implement in the United States due to its size and decentralized health care system, it would, however, be more realistic within the VA due to its centralized structure. The Danish system shows that with appropriate resource allocation and strict timeframes for treatment referrals, the timeline can be minimized.¹⁷

Despite the delay in the SFT timeline, this study found no significant difference between the distribution of in situ vs invasive melanomas in FTF dermatology and SFT groups. One possible explanation for this is that SFT increases access to dermatologist care, meaning clinicians may be more willing to consult SFT for less advanced– appearing lesions.

The finding that SFT diagnosed a larger proportion of in situ melanomas than FTF primary care is consistent with the findings of Ferrándiz et al, who reported that the mean Breslow thickness was significantly lower among patients in an SFT group compared to patients in an FTF group consisting of general practitioners. ¹⁸ However, the study population was not randomized and the results may have been impacted by ascertainment bias. Ferrándiz et al hypothesized that clinicians may have a lower threshold for consulting teledermatology, resulting in lower mean Breslow thicknesses.¹⁸ Karavan et al found the opposite results, with a higher mean Breslow thickness in SFT compared to a primary care FTF group.¹⁹ The data presented here suggest that SFT has room for process improvement yet is essentially equivalent to FTF dermatology in terms of outcomes.

Limitations

The majority of patients in this study were aged > 50 years, White, and male. The results may not be representative for other populations. The study was relatively small compared to studies that looked at other aspects of the melanoma care timeline. The study was not powered to ascertain mortality, the most important metric for melanoma.

Conclusions

The episode of care was significantly longer for melanomas diagnosed by SFT than those diagnosed by FTF; however, timelines were not statistically different when FTF lesions entered into care in dermatology were excluded. A median 6-day and mean 12.3-day delay in administrative handoffs occurred at the beginning of the SFT process and is a target for process improvement. Considering the high stakes of melanoma, the SFT timeline could be reduced if EEC, imaging, and SFT consultation all happened in the same day.

Lifeguards play a crucial role in ensuring water safety, but they also are uniquely positioned to promote skin cancer prevention and proper sunscreen use.^1,2 There are several benefits and challenges to offering skin cancer prevention training for lifeguards.³ We examine the advantages of training, highlight the role lifeguards can play in larger public skin cancer prevention efforts, and address practical techniques for developing lifeguardfocused skin cancer education programs. By providing this knowledge to lifeguards, we can improve community health outcomes and encourage sun-safe behaviors in high-risk outdoor locations.

Benefits of Skin Cancer Prevention Training for Lifeguards

Research has shown that lifeguards are at an elevated risk for basal cell carcinoma, squamous cell carcinoma, and melanoma due to frequent prolonged occupational sun exposure.^1,2,4-6 Therefore, comprehensive education on skin cancer prevention—including instruction on proper sunscreen application techniques and the importance of regular reapplication as well as how to recognize suspicious skin lesions—should be incorporated into lifeguard certification programs. One study evaluating the effectiveness of a skin cancer prevention program for lifeguards found that many of the participants lacked a thorough understanding of the different types of skin cancer.⁵ Another study found that lifeguards at pools in areas where societal norms supporting sun safety are stronger exhibited noticeably more sun protection practices, with regression estimates of 0.22 (95% CI, 0.17-0.26).⁷ Empowering lifeguards with valuable health knowledge during their regular training could potentially reduce their risk for skin cancer,⁴ as they may be more inclined to use sunscreen appropriately and reach out to a dermatologist for regular skin checks and evaluation of suspicious lesions.

Role of Lifeguards in Public Skin Cancer Prevention Efforts

Once trained on skin cancer prevention, lifeguards also can play a pivotal role in promoting sunscreen use among the public. Despite the widespread availability of high-quality sunscreens, many swimmers and beachgoers neglect to regularly apply or reapply sunscreen, especially on commonly exposed areas such as the back, shoulders, and face.⁸ Educating lifeguards on skin cancer prevention could enhance health outcomes by increasing early detection rates and promoting sun-safe behaviors among the general public.⁹ However, additional training requirements might increase the cost and time commitment for lifeguard certification, potentially leading to staffing shortages.^3,7 There also is a risk of lifeguards overstepping their role and providing inaccurate medical advice, which could cause distress or even lead to liability issues.⁷ Balancing these factors will be crucial in developing effective and sustainable skin cancer prevention programs for lifeguards.

Implementing Lifeguard Skin Cancer Training

Implementing skin cancer prevention training programs for lifeguards requires strategic collaboration between dermatologists, and lifeguard training organizations to ensure that the participants receive consistent and comprehensive training.¹⁰ Additionally, public health campaigns can support these efforts by raising awareness about the importance of sun safety and regular skin checks.⁶ Tailored training modules/materials, ongoing technical assistance, and active, multicomponent approaches that account for both individual and environmental factors can increase program implementation in a variety of community settings.

Final Thoughts

Through effective education, lifeguards can potentially have a substantial impact on skin cancer prevention, both among lifeguards themselves and the general public. By promoting proper sunscreen use, lifeguards can help reduce the incidence and mortality associated with skin cancers. Future studies should focus on developing and implementing targeted education initiatives for lifeguards, fostering collaboration between relevant stakeholders, and raising public awareness about the importance of sun safety and early skin cancer detection. These efforts ultimately could lead to improved public health outcomes and reduced skin cancer rates, particularly in high-risk populations that frequently are exposed to UV radiation.

Lifeguards play a crucial role in ensuring water safety, but they also are uniquely positioned to promote skin cancer prevention and proper sunscreen use.^1,2 There are several benefits and challenges to offering skin cancer prevention training for lifeguards.³ We examine the advantages of training, highlight the role lifeguards can play in larger public skin cancer prevention efforts, and address practical techniques for developing lifeguardfocused skin cancer education programs. By providing this knowledge to lifeguards, we can improve community health outcomes and encourage sun-safe behaviors in high-risk outdoor locations.

Benefits of Skin Cancer Prevention Training for Lifeguards

Research has shown that lifeguards are at an elevated risk for basal cell carcinoma, squamous cell carcinoma, and melanoma due to frequent prolonged occupational sun exposure.^1,2,4-6 Therefore, comprehensive education on skin cancer prevention—including instruction on proper sunscreen application techniques and the importance of regular reapplication as well as how to recognize suspicious skin lesions—should be incorporated into lifeguard certification programs. One study evaluating the effectiveness of a skin cancer prevention program for lifeguards found that many of the participants lacked a thorough understanding of the different types of skin cancer.⁵ Another study found that lifeguards at pools in areas where societal norms supporting sun safety are stronger exhibited noticeably more sun protection practices, with regression estimates of 0.22 (95% CI, 0.17-0.26).⁷ Empowering lifeguards with valuable health knowledge during their regular training could potentially reduce their risk for skin cancer,⁴ as they may be more inclined to use sunscreen appropriately and reach out to a dermatologist for regular skin checks and evaluation of suspicious lesions.

Role of Lifeguards in Public Skin Cancer Prevention Efforts

Once trained on skin cancer prevention, lifeguards also can play a pivotal role in promoting sunscreen use among the public. Despite the widespread availability of high-quality sunscreens, many swimmers and beachgoers neglect to regularly apply or reapply sunscreen, especially on commonly exposed areas such as the back, shoulders, and face.⁸ Educating lifeguards on skin cancer prevention could enhance health outcomes by increasing early detection rates and promoting sun-safe behaviors among the general public.⁹ However, additional training requirements might increase the cost and time commitment for lifeguard certification, potentially leading to staffing shortages.^3,7 There also is a risk of lifeguards overstepping their role and providing inaccurate medical advice, which could cause distress or even lead to liability issues.⁷ Balancing these factors will be crucial in developing effective and sustainable skin cancer prevention programs for lifeguards.

Implementing Lifeguard Skin Cancer Training

Implementing skin cancer prevention training programs for lifeguards requires strategic collaboration between dermatologists, and lifeguard training organizations to ensure that the participants receive consistent and comprehensive training.¹⁰ Additionally, public health campaigns can support these efforts by raising awareness about the importance of sun safety and regular skin checks.⁶ Tailored training modules/materials, ongoing technical assistance, and active, multicomponent approaches that account for both individual and environmental factors can increase program implementation in a variety of community settings.

Final Thoughts

Through effective education, lifeguards can potentially have a substantial impact on skin cancer prevention, both among lifeguards themselves and the general public. By promoting proper sunscreen use, lifeguards can help reduce the incidence and mortality associated with skin cancers. Future studies should focus on developing and implementing targeted education initiatives for lifeguards, fostering collaboration between relevant stakeholders, and raising public awareness about the importance of sun safety and early skin cancer detection. These efforts ultimately could lead to improved public health outcomes and reduced skin cancer rates, particularly in high-risk populations that frequently are exposed to UV radiation.

Lifeguards play a crucial role in ensuring water safety, but they also are uniquely positioned to promote skin cancer prevention and proper sunscreen use.^1,2 There are several benefits and challenges to offering skin cancer prevention training for lifeguards.³ We examine the advantages of training, highlight the role lifeguards can play in larger public skin cancer prevention efforts, and address practical techniques for developing lifeguardfocused skin cancer education programs. By providing this knowledge to lifeguards, we can improve community health outcomes and encourage sun-safe behaviors in high-risk outdoor locations.

