Shinohara, Michi M.

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

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase–positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase–negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

AbstractBackgroundThe reliability to non‐invasively identify features of inflammatory dermatoses by reflectance confocal microscopy (RCM) remains unknown. Lack of formal training among RCM readers can result in inconsistent assessments, limiting clinical utility. Specific consensus terminology with representative images is necessary to ensure consistent feature‐level interpretation among RCM readers.Objectives(1) Develop a glossary with representative images of RCM features of cutaneous acute graft‐versus‐host disease (aGVHD) for consistent interpretation among observers, (2) assess the interobserver reproducibility among RCM readers using the glossary, and (3) determine the concordance between RCM and histopathology for aGVHD features.MethodsThrough an iterative process of refinement and discussion among five international RCM experts, we developed a glossary with representative images of RCM features of aGVHD. From April to November 2018, patients suspected of aGVHD were imaged with RCM and subsequently biopsied. 17 lesions from 12 patients had clinically and pathologically confirmed cutaneous aGVHD. For each of these lesions, four dermatopathologists and four RCM readers independently evaluated the presence of aGVHD features in scanned histopathology slides and 1.5 × 1.5 mm RCM submosaics at 4 depths (blockstacks) respectively. RCM cases were adjudicated by a fifth RCM expert. Interobserver reproducibility was calculated by mean pairwise difference (U statistic). Concordance between modalities was determined by fraction of assignments with agreement.ResultsWe present a glossary with representative images of 18 aGVHD features by RCM. The average interobserver reproducibility among RCM readers (75%, confidence interval, CI: 71–79%) did not differ significantly from dermatopathologists (80%, 76–85%). The concordance between RCM and histopathology was 59%.ConclusionsBy using the glossary, the interobserver reproducibility among RCM readers was similar to the interobserver reproducibility among dermatopathologists. There was reasonable concordance between RCM and histopathology to visualize aGVHD features. The implementation of RCM can now be advanced in a variety of inflammatory conditions with a validated glossary and representative image set.

Abstract Pyoderma gangrenosum (PG) lacks consensus regarding treatment, and no prior studies assess treatment satisfaction in PG. The objective of this study was to determine patient‐reported satisfaction in the treatment of PG, and associations with satisfaction. Methodology was a multicenter cross‐sectional survey for patients who received systemic medication(s) to treat PG. Thirty‐five patients completed the survey (mean age: 54.0 years, 65.7% female, response rate: 81.4%). Mean (± SD) SATMED‐Q score was 75.0 (±16.2, range: 67.6‐85.3). Older patients (72.6 ± 23.6 for 18‐39 years, 74.4 ± 16.1 for 40‐59, 77.1 ± 11.6 for 60+), plus those with higher incomes (72.9 ± 20.3 for $0‐49 000; 74.0 ± 17.6 for $50 000‐99 000; 79.0 ± 14.6 for $100 000+) and education status (69.4 ± 14.3 for high school equivalent, 72.9 ± 15.9 for undergraduate, 91.7 ± 10.6 for graduate), were more satisfied with treatment. Ulcerative PG had higher SATMED‐Q scores (79.0 ± 13.2) than other subtypes (66.2 ± 19.3). For local therapy, wound care, or pain control, 63.2%, 100%, and 75% were satisfied, respectively. The mean DLQI was 8.6 (±7.6, range: 0‐29), and higher DLQI was associated with decreased satisfaction. Satisfaction with providers was positively correlated with global satisfaction (Pearson's r = 0.638). The presence of pain and/or depression influenced both SATMED‐Q (72.8 ± 18.8 with pain, 78.3 ± 11.2 without; 68.2 ± 18.8 with depression, 80.1 ± 12.2 without) and DLQI scores (12.1 ± 8.1 with pain, 3.9 ± 3.4 without; 10.3 ± 7.1 with depression, 7.4 ± 8.0 without). To optimize the patient experience, non‐modifiable associations should be individually considered, and potentially modifiable associations such as satisfaction with specific providers, pain, and depression, may be targeted for management.

AbstractBackgroundThe histopathological diagnosis of MF is challenging, and there is significant overlap with benign inflammatory processes. Clinical features may be relevant in the assessment of skin biopsies.MethodsWe provided photomicrographs to board‐certified dermatopathologists and one hematopathologist with and without accompanying clinical photographs and assessed accuracy and confidence in diagnosing MF.ResultsWe found that access to clinical photographs improved diagnostic accuracy in both MF and non‐MF (distractors); the degree of improvement was significantly higher in the non‐MF/distractor category. Across all categories, diagnostic confidence level was higher when clinical images were available.ConclusionThese findings suggest that clinical images are useful in making an accurate diagnosis of MF, and may be particularly helpful in ruling it out when an inflammatory disorder is clinically suspected.

