Fine-Tuning Low-Dose Total Skin Electron Therapy for Optimal Management of Cutaneous T-Cell Lymphoma: A Comparative Analysis of Regimens.

Purpose: Low-dose total skin electron beam therapy (TSEBT) is a proven treatment for managing cutaneous T-cell lymphoma (CTCL) and Sezary syndrome with skin burden. We performed a retrospective comparison of response rates and time to progression for patients receiving low-dose TSEBT based on dose per fractionation, total dose, and stage. Methods and Materials: One hundred and ten patients with CTCL and Sezary syndrome were treated with 135 courses of low-dose (400-1500 cGy) TSEBT or subtotal skin electron therapy at multiple centers of a single institution between August 2003 and June 2023. Patients were stratified according to total dose, dose per fraction, and stage. Results: The median follow-up was 301 days (IQR, 141, 767). The median age at treatment was 69.9 years (range, 29.7-96.5). T-stage distribution was as follows: 3 (2.7%) T1, 74 (67.3%) T2, 16 (14.5%) T3, and 17 (15.5%) T4. American Joint Committee on Cancer eighth edition stage distribution was as follows: 3 (2.7%) IA, 53 (48.2%) IB, 3 (2.7%) IIA, 16 (14.5%) IIB, 8 (7.3%) IIIA, 19 (17.3%) IVA, and 8 (7.3%) IVB. There was no significant difference in disease distribution between patients treated with different fractionation schemes. The overall response rate was 89.6%. Forty-four courses (32.6%), 34 courses (25.2%), and 43 (31.9%) resulted in a complete, near-complete, and partial response, respectively. Fourteen courses (10.4%) resulted in no clinical response. For all patients, the median time to response was 43.0 days (IQR, 23.0-70). The median time to skin progression for all patients was 107.5 days (IQR, 67.8-233.5). Conclusions: This analysis demonstrated that CTCL patients treated with low-dose radiation therapy delivered over various fractionation schemes had similar overall response rates and median time to progression.

Tailoring Radiation Therapy for Patients With Limited Cutaneous T Cell Lymphoma: Preliminary Clinical Experience With Subtotal Skin Electron Therapy.

BACKGROUND/AIM: Total skin electron beam therapy (TSEBT) is an effective treatment for managing cutaneous T-cell lymphoma (CTCL), but may result in unnecessary toxicity. With the production of a custom rolling shield holding a configurable stack of plastic slats to block uninvolved skin, we implemented a program for subtotal skin electron beam therapy (STSEBT). We report our preliminary experience with STSEBT vs. TSEBT to manage CTCL. PATIENTS AND METHODS: A retrospective review of 32 CTCL patients who were treated at a single institution between February 28th, 2017, and May 25th, 2022, was completed. Of these cases, seven patients received STSEBT and 25 received TSEBT. RESULTS: Thirty-two patients underwent a course of STSEBT or TSEBT. The median follow-up was 465 days and the median age at diagnosis was 70.8 years. Stage distribution was as follows: one (3%) IA, 16 (50%) IB, 6 (19%) IIB, two (6%) IIIA, five (16%) IVA, and two (6%) IVB. The overall response rate was 96%. For patients receiving TSEBT (n=25), three (12%), 10 (40%), and 11 (44%) had a CR, NCR, and PR, respectively. For the patients receiving STSEBT, four (57.1%), three (42.9%), and zero (0%) had a CR, NCR, and PR, respectively. There was one patient (4%) with no response. Cumulative incidence of progressive skin disease requiring additional electron therapy at three months was 21.1% [IQR=8.6, 51.5%], 36.8% [IQR=20, 68%] at six months, and 57.9% [IQR=38.5, 87.1%] at one year. Low rates of toxicities were recorded. CONCLUSION: This analysis demonstrated that treatment of CTCL patients with low disease burden with STSEBT results in similar overall response and time to progression compared to treatment with TSEBT.

Distinct sets of molecular characteristics define tumor-rejecting neoantigens.

Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

Topical Ruxolitinib in the Treatment of Necrobiosis Lipoidica: A Prospective, Open-Label Study.