Benefits of Skin Cancer Prevention Training for Lifeguards

Research has shown that lifeguards are at an elevated risk for basal cell carcinoma, squamous cell carcinoma, and melanoma due to frequent prolonged occupational sun exposure.^1,2,4-6 Therefore, comprehensive education on skin cancer prevention—including instruction on proper sunscreen application techniques and the importance of regular reapplication as well as how to recognize suspicious skin lesions—should be incorporated into lifeguard certification programs. One study evaluating the effectiveness of a skin cancer prevention program for lifeguards found that many of the participants lacked a thorough understanding of the different types of skin cancer.⁵ Another study found that lifeguards at pools in areas where societal norms supporting sun safety are stronger exhibited noticeably more sun protection practices, with regression estimates of 0.22 (95% CI, 0.17-0.26).⁷ Empowering lifeguards with valuable health knowledge during their regular training could potentially reduce their risk for skin cancer,⁴ as they may be more inclined to use sunscreen appropriately and reach out to a dermatologist for regular skin checks and evaluation of suspicious lesions.

Role of Lifeguards in Public Skin Cancer Prevention Efforts

Once trained on skin cancer prevention, lifeguards also can play a pivotal role in promoting sunscreen use among the public. Despite the widespread availability of high-quality sunscreens, many swimmers and beachgoers neglect to regularly apply or reapply sunscreen, especially on commonly exposed areas such as the back, shoulders, and face.⁸ Educating lifeguards on skin cancer prevention could enhance health outcomes by increasing early detection rates and promoting sun-safe behaviors among the general public.⁹ However, additional training requirements might increase the cost and time commitment for lifeguard certification, potentially leading to staffing shortages.^3,7 There also is a risk of lifeguards overstepping their role and providing inaccurate medical advice, which could cause distress or even lead to liability issues.⁷ Balancing these factors will be crucial in developing effective and sustainable skin cancer prevention programs for lifeguards.

Implementing Lifeguard Skin Cancer Training

Implementing skin cancer prevention training programs for lifeguards requires strategic collaboration between dermatologists, and lifeguard training organizations to ensure that the participants receive consistent and comprehensive training.¹⁰ Additionally, public health campaigns can support these efforts by raising awareness about the importance of sun safety and regular skin checks.⁶ Tailored training modules/materials, ongoing technical assistance, and active, multicomponent approaches that account for both individual and environmental factors can increase program implementation in a variety of community settings.

Final Thoughts

Through effective education, lifeguards can potentially have a substantial impact on skin cancer prevention, both among lifeguards themselves and the general public. By promoting proper sunscreen use, lifeguards can help reduce the incidence and mortality associated with skin cancers. Future studies should focus on developing and implementing targeted education initiatives for lifeguards, fostering collaboration between relevant stakeholders, and raising public awareness about the importance of sun safety and early skin cancer detection. These efforts ultimately could lead to improved public health outcomes and reduced skin cancer rates, particularly in high-risk populations that frequently are exposed to UV radiation.

A noninvasive clinicopathologic and gene expression profiling (CP-GEP)–based tool, the Merlin assay, shows promise for identifying recurrence risks in patients with early-stage melanoma who do not undergo sentinel lymph node biopsy (SNLB).

This was the conclusion of a retrospective analysis of a large cohort of patients with stage I/II disease, reported by Teresa Amaral, MD, PhD, at the 11th World Congress of Melanoma and 21st European Association of Dermato-Oncology Congress 2025.

Of 930 patients included in the study, the assay identified 879 as having a low risk for recurrence and 51 as having high risk for recurrence. The overall 5-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) rates were 90.9%, 96.9%, and 97.5%, respectively.

The corresponding rates among those stratified by the assay as having low vs high recurrence risk, respectively, were 94.6% and 26.6% for RFS (hazard ratio [HR], 25.08), 98.6% vs 62.1% for DMFS (HR, 35.39), and 99.4% vs 61.7% for MSS (HR, 71.05), said Amaral, during her presentation at the meeting.

Of 16 melanoma-specific deaths, 12 were stratified as high risk for recurrence by the CP-GEP assay, said Amaral, head of the Skin Cancer Clinical Trials Center at the University of Tübingen, Tübingen, Germany, and first author of the study.

Study participants had stages IA-IIC melanoma, 41% were women, and median age was 64 years. Median melanoma thickness was 0.5 mm, and 94% were not ulcerated. 

No systemic treatment options currently exist for patients with this early-stage disease, the author said.

The CP-GEP model, initially developed by the Mayo Clinic and SkylineDx BV to predict the positivity of SNLB, has been validated in multiple studies.

Amaral and her colleagues previously demonstrated the ability of the CP-GEP model to stratify patients with stages I-II disease as having low or high risk for recurrence — including in a small number of patients without SNLB. Those findings are confirmed in this larger population of patients who did not undergo SNLB, she said.

SkylineDx announced the findings in a press release stating the results validate the prognostic power of the Merlin assay for “identifying tumors at high risk for relapse that would otherwise be missed by traditional clinical and pathological evaluation.”

SNLB is the gold standard for nodal assessment for staging cutaneous melanoma. More than 80% of patients who undergo SNLB are negative for nodal metastases, but most patients who relapse or die from their melanoma are initially stratified by SNLB as having low-risk early-stage disease, Amaral explained. This suggests “SNLB is not enough,” she noted.

The findings suggest that CP-GEP has the potential to risk stratify patients with early-stage melanoma that did not undergo SLNB and help select those who can forgo SLNB, she said.

Without another means of assessing risk, patients considered low risk based on SNLB are closely followed, the author explained.

“If we could identify the very low-risk patient and then allocate the resources to the very high-risk patients who really need a more detailed and more tailored approach…we would be doing a favor to our patients,” the author concluded.

Amaral disclosed personal financial relationships with Delcath, Philogen, Bristol Myers Squibb, NeraCare, Novartis, Pierre Fabre, CeCaVa, and MedTrix.

A version of this article first appeared on Medscape.com.

A noninvasive clinicopathologic and gene expression profiling (CP-GEP)–based tool, the Merlin assay, shows promise for identifying recurrence risks in patients with early-stage melanoma who do not undergo sentinel lymph node biopsy (SNLB).

This was the conclusion of a retrospective analysis of a large cohort of patients with stage I/II disease, reported by Teresa Amaral, MD, PhD, at the 11th World Congress of Melanoma and 21st European Association of Dermato-Oncology Congress 2025.

Of 930 patients included in the study, the assay identified 879 as having a low risk for recurrence and 51 as having high risk for recurrence. The overall 5-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) rates were 90.9%, 96.9%, and 97.5%, respectively.

The corresponding rates among those stratified by the assay as having low vs high recurrence risk, respectively, were 94.6% and 26.6% for RFS (hazard ratio [HR], 25.08), 98.6% vs 62.1% for DMFS (HR, 35.39), and 99.4% vs 61.7% for MSS (HR, 71.05), said Amaral, during her presentation at the meeting.

Of 16 melanoma-specific deaths, 12 were stratified as high risk for recurrence by the CP-GEP assay, said Amaral, head of the Skin Cancer Clinical Trials Center at the University of Tübingen, Tübingen, Germany, and first author of the study.

Study participants had stages IA-IIC melanoma, 41% were women, and median age was 64 years. Median melanoma thickness was 0.5 mm, and 94% were not ulcerated. 

No systemic treatment options currently exist for patients with this early-stage disease, the author said.

The CP-GEP model, initially developed by the Mayo Clinic and SkylineDx BV to predict the positivity of SNLB, has been validated in multiple studies.

Amaral and her colleagues previously demonstrated the ability of the CP-GEP model to stratify patients with stages I-II disease as having low or high risk for recurrence — including in a small number of patients without SNLB. Those findings are confirmed in this larger population of patients who did not undergo SNLB, she said.

SkylineDx announced the findings in a press release stating the results validate the prognostic power of the Merlin assay for “identifying tumors at high risk for relapse that would otherwise be missed by traditional clinical and pathological evaluation.”

SNLB is the gold standard for nodal assessment for staging cutaneous melanoma. More than 80% of patients who undergo SNLB are negative for nodal metastases, but most patients who relapse or die from their melanoma are initially stratified by SNLB as having low-risk early-stage disease, Amaral explained. This suggests “SNLB is not enough,” she noted.

The findings suggest that CP-GEP has the potential to risk stratify patients with early-stage melanoma that did not undergo SLNB and help select those who can forgo SLNB, she said.

Without another means of assessing risk, patients considered low risk based on SNLB are closely followed, the author explained.

“If we could identify the very low-risk patient and then allocate the resources to the very high-risk patients who really need a more detailed and more tailored approach…we would be doing a favor to our patients,” the author concluded.

Amaral disclosed personal financial relationships with Delcath, Philogen, Bristol Myers Squibb, NeraCare, Novartis, Pierre Fabre, CeCaVa, and MedTrix.

A version of this article first appeared on Medscape.com.

A noninvasive clinicopathologic and gene expression profiling (CP-GEP)–based tool, the Merlin assay, shows promise for identifying recurrence risks in patients with early-stage melanoma who do not undergo sentinel lymph node biopsy (SNLB).

