Improving disease-specific survival for patients with Sezary syndrome in the modern era of systemic therapies.

Traditionally, Sezary syndrome (SS) has been associated with few therapeutic options and poor prognosis, with 5-year disease-specific survival (DSS) less than one-third in historical cohorts. However, newer therapies and combinations are associated with impressive time-to-next-treatment (TTNT), particularly allogeneic stem-cell transplantation (AlloSCT) and combination therapies notably those including extracorporeal photopheresis. In this multicentre, international study, we explored the prognostic outcomes of 178 patients exclusively managed for SS, diagnosed between 2012 and 2020, and treated in the modern therapeutic era. In this cohort, 58 different therapies were delivered, with 13.5% of patients receiving AlloSCT. Long-term survival exceeded historical reports with 5-year DSS and OS of 56.4% and 53.4% respectively. In those receiving AlloSCT, prognosis was excellent: 5-year DSS and OS were 90.5% and 78.0% respectively. Confirming the results from the Cutaneous Lymphoma International Consortium (CLIC), LDH and LCT had significant prognostic impact. Unlike earlier studies, stage did not have prognostic impact; we speculate that greater relative benefit favours patients with extensive lymphomatous nodal disease (Stage IVA2) compared to historical reports. For patients ineligible for AlloSCT, the prognosis remains relatively poor (5-year DSS 51.4% and OS 49.6%), representing ongoing unmet needs for more effective novel agents and investigation of improved therapeutic combinations.

Macrophage-derived CXCL9 and CXCL11, T-cell skin homing, and disease control in mogamulizumab-treated CTCL patients.

Cutaneous T-cell lymphomas (CTCLs) are rare malignancies involving primarily the skin. Responses to treatment are usually short-lived in advanced CTCL. The determinants of long-term CTCL control are unclear. Mogamulizumab, an anti-human CCR4 antibody that acts by antibody-dependent cell cytotoxicity against CCR4+ CTCL tumor cells and peripheral memory blood regulatory T cells, has been associated with long-lasting remissions and immune adverse events. Here, we reported skin rashes in 32% of 44 patients with CTCL treated with mogamulizumab, associated with significantly higher overall survival (hazard ratio, 0.16; 0.04-0.73; P = .01). Rash occurred in patients with Sézary syndrome and was associated with longer time to progression. These rashes were characterized by a CD163+ granulomatous and/or CD8+ lichenoid skin infiltrate. High-throughput sequencing analysis of T-cell receptor ß genes in skin and blood flow cytometry confirmed the depletion of CTCL tumor cells, as well as the recruitment of new reactive T-cell clones in skin at the time of skin rash. CXCL9 and CXCL11, two macrophage-derived chemokines that recruit CXCR3+ T cells to skin, were overexpressed in skin rashes. A higher frequency of TIGIT+ and PD1+ exhausted reactive blood T cells was observed at baseline in patients with rash, and this frequency decreased with mogamulizumab treatment. These data are consistent with mogamulizumab-induced long-term immune CTCL control by activation of the macrophage and T-cell responses in patients with rash.

Pegylated interferon-α2a in cutaneous T-cell lymphoma - a multicenter retrospective data analysis with 70 patients.

BACKGROUND: Interferon-alpha is an important therapeutic option for the treatment of the cutaneous T-cell lymphomas (CTCL). Since the approved recombinant interferon-α-2a (IFN-α2a) has no longer been produced since January 2020, pegylated interferon-α2a (pegIFN-α2a) can be used as an alternative treatment, even though it is not approved for the treatment of CTCL. The aim of this multicentre study was to generate comprehensive data on the efficacy and tolerability of pegIFN-α2a in the treatment of CTCL. PATIENTS AND METHODS: A multicenter retrospective study was conducted with 70 patients with CTCL from twelve German skin centers. RESULTS: In total, 70 patients were included in the study, with 57.2% male and a mean age of 58.8 ± 14.9 years. Mycosis fungoides was present in 71.4% of cases and Sézary Syndrome in 28.6%. An overall response rate of 55.2% was observed with pegIFNα-2a therapy. In 50% of cases, therapy was discontinued after 63.6 ± 33.5 weeks. The most common reason for discontinuation was adverse events, which occurred in 68.6% of cases and which were classified as severe in 29.2%. Blood count changes, fatigue and liver toxicity occurred most frequently. CONCLUSIONS: Our analysis provides comprehensive data on the efficacy and tolerability of pegIFNα-2a therapy in patients with CTCL. In terms of response rates and side effect profile, pegIFNα-2a appears to be comparable to IFN-α2a therapy.

Epidemiology of mature T/NK-cell lymphomas in Germany - A representative cross-sectional study based on SHI claims data.