Necrobiosis lipoidica (NL) is a rare granulomatous disease. There are few effective treatments for NL. We sought to investigate the efficacy and safety of the Jak1/2 inhibitor, ruxolitnib, in the treatment of NL and identify the biomarkers associated with the disease and treatment response. We conducted an open-label, phase 2 study of ruxolitinib in 12 patients with NL. We performed transcriptomic analysis of tissue samples before and after treatment. At week 12, the mean NL lesion score decreased by 58.2% (SD = 28.7%, P = .003). Transcriptomic analysis demonstrated enrichment of type I and type II IFN pathways in baseline disease. Weighted gene coexpression network analysis demonstrated post-treatment changes in IFN pathways with key hub genes IFNG and signal transducer and activator of transcription 1 gene STAT1. Limitations include small sample size and a study group limited to patients with <10% body surface area. In conclusion, ruxolitinib is an effective treatment for NL and targets the key pathogenic mediators of the disease.

Creating an atlas of normal tissue for pruning WSI patching through anomaly detection.

Patching whole slide images (WSIs) is an important task in computational pathology. While most of them are designed to classify or detect the presence of pathological lesions in a WSI, the confounding role and redundant nature of normal histology are generally overlooked. In this paper, we propose and validate the concept of an "atlas of normal tissue" solely using samples of WSIs obtained from normal biopsies. Such atlases can be employed to eliminate normal fragments of tissue samples and hence increase the representativeness of the remaining patches. We tested our proposed method by establishing a normal atlas using 107 normal skin WSIs and demonstrated how established search engines like Yottixel can be improved. We used 553 WSIs of cutaneous squamous cell carcinoma to demonstrate the advantage. We also validated our method applied to an external dataset of 451 breast WSIs. The number of selected WSI patches was reduced by 30% to 50% after utilizing the proposed normal atlas while maintaining the same indexing and search performance in leave-one-patient-out validation for both datasets. We show that the proposed concept of establishing and using a normal atlas shows promise for unsupervised selection of the most representative patches of the abnormal WSI patches.

Factors influencing receipt and time to treatment of immunotherapy relative to chemotherapy in stage III and stage IV melanoma.

BACKGROUND: Immunotherapies have changed the landscape of late-stage melanoma; however, data evaluating timely access to immunotherapy are lacking. METHODS: A retrospective cohort study utilizing the National Cancer Database was conducted. Stage III and IV melanoma cases diagnosed between 2011 and 2018 that received systemic treatment with either immunotherapy or chemotherapy were included. Chemotherapy included BRAF/MEK inhibitors. Multivariable logistic regression models were utilized to evaluate factors associated with the likelihood of receiving immunotherapy as primary systemic treatment relative to chemotherapy; additionally, Cox proportional hazards models were utilized to incorporate time from diagnosis to primary systemic therapy into the analysis. RESULTS: The study population was comprised of 14,446 cases. The cohort included 12,053 (83.4%) immunotherapy and 2393 (16.6%) chemotherapy cases. In multivariable logistic regression analysis, factors significantly associated with immunotherapy receipt included population density, circle distance, year of diagnosis, Breslow thickness, and cancer stage. Immunotherapy timing was evaluated using multivariable Cox regression analysis. Minorities were less likely to receive timely immunotherapy than non-Hispanic Whites (HR 0.83, CI 0.74-0.93, p = 0.001). Patients at circle distances of 10-49 miles (HR 0.94, CI 0.89-0.99, p = 0.02) and ≥50 miles (HR 0.83, CI 0.77-0.90, p < 0.001) were less likely to receive timely immunotherapy. CONCLUSION: Patients traveling ≥10 miles and minorities have a decreased likelihood of receiving timely immunotherapy administration for primary systemic treatment. Future research is needed to identify what barriers and approaches can be leveraged to address these inequities.

Development and Dosimetric Characterization of a Customizable Shield for Subtotal Skin Electron Beam Therapy.