This was the conclusion of a retrospective analysis of a large cohort of patients with stage I/II disease, reported by Teresa Amaral, MD, PhD, at the 11th World Congress of Melanoma and 21st European Association of Dermato-Oncology Congress 2025.

Of 930 patients included in the study, the assay identified 879 as having a low risk for recurrence and 51 as having high risk for recurrence. The overall 5-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) rates were 90.9%, 96.9%, and 97.5%, respectively.

The corresponding rates among those stratified by the assay as having low vs high recurrence risk, respectively, were 94.6% and 26.6% for RFS (hazard ratio [HR], 25.08), 98.6% vs 62.1% for DMFS (HR, 35.39), and 99.4% vs 61.7% for MSS (HR, 71.05), said Amaral, during her presentation at the meeting.

Of 16 melanoma-specific deaths, 12 were stratified as high risk for recurrence by the CP-GEP assay, said Amaral, head of the Skin Cancer Clinical Trials Center at the University of Tübingen, Tübingen, Germany, and first author of the study.

Study participants had stages IA-IIC melanoma, 41% were women, and median age was 64 years. Median melanoma thickness was 0.5 mm, and 94% were not ulcerated. 

No systemic treatment options currently exist for patients with this early-stage disease, the author said.

The CP-GEP model, initially developed by the Mayo Clinic and SkylineDx BV to predict the positivity of SNLB, has been validated in multiple studies.

Amaral and her colleagues previously demonstrated the ability of the CP-GEP model to stratify patients with stages I-II disease as having low or high risk for recurrence — including in a small number of patients without SNLB. Those findings are confirmed in this larger population of patients who did not undergo SNLB, she said.

SkylineDx announced the findings in a press release stating the results validate the prognostic power of the Merlin assay for “identifying tumors at high risk for relapse that would otherwise be missed by traditional clinical and pathological evaluation.”

SNLB is the gold standard for nodal assessment for staging cutaneous melanoma. More than 80% of patients who undergo SNLB are negative for nodal metastases, but most patients who relapse or die from their melanoma are initially stratified by SNLB as having low-risk early-stage disease, Amaral explained. This suggests “SNLB is not enough,” she noted.

The findings suggest that CP-GEP has the potential to risk stratify patients with early-stage melanoma that did not undergo SLNB and help select those who can forgo SLNB, she said.

Without another means of assessing risk, patients considered low risk based on SNLB are closely followed, the author explained.

“If we could identify the very low-risk patient and then allocate the resources to the very high-risk patients who really need a more detailed and more tailored approach…we would be doing a favor to our patients,” the author concluded.

Amaral disclosed personal financial relationships with Delcath, Philogen, Bristol Myers Squibb, NeraCare, Novartis, Pierre Fabre, CeCaVa, and MedTrix.

A version of this article first appeared on Medscape.com.

Practice Gap

Brown macules on the feet can pose diagnostic challenges, often raising suspicion of acral melanoma. Talon noir, which is benign and self-resolving, is characterized by dark patches on the skin of the feet due to hemorrhage within the stratum corneum and commonly is observed in athletes who sustain repetitive foot trauma. In one study, nearly 50% (9/20) of talon noir cases initially were misdiagnosed as acral melanoma or melanocytic nevi.¹ Accurate identification of talon noir is essential to prevent unnecessary interventions or delayed treatment of malignant lesions. Here, we describe a low-risk, cost-effective, and time-efficient diagnostic technique for talon noir using a disposable curette to potentially avoid more invasive procedures.

The Technique

A 34-year-old man presented to the dermatology department with a new brown macule on the second toe. The lesion had been present and stable for more than 4 months, showing no changes in shape or color. The patient reported that he was a frequent runner but did not recall any trauma to the toe, and he denied any associated pain, pruritus, or bleeding. Physical examination revealed a 6-mm dark-brown macule on the hyponychium of the left second toe, with numerous petechiae noted on dermoscopic examination. The findings were consistent with talon noir.

Given the clinical suspicion of talon noir, we used a 5-mm disposable curette to gently pare the superficial epidermis. The superficial curettage effectively removed the lesion, leaving behind a healthy epidermis with no pinpoint bleeding, which confirmed the diagnosis of talon noir (Figure). Pathologic changes from acral melanoma reside deeper than talon noir and consequently cannot be effectively removed by superficial curettage alone. Curettage acts as a curative technique for talon noir, but also as a low-risk, cost-effective, and time-efficient diagnostic technique to rule out insidious diagnoses, including acral melanoma.² A follow-up examination performed several weeks later showed no pigmentation or recurrence of the lesion in our patient, further supporting the diagnosis of talon noir.

Practice Implications

Talon noir refers to localized accumulation of blood within the epidermis due to repetitive trauma, pressure, and shearing forces on the skin that results in pigmented macules.^3-5 Repetitive trauma damages the microvasculature in areas of the skin with minimal subcutaneous adipose tissue.⁶ Talon noir also is known as subcorneal hematoma, intracorneal hematoma, black heel, hyperkeratosis hemorrhagica, and basketball heel.^1,3 First described by Crissey and Peachey³ in 1961 as calcaneal petechiae, the condition was identified in basketball players with well-circumscribed, deep-red lesions on the posterior lateral heels, located between the Achilles tendon insertion and calcaneal fat pad.³ Subsequent reports have documented talon noir in athletes from a range of sports such as tennis and football, whose activities involve rapid directional changes and shearing forces on the feet.⁶ Similar lesions, termed tache noir, have been observed on the hands of athletes including gymnasts, weightlifters, golfers, and climbers due to repetitive hand trauma.⁶ Gross examination reveals blood collecting in the thickened stratum corneum.⁵

The cutaneous manifestations of talon noir can mimic acral melanoma, highlighting the need for dermatologists to understand its clinical, dermoscopic, and microscopic features. Poor patient recall can complicate diagnosis; for instance, in one study only 20% (4/20) of patients remembered the inciting trauma that caused the subcorneal hematomas.¹ Balancing vigilance for melanoma with recognition of more benign conditions such as talon noir—particularly in younger active populations—is essential to minimize patient anxiety and avoid invasive procedures.

Further investigation is warranted in lesions that persist without obvious cause or in those that demonstrate concerning features such as extensive growth. One case of talon noir in a patient with diabetes required an excisional biopsy due to its atypical progression over 1 year with considerable hyperpigmentation and friability.⁷ Additional investigation such as dermoscopy may be required with paring of the skin to establish a diagnosis.¹ Using a curette to pare the thickened stratum corneum, which has no nerve endings, does not require anesthetics.⁸ In talon noir, paring completely removes the lesion, leaving behind unaffected skin, while melanomas would retain their pigmentation due to melanin in the basal layer.²

Talon noir is a benign condition frequently misdiagnosed due to its resemblance to more serious pathologies such as melanoma. Awareness of its clinical and dermoscopic features can promote cost-effective care while reducing unnecessary procedures. Diagnostic paring of the skin with a curette offers a simple and reliable means of distinguishing talon noir from acral melanoma and other potential conditions.

Practice Gap

Brown macules on the feet can pose diagnostic challenges, often raising suspicion of acral melanoma. Talon noir, which is benign and self-resolving, is characterized by dark patches on the skin of the feet due to hemorrhage within the stratum corneum and commonly is observed in athletes who sustain repetitive foot trauma. In one study, nearly 50% (9/20) of talon noir cases initially were misdiagnosed as acral melanoma or melanocytic nevi.¹ Accurate identification of talon noir is essential to prevent unnecessary interventions or delayed treatment of malignant lesions. Here, we describe a low-risk, cost-effective, and time-efficient diagnostic technique for talon noir using a disposable curette to potentially avoid more invasive procedures.

The Technique

A 34-year-old man presented to the dermatology department with a new brown macule on the second toe. The lesion had been present and stable for more than 4 months, showing no changes in shape or color. The patient reported that he was a frequent runner but did not recall any trauma to the toe, and he denied any associated pain, pruritus, or bleeding. Physical examination revealed a 6-mm dark-brown macule on the hyponychium of the left second toe, with numerous petechiae noted on dermoscopic examination. The findings were consistent with talon noir.

Given the clinical suspicion of talon noir, we used a 5-mm disposable curette to gently pare the superficial epidermis. The superficial curettage effectively removed the lesion, leaving behind a healthy epidermis with no pinpoint bleeding, which confirmed the diagnosis of talon noir (Figure). Pathologic changes from acral melanoma reside deeper than talon noir and consequently cannot be effectively removed by superficial curettage alone. Curettage acts as a curative technique for talon noir, but also as a low-risk, cost-effective, and time-efficient diagnostic technique to rule out insidious diagnoses, including acral melanoma.² A follow-up examination performed several weeks later showed no pigmentation or recurrence of the lesion in our patient, further supporting the diagnosis of talon noir.