BACKGROUND. Cutaneous erythema and histopathology features in patients post allogeneic hematopoietic cell transplantation (HCT) are nonspecific, making it difficult to distinguish acute graft-versus-host disease (aGVHD) from engraftment syndrome, drug reactions, viral infections, and other etiologies. Biopsies from different locations on the same patient frequently differ in aGVHD grade, and serial biopsies of a single lesion are not possible. Proper biopsy site selection, timing, and serial noninvasive microscopic monitoring may improve our understanding and management of aGVHD. In this study, we tested the feasibility of noninvasive reflectance confocal microscopy (RCM) to detect key histopathology features of cutaneous aGVHD. STUDY POPULATION. We enrolled 11 patients with high clinical suspicion of cutaneous aGVHD, as determined by a transplant physician. In total, 16 lesions of cutaneous aGVHD-affected site were imaged by RCM (6x6 mm2en face images at four different depths) and subsequently biopsied (4x4 mm punch biopsy). 9 out of 11 patients had only skin involvement, and 2 patients had skin and gut aGVHD. 5 patients had >50% body surface area (BSA) affected, 1 had 18-50% BSA, and 5 had <18% BSA. 8 out of 11 patients required systemic corticosteroids and 3 patients received topical corticosteroids. All patients were imaged before starting treatment. METHODS. We used a clinical confocal microscope (Vivascope 1500, Caliber I.D.), which enables real-time evaluation of epidermal and superficial dermal tissue at sub-cellular resolution. Four reflectance confocal microscopists blinded to histopathology independently evaluated the presence or absence of 18 RCM features1. Concurrently, four dermatopathologists blinded to clinical and confocal information determined the presence or absence of 19 histopathology features, as well as the Lerner aGVHD grade. A histologic feature was determined as "present" in a lesion when marked by most experts (expert vote) or resolved by a fifth expert in case of a disagreement among four experts. The reflectance confocal microscopist vote was then correlated to the dermatopathologist expert vote for 17 overlapping features. We also evaluated the interrater variability among microscopists and among dermatopathologists. RESULTS. The main aGVHD features by Lerner grade had > 88% correlation between RCM and histopathology: (1) basal vacuolar change, (2) presence of dyskeratotic keratinocytes, and (3) dermal inflammation. By contrast, dyskeratotic cells and inflammation at the adnexal structures had <50% correlation. This may be attributed to the fact that more adnexal structures are typically visible in the 6x6 mm2 RCM horizontal tissue view compared to vertical section histopathology. We found a similar interrater variability among RCM experts (70%) and dermatopathologists (68%). CONCLUSIONS. In this pilot study, we show that noninvasive label-free RCM of skin enables detection of the main Lerner grade features of cutaneous aGVHD. We found a similar interrater variability among reflectance confocal microscopists and among dermatopathologists who each independently evaluated the presence or absence of a list of aGVHD features. Future studies can build on this work to evaluate the feasibility of RCM to determine cutaneous aGVHD grade, as well as distinguish between rash due to aGVHD and drug reactions. ACKNOWLEDGEMENT. This work was supported in part by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service. Saknite I, Gill M, Alessi-Fox C, Byrne M, Jagasia M, Gonzalez S, Ardigo M, Tkaczyk ER. Features of cutaneous acute graft-versus-host disease by reflectance confocal microscopy. Br J Dermatol (2019). Disclosures Christi: Caliber I.D.: Employment, Equity Ownership. Byrne:Karyopharm: Research Funding. Jagasia:Kadmon: Consultancy; Incyte: Consultancy; Janssen: Research Funding. Tkaczyk:Incyte: Consultancy.

This pathology PILOT study aims to define the role and feasibility of centralized pathology review in a cohort of 75 patients from different centers in the United States and Europe using digital slide scanning. The pathologic material from 75 patients who had been diagnosed with mycosis fungoides/Sézary syndrome and were clinically staged as IIb or above was retrieved from 11 participating centers. Each pathology reviewer was provided with the pathologic diagnosis (by the referring pathologist), and the following list of histopathologic criteria (presence or absence) from the initial report: epidermotropism, folliculotropism (FT), large cell transformation, syringotropism, and granulomas. Patients with advance stage were selected for this study as this is a population where there is significant variability in the diagnosis of pathologic prognostic and predictive biomarkers. The slides were digitally scanned with an Aperio scanner and consensus review of cases occurred when major or minor discrepancies between the referral diagnosis and central pathology review occurred. Among the 75 cases, 70 (93.3%) had a final consensus diagnosis between the 3 central review pathologists. The overall agreement between the consensus review and the referring pathologist was 60%. The overall agreement was also higher between the reviewers and consensus review, compared with the referring pathologist and consensus. 65.3% of cases had some type of discrepancy (major or minor) between the outside and consensus review. Major discrepancies were seen in 34 of 73 cases (46.6%; 73 cases indicated a yes or no response). Minor discrepancies were seen in 32 of 75 (42.7%) of cases. Most of the major discrepancies were accounted by a difference in interpretation in the presence or absence of large cell transformation or FT. Most minor discrepancies were explained by a different interpretation in the expression of CD30. We found digital slide scanning to be a beneficial, reliable, and practical for a methodical approach to perform central pathology review in the context of a large clinical prospective study.