BACKGROUND: Primary cutaneous lymphomas (PCL) are rare skin tumors of lymphoproliferative neoplasms and belong to the heterogeneous group of non-Hodgkin's lymphomas. PCL encompass a broad spectrum of clinical and histologic manifestations, with cutaneous T-cell lymphoma (CTCL) being the most common (73%). Due to the rarity of the diseases, population-based studies of care and epidemiology are limited. PATIENTS AND METHODS: Based on anonymized, age- and sex-adjusted SHI (statutory health insurance) claims data of approximately five million SHI-insured patients, a retrospective analysis was conducted over a six-year period (2012-2017) to determine the prevalence, incidence, and lethality in patients with mature-cell T/NK-cell lymphoma in Germany. RESULTS: A total of 1,336 patients with T-cell lymphoma were identified during the observation period. The six-year prevalence ranged from 27.35 to 43.58 per 100,000. Patients were 65% male with a mean age of 66 years (SD 15). There were 246 patients (approx. 20%) who died within the 6 years, up to 7% per year. The calculated incidence in 153 identified patients in 2017 is 3.65 to 3.92 per 100,000. CONCLUSIONS: For the first time, valid epidemiologic findings of patients with mature T-cell and NK-cell lymphomas were obtained using SHI claims data in Germany. Further analyses are needed to gain a deeper insight into the healthcare reality of patients with this rare disease.

Care structure of patients with mycosis fungoides and Sézary syndrome in Germany - Care research based on SHI claims data.

BACKGROUND: Cutaneous T-cell lymphomas (CTCLs) are rare forms of non-Hodgkin's lymphoma of T-cell origin that occur mainly in the skin. The most common form is mycosis fungoides (MF), but Sézary syndrome (SS), a more aggressive form of CTCL, is another relevant subgroup. Due to the rare nature of the disease, population-based studies of the epidemiology and disease burden and insights into care delivery are limited. PATIENTS AND METHODS: Based on an anonymized, age and sex-adjusted routine dataset comprising approximately five million people with statutory health insurance, a retrospective, longitudinal healthcare research study was conducted over a six-year period (2012-2017). RESULTS: In 55 % of patients with MF and SS, the initial diagnosis was documented in an outpatient setting; in 59 % of cases by a dermatologist. Immunophenotyping by flow cytometry is considered an important investigative tool for the detection and follow-up surveillance of blood involvement of cutaneous lymphomas, as the disease stage is the most important prognostic factor in MF and SS; this was performed in only 10 % of patients. The first-line treatment was topical (76 %), in particular with corticosteroids (66 %). CONCLUSIONS: The findings from this healthcare research point to the need for increased guideline-based care.

Mogamulizumab-induced Mucocutaneous Lichenoid Reaction: A Case Report and Short Review.

is missing (Short communication).

Lupus Erythematosus Tumidus Mimicking Primary Cutaneous Marginal Zone B-cell Lymphoma.

is missing (Short communication).

Reduction of Inflammatory and Noninflammatory Lesions with Topical Tyrothricin 0.1% in the Treatment of Mild to Severe Acne Papulopustulosa: A Randomized Controlled Clinical Trial.

BACKGROUND/AIMS: Antibiotic-induced drug resistance requires new approaches in topical acne treatment. Tyrothricin is known to produce no resistance. In this study, it was tested for the first time in topical acne treatment. The efficacy and tolerability of topical tyrothricin 0.1% was evaluated. METHODS: A randomized, active comparator-controlled, exploratory, observer-blind clinical study was conducted in 24 patients with acne papulopustulosa. Randomization on a split-face was either tyrothricin versus clindamycin + benzoyl peroxide (BPO) (n = 12) or tyrothricin versus BPO 5% (n = 12). The main outcome was change in inflammatory and noninflammatory lesion counts. RESULTS: The mean differences in inflammatory lesion counts from baseline were -12.3 (95% CI: -20.5 to -4.1) in clindamycin + BPO, -10.2 (95% CI: -15.3 to -5.0) in BPO 5%, and -7.7 (95% CI: -11.7 to -3.7) in tyrothricin. Tyrothricin reduced noninflammatory lesions (mean difference: -6.5 (95% CI: -11.6 to -1.4) and caused less product-related adverse events (n = 31) compared to BPO (n = 37) and clindamycin + BPO (n = 20). CONCLUSION: The results indicate that tyrothricin might be a candidate for treating acne and it seems to be more tolerable than both comparator treatments.

Weight-bearing-induced changes in the microtopography and structural stiffness of human skin in vivo following immobility periods.