Practice Implications

Talon noir refers to localized accumulation of blood within the epidermis due to repetitive trauma, pressure, and shearing forces on the skin that results in pigmented macules.^3-5 Repetitive trauma damages the microvasculature in areas of the skin with minimal subcutaneous adipose tissue.⁶ Talon noir also is known as subcorneal hematoma, intracorneal hematoma, black heel, hyperkeratosis hemorrhagica, and basketball heel.^1,3 First described by Crissey and Peachey³ in 1961 as calcaneal petechiae, the condition was identified in basketball players with well-circumscribed, deep-red lesions on the posterior lateral heels, located between the Achilles tendon insertion and calcaneal fat pad.³ Subsequent reports have documented talon noir in athletes from a range of sports such as tennis and football, whose activities involve rapid directional changes and shearing forces on the feet.⁶ Similar lesions, termed tache noir, have been observed on the hands of athletes including gymnasts, weightlifters, golfers, and climbers due to repetitive hand trauma.⁶ Gross examination reveals blood collecting in the thickened stratum corneum.⁵

The cutaneous manifestations of talon noir can mimic acral melanoma, highlighting the need for dermatologists to understand its clinical, dermoscopic, and microscopic features. Poor patient recall can complicate diagnosis; for instance, in one study only 20% (4/20) of patients remembered the inciting trauma that caused the subcorneal hematomas.¹ Balancing vigilance for melanoma with recognition of more benign conditions such as talon noir—particularly in younger active populations—is essential to minimize patient anxiety and avoid invasive procedures.

Further investigation is warranted in lesions that persist without obvious cause or in those that demonstrate concerning features such as extensive growth. One case of talon noir in a patient with diabetes required an excisional biopsy due to its atypical progression over 1 year with considerable hyperpigmentation and friability.⁷ Additional investigation such as dermoscopy may be required with paring of the skin to establish a diagnosis.¹ Using a curette to pare the thickened stratum corneum, which has no nerve endings, does not require anesthetics.⁸ In talon noir, paring completely removes the lesion, leaving behind unaffected skin, while melanomas would retain their pigmentation due to melanin in the basal layer.²

Talon noir is a benign condition frequently misdiagnosed due to its resemblance to more serious pathologies such as melanoma. Awareness of its clinical and dermoscopic features can promote cost-effective care while reducing unnecessary procedures. Diagnostic paring of the skin with a curette offers a simple and reliable means of distinguishing talon noir from acral melanoma and other potential conditions.

Practice Gap

Brown macules on the feet can pose diagnostic challenges, often raising suspicion of acral melanoma. Talon noir, which is benign and self-resolving, is characterized by dark patches on the skin of the feet due to hemorrhage within the stratum corneum and commonly is observed in athletes who sustain repetitive foot trauma. In one study, nearly 50% (9/20) of talon noir cases initially were misdiagnosed as acral melanoma or melanocytic nevi.¹ Accurate identification of talon noir is essential to prevent unnecessary interventions or delayed treatment of malignant lesions. Here, we describe a low-risk, cost-effective, and time-efficient diagnostic technique for talon noir using a disposable curette to potentially avoid more invasive procedures.

The Technique

A 34-year-old man presented to the dermatology department with a new brown macule on the second toe. The lesion had been present and stable for more than 4 months, showing no changes in shape or color. The patient reported that he was a frequent runner but did not recall any trauma to the toe, and he denied any associated pain, pruritus, or bleeding. Physical examination revealed a 6-mm dark-brown macule on the hyponychium of the left second toe, with numerous petechiae noted on dermoscopic examination. The findings were consistent with talon noir.

Given the clinical suspicion of talon noir, we used a 5-mm disposable curette to gently pare the superficial epidermis. The superficial curettage effectively removed the lesion, leaving behind a healthy epidermis with no pinpoint bleeding, which confirmed the diagnosis of talon noir (Figure). Pathologic changes from acral melanoma reside deeper than talon noir and consequently cannot be effectively removed by superficial curettage alone. Curettage acts as a curative technique for talon noir, but also as a low-risk, cost-effective, and time-efficient diagnostic technique to rule out insidious diagnoses, including acral melanoma.² A follow-up examination performed several weeks later showed no pigmentation or recurrence of the lesion in our patient, further supporting the diagnosis of talon noir.

Practice Implications

Talon noir refers to localized accumulation of blood within the epidermis due to repetitive trauma, pressure, and shearing forces on the skin that results in pigmented macules.^3-5 Repetitive trauma damages the microvasculature in areas of the skin with minimal subcutaneous adipose tissue.⁶ Talon noir also is known as subcorneal hematoma, intracorneal hematoma, black heel, hyperkeratosis hemorrhagica, and basketball heel.^1,3 First described by Crissey and Peachey³ in 1961 as calcaneal petechiae, the condition was identified in basketball players with well-circumscribed, deep-red lesions on the posterior lateral heels, located between the Achilles tendon insertion and calcaneal fat pad.³ Subsequent reports have documented talon noir in athletes from a range of sports such as tennis and football, whose activities involve rapid directional changes and shearing forces on the feet.⁶ Similar lesions, termed tache noir, have been observed on the hands of athletes including gymnasts, weightlifters, golfers, and climbers due to repetitive hand trauma.⁶ Gross examination reveals blood collecting in the thickened stratum corneum.⁵

The cutaneous manifestations of talon noir can mimic acral melanoma, highlighting the need for dermatologists to understand its clinical, dermoscopic, and microscopic features. Poor patient recall can complicate diagnosis; for instance, in one study only 20% (4/20) of patients remembered the inciting trauma that caused the subcorneal hematomas.¹ Balancing vigilance for melanoma with recognition of more benign conditions such as talon noir—particularly in younger active populations—is essential to minimize patient anxiety and avoid invasive procedures.

Further investigation is warranted in lesions that persist without obvious cause or in those that demonstrate concerning features such as extensive growth. One case of talon noir in a patient with diabetes required an excisional biopsy due to its atypical progression over 1 year with considerable hyperpigmentation and friability.⁷ Additional investigation such as dermoscopy may be required with paring of the skin to establish a diagnosis.¹ Using a curette to pare the thickened stratum corneum, which has no nerve endings, does not require anesthetics.⁸ In talon noir, paring completely removes the lesion, leaving behind unaffected skin, while melanomas would retain their pigmentation due to melanin in the basal layer.²

Talon noir is a benign condition frequently misdiagnosed due to its resemblance to more serious pathologies such as melanoma. Awareness of its clinical and dermoscopic features can promote cost-effective care while reducing unnecessary procedures. Diagnostic paring of the skin with a curette offers a simple and reliable means of distinguishing talon noir from acral melanoma and other potential conditions.

TOPLINE:

Immune checkpoint inhibitors (ICIs) show promise for field cancerization, based on their ability to reduce actinic keratoses (AKs) in a new study.

METHODOLOGY:

• This prospective cohort study included 23 immunocompetent participants (26.1% women; mean age, 69.7 years) from Australia who received ICIs for any cancer between April 2022 and November 2023.
• The most frequently prescribed ICI regimen was a combination of nivolumab and ipilimumab (34.8%), followed by nivolumab monotherapy (26.1%) and cemiplimab (21.7%) or pembrolizumab (17.4%) monotherapy.
• More than half of the patients received ICI therapy for skin cancer (melanoma, 30.4%; cutaneous squamous cell carcinoma, 26.1%); 34.8% had lung cancer; two had other carcinomas.
• The primary outcome was the number of AKs at 12 months after starting ICI therapy; the secondary outcome was the number of keratinocyte carcinomas (KCs) excised 12 months before and after ICI therapy.

TAKEAWAY:

• At 12 months, one patient had complete resolution from AK, and the mean number of AKs significantly decreased from 47.2 at baseline to 14.3 (P < .001).
• Younger patients (66.7% vs 33.3%; P = .007) and those with a history of blistering sunburn (100% vs 0; P = .005) were more likely to experience ≥ 65% reduction in AK count.
• KC incidence in the year before ICI therapy vs the year after initiation dropped from 42 to 17 cases, respectively, and the number of cutaneous squamous cell carcinomas decreased from 16 to 5.
• Adverse events occurred in 11 participants (47.8%), with maculopapular rash or pruritus the most common.

IN PRACTICE:

“This pilot cohort study highlights the potential association of ICI therapy, originally used in cancer treatment, with significant reduction of clinical AKs,” the authors wrote. These findings, they said, “underscore ICIs’ potential as a novel approach to mitigating field cancerization in high-risk populations.”

SOURCE:

Charlotte Cox, MD, MPhil, MPHTM, BMSt, University of Queensland, Brisbane, Australia, led the study, which was published online in JAMA Dermatology.

LIMITATIONS:

Limitations included interrater reliability issues in AK counting. Not all patients completed the follow-up period, and observations about changes after stopping ICI therapy were limited. Surveillance bias could be present in KC reporting.

DISCLOSURES:

This work was supported by grants from the Metro South Health SERTA project and by the French Society of Dermatology, La Ligue Contre le Cancer, the Collège des Enseignants en Dermatologie de France, and the European Association of Dermatology and Venereology. Cox received personal fees from the University of Queensland scholarship funds during this work. Some authors reported receiving personal fees and support from pharmaceutical and cosmetic companies.

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:

Immune checkpoint inhibitors (ICIs) show promise for field cancerization, based on their ability to reduce actinic keratoses (AKs) in a new study.