Purpose: Purpose: Subtotal skin electron beam therapy may be an option for patients with cutaneous lymphoma receiving radiation therapy to treat large areas of their skin but may benefit from sparing specific areas that may have had previous radiation therapy, are of specific cosmetic concern, and/or show no evidence of disease. We report here on the design, implementation, and dosimetric characteristics of a reusable and transparent customizable shield for use with the large fields used to deliver total skin electron beam therapy at extended distance with a conventional linear accelerator. Methods and Materials: A shield was designed and manufactured consisting of acrylic blocks that can be mounted on a steel frame to allow patient-specific shielding. The dosimetry of the device was measured using radiochromic film. Results: The shield is easy to use and well-tolerated for patient treatment, providing minimal electron transmission through the shield with a sharp penumbra at the field edge, with no increase in x-ray dose. We report on the dosimetry of a commercial device that has been used to treat more than 30 patients to date. Conclusions: The customizable shield is well suited to providing patient-specific shielding for subtotal skin electron beam therapy.

Skin Cancer Knowledge, Attitudes and Sun Protection Practices in the Hispanic Population: A Cross-Sectional Survey.

Hispanics are more likely to be diagnosed with skin cancer at a later stage and experience worse overall survival than Whites. The objective of this cross-sectional study was to assess the skin cancer knowledge, attitudes, perceived risk, and sun protection practices among an underserved population in the Phoenix area. We recruited participants from the greater Phoenix area to undergo skin examination and complete a questionnaire. 208 participants were included. The majority were Hispanic (64.9%). Of this Hispanic group, most were from Mexico (87.9%). The Hispanic cohort had an overall mean skin cancer knowledge score of 3.68/6, the lowest of any other racial/ethnic group, but had the highest desire to learn more about skin cancer (64.6%, "strongly agree"). They were the most concerned about developing skin cancer (50.4%, "very concerned") but had relatively lower rates of sun protection practices (7.9% "always use" sunscreen, 22.0% "always use" sun-protective clothing). Limitations of this study include a small sample size, lack of validation for the skin cancer knowledge score, lack of season as a covariate in the multivariate analysis, lack of follow-up, and lack of robust skin cancer risk assessment. In conclusion, despite poorer skin cancer knowledge and sun protection practices, the Hispanic population had the highest concern for developing skin cancer and desire to learn more about skin cancer. Targeted and culturally relevant skin cancer and sun protection education for this group is needed.

Single-cell analysis of Sézary syndrome reveals novel markers and shifting gene profiles associated with treatment.

Cutaneous T-cell lymphomas (CTCLs) are a spectrum of diseases with varied clinical courses caused by malignant clonal proliferation of skin-tropic T cells. Most patients have an indolent disease course managed with skin-directed therapies. In contrast, others, especially in advanced stages of disease or with specific forms, have aggressive progression and poor median survival. Sézary syndrome (SS), a leukemic variant of CTCL, lacks highly consistent phenotypic and genetic markers that may be leveraged to prevent the delay in diagnosis experienced by most patients with CTCL and could be useful for optimal treatment selection. Using single-cell mRNA and T-cell receptor sequencing of peripheral blood immune cells in SS, we extensively mapped the transcriptomic variations of nearly 50 000 T cells of both malignant and nonmalignant origins. We identified potential diverging SS cell populations, including quiescent and proliferative populations shared across multiple patients. In particular, the expression of AIRE was the most highly upregulated gene in our analysis, and AIRE protein expression could be observed over a variety of CTCLs. Furthermore, within a single patient, we were able to characterize differences in cell populations by comparing malignant T cells over the course of treatment with histone deacetylase inhibition and photopheresis. New cellular clusters after progression of the therapy notably exhibited increased expression of the transcriptional factor FOXP3, a master regulator of regulatory T-cell function, raising the potential implication of an evolving mechanism of immune evasion.