Pressure ulcers (PUs) are injuries to the skin and underlying tissues, caused by sustained deformations and occur frequently in aged patients. Skin microtopography and stiffness affect the interaction of skin with contact surfaces contributing to PU development. We simulated immobility in 20 healthy females (mean age 69.9 years). Skin microtopography and stiffness were measured at the PU predilection sites before and after loading. Skin roughness decreased at the heels by 18.1% after 90 minutes (p = 0.022), but remained unchanged at the sacrum and the upper back. Structural elasticity and elastic deformations increased at all skin areas; changes over time were significant at the sacrum (p = 0.005) and the heel, (p = 0.002). The residual skin deformation increased at all skin areas after loading significantly at the sacrum (32.0%, p = 0.013) and upper back (20.6%, p = 0.007). The structural "biological" elasticity of the skin decreased significantly at the upper back after loading, but remained unchanged at the heels. All skin changes recovered after unloading. Results indicate that prolonged loading causes structural skin changes in humans in vivo in PU predilection sites. The pathogenesis of PUs is different at the heels, the sacral and upper back skin.

[Monoclonal antibodies for inflammatory, autoimmune and oncological skin diseases]. / Monoklonale Antikörper für entzündliche, autoimmune und onkologische Hauterkrankungen.

In 1997 rituximab, a genetically engineered chimeric monoclonal antibody (mAb) targeting CD20 expressed on B cells was approved for treatment of non-Hodgkin's lymphoma. Since then, pharmacological improvements combined with increased knowledge on the immunopathogenesis of diseases led to the development of specific mAb targeting different antigens (e.g., interleukins or transmembrane receptors). This approach reshaped the therapeutic methodology in many fields, including dermatology. Nowadays, the treatment of frequent and possibly impairing inflammatory disorders such as psoriasis, atopic dermatitis or hidradenitis suppurativa have different mAbs approved for both adult and pediatric patients. This class of drugs often shows a more favorable outcome and a better safety profile than routine immunosuppressants, such as steroids and steroid-sparing substances. For many years mAbs also represented a pillar of oncological treatment for severe diseases such as malignant melanoma or Merkel cell carcinoma. This review summarizes the current knowledge on already approved and promising new mAbs for the treatment of inflammatory and oncological skin diseases.

Radiotherapy in cutaneous lymphomas: Recommendations from the EORTC cutaneous lymphoma tumour group.

The number of primary cutaneous lymphoma patients receiving low-dose radiotherapy is increasing, though controlled clinical trials defining the standard radiation dose for each specific entity have not yet been completed. Radiation oncologists are left with making highly individualized decisions that would be better enriched by additional clinical evidence. In this expert opinion, we aim to provide a clear recommendation to improve the current practice of radiation oncology. In addition, existing literature has been reviewed to develop recommendations for all types of primary cutaneous lymphoma. A prospective trial is urgently needed to identify the factors influencing patient outcomes following different radiation doses.

Real-life efficacy of immunotherapy for Sézary syndrome: a multicenter observational cohort study.

Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013). Interpretation: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome. Funding: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3_200253/1) and SKINTEGRITY.CH collaborative research program.

SEM and EDS investigation of a pyrolytic carbon covered C/C composite maxillofacial implant retrieved from the human body after 8 years.

The long term effect of the human body on a pyrolytic carbon covered C/C composite maxillofacial implant (CarBulat(Tm)) was investigated by comparing the structure, the surface morphology and composition of an implant retrieved after 8 years to a sterilized, but not implanted one. Although the thickness of the carbon fibres constituting the implants did not change during the 8 year period, the surface of the implant retrieved was covered with a thin surface layer not present on the unimplanted implant. The composition of this layer is identical to the composition of the underlying carbon fibres. Calcium can only be detected on the surface as a trace element implying that the new layer is not formed by bone tissue. Residual soft tissue penetrating the bulk material between the carbon fibre bunches was found on the retrieved implant indicating the importance of the surface morphology in tissue growth and adhering to implants.

Mycosis Fungoides and Sézary Syndrome: Microenvironment and Cancer Progression.

Mycosis fungoides and Sézary syndrome are epidermotropic cutaneous lymphomas, and both of them are rare diseases. Mycosis fungoides is the most frequent primary cutaneous lymphoma. In about 25% of patients with mycosis fungoides, the disease may progress to higher stages. The pathogenesis and risk factors of progression in mycosis fungoides and Sézary syndrome are not yet fully understood. Previous works have investigated inter- and intrapatient tumor cell heterogeneity. Here, we overview the role of the tumor microenvironment of mycosis fungoides and Sézary syndrome by describing its key components and functions. Emphasis is put on the role of the microenvironment in promoting tumor growth or antitumor immune response, as well as possible therapeutic targets. We focus on recent advances in the field and point out treatment-related alterations of the microenvironment. Deciphering the tumor microenvironment may help to develop strategies that lead to long-term disease control and cure.