METHODOLOGY:

• This prospective cohort study included 23 immunocompetent participants (26.1% women; mean age, 69.7 years) from Australia who received ICIs for any cancer between April 2022 and November 2023.
• The most frequently prescribed ICI regimen was a combination of nivolumab and ipilimumab (34.8%), followed by nivolumab monotherapy (26.1%) and cemiplimab (21.7%) or pembrolizumab (17.4%) monotherapy.
• More than half of the patients received ICI therapy for skin cancer (melanoma, 30.4%; cutaneous squamous cell carcinoma, 26.1%); 34.8% had lung cancer; two had other carcinomas.
• The primary outcome was the number of AKs at 12 months after starting ICI therapy; the secondary outcome was the number of keratinocyte carcinomas (KCs) excised 12 months before and after ICI therapy.

TAKEAWAY:

• At 12 months, one patient had complete resolution from AK, and the mean number of AKs significantly decreased from 47.2 at baseline to 14.3 (P < .001).
• Younger patients (66.7% vs 33.3%; P = .007) and those with a history of blistering sunburn (100% vs 0; P = .005) were more likely to experience ≥ 65% reduction in AK count.
• KC incidence in the year before ICI therapy vs the year after initiation dropped from 42 to 17 cases, respectively, and the number of cutaneous squamous cell carcinomas decreased from 16 to 5.
• Adverse events occurred in 11 participants (47.8%), with maculopapular rash or pruritus the most common.

IN PRACTICE:

“This pilot cohort study highlights the potential association of ICI therapy, originally used in cancer treatment, with significant reduction of clinical AKs,” the authors wrote. These findings, they said, “underscore ICIs’ potential as a novel approach to mitigating field cancerization in high-risk populations.”

SOURCE:

Charlotte Cox, MD, MPhil, MPHTM, BMSt, University of Queensland, Brisbane, Australia, led the study, which was published online in JAMA Dermatology.

LIMITATIONS:

Limitations included interrater reliability issues in AK counting. Not all patients completed the follow-up period, and observations about changes after stopping ICI therapy were limited. Surveillance bias could be present in KC reporting.

DISCLOSURES:

This work was supported by grants from the Metro South Health SERTA project and by the French Society of Dermatology, La Ligue Contre le Cancer, the Collège des Enseignants en Dermatologie de France, and the European Association of Dermatology and Venereology. Cox received personal fees from the University of Queensland scholarship funds during this work. Some authors reported receiving personal fees and support from pharmaceutical and cosmetic companies.

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:

Immune checkpoint inhibitors (ICIs) show promise for field cancerization, based on their ability to reduce actinic keratoses (AKs) in a new study.

METHODOLOGY:

• This prospective cohort study included 23 immunocompetent participants (26.1% women; mean age, 69.7 years) from Australia who received ICIs for any cancer between April 2022 and November 2023.
• The most frequently prescribed ICI regimen was a combination of nivolumab and ipilimumab (34.8%), followed by nivolumab monotherapy (26.1%) and cemiplimab (21.7%) or pembrolizumab (17.4%) monotherapy.
• More than half of the patients received ICI therapy for skin cancer (melanoma, 30.4%; cutaneous squamous cell carcinoma, 26.1%); 34.8% had lung cancer; two had other carcinomas.
• The primary outcome was the number of AKs at 12 months after starting ICI therapy; the secondary outcome was the number of keratinocyte carcinomas (KCs) excised 12 months before and after ICI therapy.

TAKEAWAY:

• At 12 months, one patient had complete resolution from AK, and the mean number of AKs significantly decreased from 47.2 at baseline to 14.3 (P < .001).
• Younger patients (66.7% vs 33.3%; P = .007) and those with a history of blistering sunburn (100% vs 0; P = .005) were more likely to experience ≥ 65% reduction in AK count.
• KC incidence in the year before ICI therapy vs the year after initiation dropped from 42 to 17 cases, respectively, and the number of cutaneous squamous cell carcinomas decreased from 16 to 5.
• Adverse events occurred in 11 participants (47.8%), with maculopapular rash or pruritus the most common.

IN PRACTICE:

“This pilot cohort study highlights the potential association of ICI therapy, originally used in cancer treatment, with significant reduction of clinical AKs,” the authors wrote. These findings, they said, “underscore ICIs’ potential as a novel approach to mitigating field cancerization in high-risk populations.”

SOURCE:

Charlotte Cox, MD, MPhil, MPHTM, BMSt, University of Queensland, Brisbane, Australia, led the study, which was published online in JAMA Dermatology.

LIMITATIONS:

Limitations included interrater reliability issues in AK counting. Not all patients completed the follow-up period, and observations about changes after stopping ICI therapy were limited. Surveillance bias could be present in KC reporting.

DISCLOSURES:

This work was supported by grants from the Metro South Health SERTA project and by the French Society of Dermatology, La Ligue Contre le Cancer, the Collège des Enseignants en Dermatologie de France, and the European Association of Dermatology and Venereology. Cox received personal fees from the University of Queensland scholarship funds during this work. Some authors reported receiving personal fees and support from pharmaceutical and cosmetic companies.

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:

Merkel cell carcinoma (MCC) is less common and is associated with higher mortality rates than melanoma, according to a study that also reported that male gender, older age, and exposure to ultraviolet radiation (UVR) are significant risk factors.

METHODOLOGY:

• Researchers identified 19,444 MCC cases and 646,619 melanoma cases diagnosed between 2000 and 2021 using data from the Surveillance, Epidemiology, and End Results (SEER) Program.
• Ambient UVR exposure data were obtained from the National Aeronautics and Space Administration’s total ozone mapping spectrometer database.
• Risk factors and cancer-specific mortality rates were evaluated for both cancers.

TAKEAWAY:

• Incidence rates per 100,000 person-years of MCC and melanoma were 0.8 and 27.3, respectively.
• Men (adjusted incidence rate ratio [IRR], 1.72 for MCC and 1.23 for melanoma), older age groups (IRR: 2.69 for MCC and 1.62 for melanoma among those 70-79 years; and 5.68 for MCC and 2.26 for melanoma among those 80 years or older) showed higher incidences of MCC and melanoma. Non-Hispanic White individuals were at higher risk for MCC and melanoma than other racial/ethnic groups.
• Exposure to UVR was associated with higher incidences of melanoma (IRR, 1.24-1.49) and MCC (IRR, 1.15-1.20) in non-Hispanic White individuals, particularly on the head and neck. These associations were unclear among racial/ethnic groups.
• Individuals with MCC had a higher risk for cancer-specific mortality than those with melanoma (adjusted hazard ratio [HR], 2.33; 95% CI, 2.26-2.42). Cancer-specific survival for both cancers improved for cases diagnosed during 2012-2021 vs 2004-2011 (MCC: HR, 0.83; 95% CI, 0.78-0.89; melanoma: HR, 0.75; 95% CI, 0.74-0.76).

IN PRACTICE:

“MCC and melanoma are aggressive skin cancers with similar risk factors including male sex, older age, and UV radiation exposure. Clinicians should be alert to diagnosis of these cancers to allow for prompt treatment,” the authors wrote, adding: “It is encouraging that survival for both cancers has increased in recent years, with the largest gains in survival seen in distant stage melanoma, coinciding with the approval of BRAF and PD-1 inhibitors used for distant stage disease,” although mortality for advanced stage tumors “continues to be very high.”

SOURCE:

The study was led by Jacob T. Tribble, BA, National Cancer Institute, Rockville, Maryland. It was published online on January 5 in the Journal of Investigative Dermatology.

LIMITATIONS:

The study relied on SEER’s general staging system rather than the American Joint Committee on Cancer standard, and UVR exposure estimates did not account for individual sun protection behaviors or prior residential history. Race and ethnicity served as a proxy for UVR sensitivity, which may introduce misclassification bias.

DISCLOSURES:

The research was supported by the Intramural Research Program of the National Cancer Institute, the National Institutes of Health, the American Association for Dental Research, and the Colgate-Palmolive Company. The authors reported no conflict of interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Merkel cell carcinoma (MCC) is less common and is associated with higher mortality rates than melanoma, according to a study that also reported that male gender, older age, and exposure to ultraviolet radiation (UVR) are significant risk factors.

METHODOLOGY:

• Researchers identified 19,444 MCC cases and 646,619 melanoma cases diagnosed between 2000 and 2021 using data from the Surveillance, Epidemiology, and End Results (SEER) Program.
• Ambient UVR exposure data were obtained from the National Aeronautics and Space Administration’s total ozone mapping spectrometer database.
• Risk factors and cancer-specific mortality rates were evaluated for both cancers.

TAKEAWAY:

• Incidence rates per 100,000 person-years of MCC and melanoma were 0.8 and 27.3, respectively.
• Men (adjusted incidence rate ratio [IRR], 1.72 for MCC and 1.23 for melanoma), older age groups (IRR: 2.69 for MCC and 1.62 for melanoma among those 70-79 years; and 5.68 for MCC and 2.26 for melanoma among those 80 years or older) showed higher incidences of MCC and melanoma. Non-Hispanic White individuals were at higher risk for MCC and melanoma than other racial/ethnic groups.
• Exposure to UVR was associated with higher incidences of melanoma (IRR, 1.24-1.49) and MCC (IRR, 1.15-1.20) in non-Hispanic White individuals, particularly on the head and neck. These associations were unclear among racial/ethnic groups.
• Individuals with MCC had a higher risk for cancer-specific mortality than those with melanoma (adjusted hazard ratio [HR], 2.33; 95% CI, 2.26-2.42). Cancer-specific survival for both cancers improved for cases diagnosed during 2012-2021 vs 2004-2011 (MCC: HR, 0.83; 95% CI, 0.78-0.89; melanoma: HR, 0.75; 95% CI, 0.74-0.76).