Characteristics of ulcerated and non-ulcerated necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is complicated by ulceration in up to 35% of cases. METHODS: Retrospective study of patients with NL seen at our institution between January 1, 1992, and May 25, 2021, was conducted. Ulcerated NL (UNL, n = 83) and non-ulcerated NL (NUNL, n = 233) groups were compared. RESULTS: Twenty-six percent (83/316) of patients with NL experienced ulceration. UNL was significantly more likely to be painful (52% vs. 36%, P = 0.01), was more likely to have a lesion-associated cutaneous malignancy (7% vs. 0%, P < 0.001), and had a larger median size (7 vs. 5 cm, P = 0.004) compared to NUNL. Vascular studies were performed on a subset of patients and revealed transcutaneous oxygen pressure (TcPO2) < 40 mm Hg in 53% and venous insufficiency in 62% with no significant differences between UNL and NUNL groups. In patients with unilateral ulceration, mean TcPO2 values (39.7 vs. 46.6 mm Hg), regional perfusion index <0.6 (29% vs. 14%), and TcPO2 < 40 mm Hg (43% vs. 14%) were worse in the ulcerated leg compared to the non-ulcerated leg, but these differences were not statistically significant. CONCLUSIONS: UNL was more likely to be painful, develop lesion-associated malignancy, and be larger in size compared to NUNL. There were no statistically significant differences in venous insufficiency, arterial Doppler/ankle brachial index, or TcPO2 values between UNL and NUNL patients, however, a significant portion of the cohort demonstrated abnormal vascular studies, particularly on TcPO2 and venous insufficiency testing.

Clinical and Pathological Characteristics and Outcomes Among Patients With Subcutaneous Panniculitis-like T-Cell Lymphoma and Related Adipotropic Lymphoproliferative Disorders.

Importance: There is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date. Objective: To generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions. Design, Setting, and Participants: This retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort was classified as (1) SPTCL or (2) adipotropic lymphoproliferative disorder (ALPD) for similar cases with incomplete histopathological criteria for SPTCL designation. Exposures: Cases of SPTCL diagnosed between 1998 and 2018. Main Outcomes and Measures: The main outcome was disease presentation and evolution, including response to therapy, disease progression, and development of hemophagocytic lymphohistiocytosis. Results: The cohort of 95 patients (median [range] age, 38 [2-81] years; female-to-male ratio, 2.7) included 75 cases of SPTCL and 20 cases of ALPD. The clinical presentation was similar for both groups with multiple (61 of 72 [85%]) or single (11 of 72 [15%]) tender nodules mostly involving extremities, occasionally resulting in lipoatrophy. Hemophagocytic lymphohistiocytosis (HLH) was only observed in SPTCL cases. With a mean follow-up of 56 months, 60 of 90 patients (67%) achieved complete remission with a median (range) of 3 (1-7) cumulative therapies. Relapse was common. None of the patients died of disease progression or HLH. Two patients with ALPD eventually progressed to SPTCL without associated systemic symptoms or HLH. Conclusions and Relevance: In this case series of patients initially diagnosed as having SPTCL, results showed no evidence of systemic tumoral progression beyond the adipose tissue. The SPTCL experience in this study confirmed an indolent course and favorable response to a variety of treatments ranging from immune modulation to chemotherapy followed by hematopoietic stem cell transplantation. Morbidity was primarily associated with HLH.

Efficacy and Safety of Topical Hypericin Photodynamic Therapy for Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 Randomized Clinical Trial.

Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives: To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants: This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions: In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures: The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results: The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT (P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles (P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance: The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02448381.

Histopathologic features of necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is an uncommon granulomatous dermatosis that can occur in patients with or without associated diabetes mellitus (DM). Prior studies have attempted to determine distinctive histopathologic features of NL in patients with and without DM. METHODS: A retrospective review of 97 patients with NL was performed to determine the similar and distinctive histopathologic features in patients with DM and without DM. RESULTS: Of the 97 patients, 32% (n = 31) had DM. Epidermal acanthosis was seen more commonly in diabetics than nondiabetics (32.3% vs. 12.1%; p = 0.017). Naked (sarcoidal/tuberculoid) granulomas were more frequently observed in nondiabetics than diabetics (22.7% vs. 3.2%; p = 0.016). Eosinophils were more common in nondiabetics than diabetics (38.5% vs. 9.7%; p = 0.004), while neutrophilic infiltration was more common in diabetics than nondiabetics (45.2% vs. 17.5%; p = 0.004). CONCLUSIONS: This study corroborates well-documented histopathologic features of NL and shows distinctive histopathologic features of NL among patients with DM-I, DM-II, and without DM. These results support the hypothesis that there are different underlying drivers of NL between diabetics and nondiabetics.