IN PRACTICE:

“MCC and melanoma are aggressive skin cancers with similar risk factors including male sex, older age, and UV radiation exposure. Clinicians should be alert to diagnosis of these cancers to allow for prompt treatment,” the authors wrote, adding: “It is encouraging that survival for both cancers has increased in recent years, with the largest gains in survival seen in distant stage melanoma, coinciding with the approval of BRAF and PD-1 inhibitors used for distant stage disease,” although mortality for advanced stage tumors “continues to be very high.”

SOURCE:

The study was led by Jacob T. Tribble, BA, National Cancer Institute, Rockville, Maryland. It was published online on January 5 in the Journal of Investigative Dermatology.

LIMITATIONS:

The study relied on SEER’s general staging system rather than the American Joint Committee on Cancer standard, and UVR exposure estimates did not account for individual sun protection behaviors or prior residential history. Race and ethnicity served as a proxy for UVR sensitivity, which may introduce misclassification bias.

DISCLOSURES:

The research was supported by the Intramural Research Program of the National Cancer Institute, the National Institutes of Health, the American Association for Dental Research, and the Colgate-Palmolive Company. The authors reported no conflict of interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Merkel cell carcinoma (MCC) is less common and is associated with higher mortality rates than melanoma, according to a study that also reported that male gender, older age, and exposure to ultraviolet radiation (UVR) are significant risk factors.

METHODOLOGY:

• Researchers identified 19,444 MCC cases and 646,619 melanoma cases diagnosed between 2000 and 2021 using data from the Surveillance, Epidemiology, and End Results (SEER) Program.
• Ambient UVR exposure data were obtained from the National Aeronautics and Space Administration’s total ozone mapping spectrometer database.
• Risk factors and cancer-specific mortality rates were evaluated for both cancers.

TAKEAWAY:

• Incidence rates per 100,000 person-years of MCC and melanoma were 0.8 and 27.3, respectively.
• Men (adjusted incidence rate ratio [IRR], 1.72 for MCC and 1.23 for melanoma), older age groups (IRR: 2.69 for MCC and 1.62 for melanoma among those 70-79 years; and 5.68 for MCC and 2.26 for melanoma among those 80 years or older) showed higher incidences of MCC and melanoma. Non-Hispanic White individuals were at higher risk for MCC and melanoma than other racial/ethnic groups.
• Exposure to UVR was associated with higher incidences of melanoma (IRR, 1.24-1.49) and MCC (IRR, 1.15-1.20) in non-Hispanic White individuals, particularly on the head and neck. These associations were unclear among racial/ethnic groups.
• Individuals with MCC had a higher risk for cancer-specific mortality than those with melanoma (adjusted hazard ratio [HR], 2.33; 95% CI, 2.26-2.42). Cancer-specific survival for both cancers improved for cases diagnosed during 2012-2021 vs 2004-2011 (MCC: HR, 0.83; 95% CI, 0.78-0.89; melanoma: HR, 0.75; 95% CI, 0.74-0.76).

IN PRACTICE:

“MCC and melanoma are aggressive skin cancers with similar risk factors including male sex, older age, and UV radiation exposure. Clinicians should be alert to diagnosis of these cancers to allow for prompt treatment,” the authors wrote, adding: “It is encouraging that survival for both cancers has increased in recent years, with the largest gains in survival seen in distant stage melanoma, coinciding with the approval of BRAF and PD-1 inhibitors used for distant stage disease,” although mortality for advanced stage tumors “continues to be very high.”

SOURCE:

The study was led by Jacob T. Tribble, BA, National Cancer Institute, Rockville, Maryland. It was published online on January 5 in the Journal of Investigative Dermatology.

LIMITATIONS:

The study relied on SEER’s general staging system rather than the American Joint Committee on Cancer standard, and UVR exposure estimates did not account for individual sun protection behaviors or prior residential history. Race and ethnicity served as a proxy for UVR sensitivity, which may introduce misclassification bias.

DISCLOSURES:

The research was supported by the Intramural Research Program of the National Cancer Institute, the National Institutes of Health, the American Association for Dental Research, and the Colgate-Palmolive Company. The authors reported no conflict of interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

To the Editor:
Patients with nonmelanoma skin cancers exhibit high quality-of-life satisfaction after treatment with Mohs micrographic surgery (MMS) or excision.^1,2 However, perioperative anxiety in patients undergoing MMS is common, especially during the immediate preoperative period.³ Anxiety activates the sympathetic nervous system, resulting in physiologic changes such as tachycardia and hypertension.^4,5 These sequelae may not only increase patient distress but also increase intraoperative bleeding, complication rates, and recovery times.^4,5 Thus, the preoperative period represents a critical window for interventions aimed at reducing anxiety. Anxiety peaks during the perioperative period for a myriad of reasons, including anticipation of pain or potential complications. Enhancing patient comfort and well-being during the procedure may help reduce negative emotional sequelae, alleviate fear during procedures, and increase patient satisfaction.³

Weighted blankets (WBs) frequently are utilized in occupational and physical therapy as a deep pressure stimulation tool to alleviate anxiety by mimicking the experience of being massaged or swaddled.⁶ Deep pressure tools increase parasympathetic tone, help reduce anxiety, and provide a calming effect.^7,8 Nonhospitalized individuals were more relaxed during mental health evaluations when using a WB, and deep pressure tools have frequently been used to calm individuals with autism spectrum disorders or attention-deficit/hyperactivity disorders.⁶ Furthermore, WBs have successfully been used to reduce anxiety in mental health care settings, as well as during chemotherapy infusions.^6,9 The literature is sparse regarding the use of WB in the perioperative setting. Potential benefit has been demonstrated in the setting of dental cleanings and wisdom teeth extractions.^7,8 In the current study, we investigated whether use of a WB could reduce preoperative anxiety in the setting of MMS.

Institutional review board approval was obtained from the University of Virginia (Charlottesville, Virginia), and adult patients undergoing MMS to the head or neck were recruited to participate in a single-blind randomized controlled trial in the spring of 2023. Patients undergoing MMS on other areas of the body were excluded because the placement of the WB could interfere with the procedure. Other exclusion criteria included pregnancy, dementia, or current treatment with an anxiolytic medication.

Twenty-seven patients were included in the study, and informed consent was obtained. Patients were randomized to use a WB or standard hospital towel (control). The medical-grade WBs weighed 8.5 pounds, while the cotton hospital towels weighed less than 1 pound. The WBs were cleaned in between patients with standard germicidal disposable wipes.

Patient data were collected from electronic medical records including age, sex, weight, history of prior MMS, and current use of antihypertensives and/or beta-blockers. Data also were collected on the presence of anxiety disorders, major depression, fibromyalgia, tobacco and alcohol use, hyperthyroidism, hyperhidrosis, cardiac arrhythmias (including atrial fibrillation), chronic obstructive pulmonary disease, asthma, coronary artery disease, diabetes mellitus, peripheral neuropathy, and menopausal symptoms.

During the procedure, anxiety was monitored using the State-Trait Anxiety Inventory (STAI) Form Y-1, the visual analogue scale for anxiety (VAS-A), and vital signs including heart rate, blood pressure, and respiratory rate. Vital signs were evaluated by nursing staff with the patient sitting up and the WB or hospital towel removed. Using these assessments, anxiety was measured at 3 different timepoints: upon arrival to the clinic (timepoint A), after the patient rested in a reclined beach-chair position with the WB or hospital towel placed over them for 10 minutes before administration of local anesthetic and starting the procedure (timepoint B), and after the first MMS stage was taken (timepoint C).

A power analysis was not completed due to a lack of previous studies on the use of WBs during MMS. Group means were analyzed using two-tailed t-tests and one-way analysis of variance. A P value of .05 indicated statistical significance.

Fourteen patients were randomized to the WB group and 13 were randomized to the control group. Patient demographics are outlined in the eTable. In the WB group, mean STAI scores progressively decreased at each timepoint (A: 15.3, B: 13.6, C: 12.7) and mean VAS-A scores followed a similar trend (A: 24.2, B: 19.3, C: 10.5). In the control group, the mean STAI scores remained stable at timepoints A and B (17.7) and then decreased at timepoint C (14.8). The mean VAS-A scores in the control group followed a similar pattern, remaining stable at timepoints A (22.9) and B (22.8) and then decreasing at timepoint C (14.4). These changes were not statistically significant.

Mean vital signs for both the WB and control groups were relatively stable across all timepoints, although they tended to decrease by timepoint C. In the WB group, mean heart rates were 69, 69, and 67 beats per minute at timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 136 mm Hg and mean diastolic pressures were 71 mm Hg, 68 mm Hg, and 66 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 20, 19, and 18 breaths per minute at timepoints A, B, and C, respectively. In the control group, mean heart rates were 70, 69, and 68 beats per minute across timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 133 mm Hg and mean diastolic pressures were 71 mm Hg, 74 mm Hg, and 68 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 19, 18, and 18 breaths per minute at timepoints A, B, and C, respectively. These changes were not statistically significant.

Our pilot study examined the effects of using a WB to alleviate preoperative anxiety during MMS. Our results suggest that WBs may modestly improve subjective anxiety immediately prior to undergoing MMS. Mean STAI and VAS-A scores decreased from timepoint A to timepoint B in the WB group vs the control group in which these scores remained stable. Although our study was not powered to determine statistical differences and significance was not reached, our results suggest a favorable trend in decreased anxiety scores. Our analysis was limited by a small sample size; therefore, additional larger-scale studies will be needed to confirm this trend.

Our results are broadly consistent with earlier studies that found improvement in physiologic proxies of anxiety with the use of WBs during chemotherapy infusions, dental procedures, and acute inpatient mental health hospitalizations.^7-10 During periods of high anxiety, use of WBs shifts the autonomic nervous system from a sympathetic to a parasympathetic state, as demonstrated by increased high-frequency heart rate variability, a marker of parasympathetic activity.^6,11 While the exact mechanism of how WBs and other deep pressure stimulation tools affect high-frequency heart rate variability is unclear, one study showed that patients undergoing dental extractions were better equipped when using deep pressure stimulation tools to utilize calming techniques and regulate stress.¹² The use of WBs and other deep pressure stimulation tools may extend beyond the perioperative setting and also may be an effective tool for clinicians in other settings (eg, clinic visits, physical examinations).

In our study, all participants demonstrated the greatest reduction in anxiety at timepoint C after the first MMS stage, likely related to patients relaxing more after knowing what to expect from the surgery; this also may have been reflected somewhat in the slight downward trend noted in vital signs across both study groups. One concern regarding WB use in surgical settings is whether the added pressure could trigger unfavorable circulatory effects, such as elevated blood pressure. In our study, with the exception of diastolic blood pressure, vital signs appeared unaffected by the type of blanket used and remained relatively stable from timepoint A to timepoint B and decreased at timepoint C. Diastolic blood pressure in the WB group decreased from timepoint A to timepoint B, then decreased further from timepoint B to timepoint C. This mirrored the decreasing STAI score trend, compared to the control group who increased from timepoint A to timepoint B and reached a nadir at timepoint C. Consistent with prior WB studies, there were no adverse effects from WBs, including adverse impacts on vital signs.^6,9

The original recruitment goal was not met due to staffing issues related to the COVID-19 pandemic, and subgroup analyses were deferred as a result of sample size limitations. It is possible that the WB intervention may have a larger impact on subpopulations more prone to perioperative anxiety (eg, patients undergoing MMS for the first time). However, the results of our pilot study suggest a beneficial effect from the use of WBs. While these preliminary data are promising, additional studies in the perioperative setting are needed to more accurately determine the clinical utility of WBs during MMS and other procedures.

To the Editor:
Patients with nonmelanoma skin cancers exhibit high quality-of-life satisfaction after treatment with Mohs micrographic surgery (MMS) or excision.^1,2 However, perioperative anxiety in patients undergoing MMS is common, especially during the immediate preoperative period.³ Anxiety activates the sympathetic nervous system, resulting in physiologic changes such as tachycardia and hypertension.^4,5 These sequelae may not only increase patient distress but also increase intraoperative bleeding, complication rates, and recovery times.^4,5 Thus, the preoperative period represents a critical window for interventions aimed at reducing anxiety. Anxiety peaks during the perioperative period for a myriad of reasons, including anticipation of pain or potential complications. Enhancing patient comfort and well-being during the procedure may help reduce negative emotional sequelae, alleviate fear during procedures, and increase patient satisfaction.³

Weighted blankets (WBs) frequently are utilized in occupational and physical therapy as a deep pressure stimulation tool to alleviate anxiety by mimicking the experience of being massaged or swaddled.⁶ Deep pressure tools increase parasympathetic tone, help reduce anxiety, and provide a calming effect.^7,8 Nonhospitalized individuals were more relaxed during mental health evaluations when using a WB, and deep pressure tools have frequently been used to calm individuals with autism spectrum disorders or attention-deficit/hyperactivity disorders.⁶ Furthermore, WBs have successfully been used to reduce anxiety in mental health care settings, as well as during chemotherapy infusions.^6,9 The literature is sparse regarding the use of WB in the perioperative setting. Potential benefit has been demonstrated in the setting of dental cleanings and wisdom teeth extractions.^7,8 In the current study, we investigated whether use of a WB could reduce preoperative anxiety in the setting of MMS.

Institutional review board approval was obtained from the University of Virginia (Charlottesville, Virginia), and adult patients undergoing MMS to the head or neck were recruited to participate in a single-blind randomized controlled trial in the spring of 2023. Patients undergoing MMS on other areas of the body were excluded because the placement of the WB could interfere with the procedure. Other exclusion criteria included pregnancy, dementia, or current treatment with an anxiolytic medication.

Twenty-seven patients were included in the study, and informed consent was obtained. Patients were randomized to use a WB or standard hospital towel (control). The medical-grade WBs weighed 8.5 pounds, while the cotton hospital towels weighed less than 1 pound. The WBs were cleaned in between patients with standard germicidal disposable wipes.

Patient data were collected from electronic medical records including age, sex, weight, history of prior MMS, and current use of antihypertensives and/or beta-blockers. Data also were collected on the presence of anxiety disorders, major depression, fibromyalgia, tobacco and alcohol use, hyperthyroidism, hyperhidrosis, cardiac arrhythmias (including atrial fibrillation), chronic obstructive pulmonary disease, asthma, coronary artery disease, diabetes mellitus, peripheral neuropathy, and menopausal symptoms.

During the procedure, anxiety was monitored using the State-Trait Anxiety Inventory (STAI) Form Y-1, the visual analogue scale for anxiety (VAS-A), and vital signs including heart rate, blood pressure, and respiratory rate. Vital signs were evaluated by nursing staff with the patient sitting up and the WB or hospital towel removed. Using these assessments, anxiety was measured at 3 different timepoints: upon arrival to the clinic (timepoint A), after the patient rested in a reclined beach-chair position with the WB or hospital towel placed over them for 10 minutes before administration of local anesthetic and starting the procedure (timepoint B), and after the first MMS stage was taken (timepoint C).

A power analysis was not completed due to a lack of previous studies on the use of WBs during MMS. Group means were analyzed using two-tailed t-tests and one-way analysis of variance. A P value of .05 indicated statistical significance.

Fourteen patients were randomized to the WB group and 13 were randomized to the control group. Patient demographics are outlined in the eTable. In the WB group, mean STAI scores progressively decreased at each timepoint (A: 15.3, B: 13.6, C: 12.7) and mean VAS-A scores followed a similar trend (A: 24.2, B: 19.3, C: 10.5). In the control group, the mean STAI scores remained stable at timepoints A and B (17.7) and then decreased at timepoint C (14.8). The mean VAS-A scores in the control group followed a similar pattern, remaining stable at timepoints A (22.9) and B (22.8) and then decreasing at timepoint C (14.4). These changes were not statistically significant.

Mean vital signs for both the WB and control groups were relatively stable across all timepoints, although they tended to decrease by timepoint C. In the WB group, mean heart rates were 69, 69, and 67 beats per minute at timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 136 mm Hg and mean diastolic pressures were 71 mm Hg, 68 mm Hg, and 66 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 20, 19, and 18 breaths per minute at timepoints A, B, and C, respectively. In the control group, mean heart rates were 70, 69, and 68 beats per minute across timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 133 mm Hg and mean diastolic pressures were 71 mm Hg, 74 mm Hg, and 68 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 19, 18, and 18 breaths per minute at timepoints A, B, and C, respectively. These changes were not statistically significant.

Our pilot study examined the effects of using a WB to alleviate preoperative anxiety during MMS. Our results suggest that WBs may modestly improve subjective anxiety immediately prior to undergoing MMS. Mean STAI and VAS-A scores decreased from timepoint A to timepoint B in the WB group vs the control group in which these scores remained stable. Although our study was not powered to determine statistical differences and significance was not reached, our results suggest a favorable trend in decreased anxiety scores. Our analysis was limited by a small sample size; therefore, additional larger-scale studies will be needed to confirm this trend.

Our results are broadly consistent with earlier studies that found improvement in physiologic proxies of anxiety with the use of WBs during chemotherapy infusions, dental procedures, and acute inpatient mental health hospitalizations.^7-10 During periods of high anxiety, use of WBs shifts the autonomic nervous system from a sympathetic to a parasympathetic state, as demonstrated by increased high-frequency heart rate variability, a marker of parasympathetic activity.^6,11 While the exact mechanism of how WBs and other deep pressure stimulation tools affect high-frequency heart rate variability is unclear, one study showed that patients undergoing dental extractions were better equipped when using deep pressure stimulation tools to utilize calming techniques and regulate stress.¹² The use of WBs and other deep pressure stimulation tools may extend beyond the perioperative setting and also may be an effective tool for clinicians in other settings (eg, clinic visits, physical examinations).

In our study, all participants demonstrated the greatest reduction in anxiety at timepoint C after the first MMS stage, likely related to patients relaxing more after knowing what to expect from the surgery; this also may have been reflected somewhat in the slight downward trend noted in vital signs across both study groups. One concern regarding WB use in surgical settings is whether the added pressure could trigger unfavorable circulatory effects, such as elevated blood pressure. In our study, with the exception of diastolic blood pressure, vital signs appeared unaffected by the type of blanket used and remained relatively stable from timepoint A to timepoint B and decreased at timepoint C. Diastolic blood pressure in the WB group decreased from timepoint A to timepoint B, then decreased further from timepoint B to timepoint C. This mirrored the decreasing STAI score trend, compared to the control group who increased from timepoint A to timepoint B and reached a nadir at timepoint C. Consistent with prior WB studies, there were no adverse effects from WBs, including adverse impacts on vital signs.^6,9

The original recruitment goal was not met due to staffing issues related to the COVID-19 pandemic, and subgroup analyses were deferred as a result of sample size limitations. It is possible that the WB intervention may have a larger impact on subpopulations more prone to perioperative anxiety (eg, patients undergoing MMS for the first time). However, the results of our pilot study suggest a beneficial effect from the use of WBs. While these preliminary data are promising, additional studies in the perioperative setting are needed to more accurately determine the clinical utility of WBs during MMS and other procedures.

To the Editor:
Patients with nonmelanoma skin cancers exhibit high quality-of-life satisfaction after treatment with Mohs micrographic surgery (MMS) or excision.^1,2 However, perioperative anxiety in patients undergoing MMS is common, especially during the immediate preoperative period.³ Anxiety activates the sympathetic nervous system, resulting in physiologic changes such as tachycardia and hypertension.^4,5 These sequelae may not only increase patient distress but also increase intraoperative bleeding, complication rates, and recovery times.^4,5 Thus, the preoperative period represents a critical window for interventions aimed at reducing anxiety. Anxiety peaks during the perioperative period for a myriad of reasons, including anticipation of pain or potential complications. Enhancing patient comfort and well-being during the procedure may help reduce negative emotional sequelae, alleviate fear during procedures, and increase patient satisfaction.³

Weighted blankets (WBs) frequently are utilized in occupational and physical therapy as a deep pressure stimulation tool to alleviate anxiety by mimicking the experience of being massaged or swaddled.⁶ Deep pressure tools increase parasympathetic tone, help reduce anxiety, and provide a calming effect.^7,8 Nonhospitalized individuals were more relaxed during mental health evaluations when using a WB, and deep pressure tools have frequently been used to calm individuals with autism spectrum disorders or attention-deficit/hyperactivity disorders.⁶ Furthermore, WBs have successfully been used to reduce anxiety in mental health care settings, as well as during chemotherapy infusions.^6,9 The literature is sparse regarding the use of WB in the perioperative setting. Potential benefit has been demonstrated in the setting of dental cleanings and wisdom teeth extractions.^7,8 In the current study, we investigated whether use of a WB could reduce preoperative anxiety in the setting of MMS.

Institutional review board approval was obtained from the University of Virginia (Charlottesville, Virginia), and adult patients undergoing MMS to the head or neck were recruited to participate in a single-blind randomized controlled trial in the spring of 2023. Patients undergoing MMS on other areas of the body were excluded because the placement of the WB could interfere with the procedure. Other exclusion criteria included pregnancy, dementia, or current treatment with an anxiolytic medication.

Twenty-seven patients were included in the study, and informed consent was obtained. Patients were randomized to use a WB or standard hospital towel (control). The medical-grade WBs weighed 8.5 pounds, while the cotton hospital towels weighed less than 1 pound. The WBs were cleaned in between patients with standard germicidal disposable wipes.

Patient data were collected from electronic medical records including age, sex, weight, history of prior MMS, and current use of antihypertensives and/or beta-blockers. Data also were collected on the presence of anxiety disorders, major depression, fibromyalgia, tobacco and alcohol use, hyperthyroidism, hyperhidrosis, cardiac arrhythmias (including atrial fibrillation), chronic obstructive pulmonary disease, asthma, coronary artery disease, diabetes mellitus, peripheral neuropathy, and menopausal symptoms.

During the procedure, anxiety was monitored using the State-Trait Anxiety Inventory (STAI) Form Y-1, the visual analogue scale for anxiety (VAS-A), and vital signs including heart rate, blood pressure, and respiratory rate. Vital signs were evaluated by nursing staff with the patient sitting up and the WB or hospital towel removed. Using these assessments, anxiety was measured at 3 different timepoints: upon arrival to the clinic (timepoint A), after the patient rested in a reclined beach-chair position with the WB or hospital towel placed over them for 10 minutes before administration of local anesthetic and starting the procedure (timepoint B), and after the first MMS stage was taken (timepoint C).

A power analysis was not completed due to a lack of previous studies on the use of WBs during MMS. Group means were analyzed using two-tailed t-tests and one-way analysis of variance. A P value of .05 indicated statistical significance.

Fourteen patients were randomized to the WB group and 13 were randomized to the control group. Patient demographics are outlined in the eTable. In the WB group, mean STAI scores progressively decreased at each timepoint (A: 15.3, B: 13.6, C: 12.7) and mean VAS-A scores followed a similar trend (A: 24.2, B: 19.3, C: 10.5). In the control group, the mean STAI scores remained stable at timepoints A and B (17.7) and then decreased at timepoint C (14.8). The mean VAS-A scores in the control group followed a similar pattern, remaining stable at timepoints A (22.9) and B (22.8) and then decreasing at timepoint C (14.4). These changes were not statistically significant.

Mean vital signs for both the WB and control groups were relatively stable across all timepoints, although they tended to decrease by timepoint C. In the WB group, mean heart rates were 69, 69, and 67 beats per minute at timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 136 mm Hg and mean diastolic pressures were 71 mm Hg, 68 mm Hg, and 66 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 20, 19, and 18 breaths per minute at timepoints A, B, and C, respectively. In the control group, mean heart rates were 70, 69, and 68 beats per minute across timepoints A, B, and C, respectively. Mean systolic blood pressures were 137 mm Hg, 138 mm Hg, and 133 mm Hg and mean diastolic pressures were 71 mm Hg, 74 mm Hg, and 68 mm Hg at timepoints A, B, and C, respectively. Mean respiratory rates were 19, 18, and 18 breaths per minute at timepoints A, B, and C, respectively. These changes were not statistically significant.

Our pilot study examined the effects of using a WB to alleviate preoperative anxiety during MMS. Our results suggest that WBs may modestly improve subjective anxiety immediately prior to undergoing MMS. Mean STAI and VAS-A scores decreased from timepoint A to timepoint B in the WB group vs the control group in which these scores remained stable. Although our study was not powered to determine statistical differences and significance was not reached, our results suggest a favorable trend in decreased anxiety scores. Our analysis was limited by a small sample size; therefore, additional larger-scale studies will be needed to confirm this trend.

Our results are broadly consistent with earlier studies that found improvement in physiologic proxies of anxiety with the use of WBs during chemotherapy infusions, dental procedures, and acute inpatient mental health hospitalizations.^7-10 During periods of high anxiety, use of WBs shifts the autonomic nervous system from a sympathetic to a parasympathetic state, as demonstrated by increased high-frequency heart rate variability, a marker of parasympathetic activity.^6,11 While the exact mechanism of how WBs and other deep pressure stimulation tools affect high-frequency heart rate variability is unclear, one study showed that patients undergoing dental extractions were better equipped when using deep pressure stimulation tools to utilize calming techniques and regulate stress.¹² The use of WBs and other deep pressure stimulation tools may extend beyond the perioperative setting and also may be an effective tool for clinicians in other settings (eg, clinic visits, physical examinations).

In our study, all participants demonstrated the greatest reduction in anxiety at timepoint C after the first MMS stage, likely related to patients relaxing more after knowing what to expect from the surgery; this also may have been reflected somewhat in the slight downward trend noted in vital signs across both study groups. One concern regarding WB use in surgical settings is whether the added pressure could trigger unfavorable circulatory effects, such as elevated blood pressure. In our study, with the exception of diastolic blood pressure, vital signs appeared unaffected by the type of blanket used and remained relatively stable from timepoint A to timepoint B and decreased at timepoint C. Diastolic blood pressure in the WB group decreased from timepoint A to timepoint B, then decreased further from timepoint B to timepoint C. This mirrored the decreasing STAI score trend, compared to the control group who increased from timepoint A to timepoint B and reached a nadir at timepoint C. Consistent with prior WB studies, there were no adverse effects from WBs, including adverse impacts on vital signs.^6,9

The original recruitment goal was not met due to staffing issues related to the COVID-19 pandemic, and subgroup analyses were deferred as a result of sample size limitations. It is possible that the WB intervention may have a larger impact on subpopulations more prone to perioperative anxiety (eg, patients undergoing MMS for the first time). However, the results of our pilot study suggest a beneficial effect from the use of WBs. While these preliminary data are promising, additional studies in the perioperative setting are needed to more accurately determine the clinical utility of WBs during MMS and other procedures.