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Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88-1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73-2.38; p = 0.44). Grade 3-4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed., (© 2024. The Author(s).)

Background: Time trend analysis of cutaneous melanoma (CM) mortality in fair skin populations shows both a gradual decrease and/or an increase. To explain these differences, we analyzed long-term time trends in the incidence of the most common histological subtypes of CM: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM)., Methods: Using data from the Netherlands Cancer Registry and Statistics Netherlands, the number and rates of cases diagnosed with SSM, LLM, and NM from 1989 to 2016 were analyzed by age, calendar period, and birth cohort of people born in successive periods from 1925 to 1973., Results: Primary CM was diagnosed in 52,000 men and 66,588 women in the study period. The annual age-standardized incidence rate increased three-fold from 14 to 42 per 100,000 person-years. The most common subtype was SSM (50%), followed by LMM (23%) and NM (14%). Age-specific subtype rates showed an upward trend over time for both men and women. Younger birth cohorts had higher rates of SSM and LMM diagnosis than older birth cohorts. This birth cohort pattern was not observed for NM., Conclusions: We observed a strong increase in the melanoma epidemic curves in the light-skinned Dutch population over the last three decades. This increase is explained by younger generations having higher rates of SSM and LMM than older generations., (© 2022 The Authors. International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Purpose: To determine the optimal radiation dose for treatment of primary cutaneous anaplastic large cell lymphoma (C-ALCL) with solitary or localized, multifocal or recurrent skin lesions., Methods and Materials: In this multicenter study, patients with C-ALCL who had been treated with radiation therapy (RT) between 1984 and 2016 were retrieved from the Dutch registry of cutaneous lymphomas. Distinction was made between patients first presenting with solitary or localized lesions (n=63), with multifocal skin lesions (n=6), and patients with a skin relapse (n=22). Radiation doses, treatment response, and follow-up were evaluated. Radiation doses were categorized as low-dose (≤20 Gy), intermediate-dose (21-39 Gy), and high-dose (≥40 Gy) RT., Results: Of 63 patients presenting with solitary or localized skin lesions, 61 (97%) showed a complete response (CR). There were no differences in CR between low-dose (16 of 17), intermediate-dose (15 of 15), and high-dose RT (30 of 31). After a median follow-up of 46 months, 30 of 63 patients (48%) had a relapse, but in-field relapses were never observed. Six of 6 patients (100%) initially presenting with multifocal skin lesions showed a CR (3 of 3 low-dose, 2 of 2 intermediate-dose, 1 of 1 high-dose RT). After a median follow-up of 27 months, 3 of 6 patients had a relapse. Treatment of 33 skin relapses in 22 patients showed no differences in CR between low-dose (18 of 19), intermediate-dose (6 of 6), and high-dose RT (8 of 8). In the last 10 years there has been a decrease in radiation dose used in the treatment of C-ALCL. Treatment of multifocal and recurrent lesions with a dose of 8 Gy (2 × 4 Gy) resulted in CR of 17 of 18 lesions., Conclusions: Our results show that a radiation dose of 20 Gy (8 × 2.5 Gy) is effective in patients presenting with solitary or localized skin lesions. For patients with multifocal skin lesions and patients with a skin relapse, a dose of 8 Gy (2 × 4 Gy) may be sufficient., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: Large case series suggest that patients with folliculotropic mycosis fungoides (FMF) have a worse prognosis than patients with classic mycosis fungoides (MF). However, recent studies described a subgroup of patients with FMF with a more favorable prognosis. Distinction between indolent and aggressive FMF may have important therapeutic consequences but is hampered by the inability of the current tumor-node-metastasis-blood (TNMB) staging system to classify patients with FMF in a clinically meaningful way., Objective: To differentiate between indolent and aggressive FMF using clinicopathological criteria and to define prognostic factors in patients with FMF., Design, Setting, and Participants: In this prospective cohort study, we followed 203 patients with FMF, included in the Dutch Cutaneous Lymphoma Registry between October 1985 and May 2014 at a tertiary referral center hosting the Dutch Cutaneous Lymphoma Registry. Overall, 220 patients with FMF had been registered, but 17 patients with incomplete follow-up data or a history of classic MF were excluded., Main Outcomes and Measures: Main outcomes included clinical and histological characteristics, disease progression, and survival. Prognostic factors were investigated using Cox proportional hazard regression analysis. Distinction between early plaque-stage FMF and advanced plaque-stage FMF was made by a blinded review of skin biopsy specimens from patients presenting with plaques., Results: In a cohort of 147 men and 56 women (median [range] age, 59 [15-93] years), patients with histologically early plaque-stage FMF had a very similar overall survival (OS) rate to patients with only patches and/or follicular papules (10-year OS, 71% vs 80%), while the survival rate of patients with histologically advanced plaque-stage FMF was almost identical to that of patients presenting with tumors (10-year OS, 25% vs 27%). Subsequently, 3 clinical subgroups with significantly different survival data were distinguished: early skin-limited FMF (group A; n = 84; 5-year and 10-year OS, 92% and 72%); advanced skin-limited FMF (group B; n = 102; 5-year and 10-year OS, 55% and 28%); and FMF presenting with extracutaneous disease (group C; n = 17; 5-year and 10-year OS, 23% and 2%). Age at diagnosis, large cell transformation and secondary bacterial infection were independent risk factors for disease progression and/or poor survival., Conclusions and Relevance: The results of this study provide useful criteria to differentiate between indolent and aggressive FMF and confirm the existence of a subgroup of FMF with a favorable prognosis.

As melanoma researchers continue to investigate environmental and lifestyle-related risk factors, questionnaire data remain important. The reproducibility of a questionnaire on melanoma risk factors was investigated using a test-retest approach in 389 Dutch melanoma patients. In 2011, 389 melanoma patients filled out a questionnaire on melanoma risk factors twice. Test-retest reproducibility was assessed by calculating kappas (κ), weighted kappas (κw), and intraclass correlation coefficients (ICCs) for categorical, ordinal, and continuous variables, respectively. Stratified analyses were carried out by sex, age group, education level, and time since diagnosis. The median time between the questionnaires was 31 days. The reproducibility was substantial for questions on phenotypic characteristics (κ/κw/ICC=0.62-0.77), fair-to-substantial for sun exposure and sun protection behavior (κ/κw/ICC=0.38-0.79), and moderate for sunburn history (κ/κw=0.42-0.51). No clear differences were observed between men and women. Younger patients showed a better reproducibility in nine of the 29 questions compared with older patients and higher educated patients showed a better reproducibility in four of the 29 questions. Patients with a diagnosis shorter than 1.5 years ago had a better reproducibility in four out of 29 items compared with patients with a diagnosis 1.5-3.0 years ago. Our study showed that self-reported information on melanoma risk factors is fairly well reproducible. Although this does not guarantee validity, this type of questionnaire seems to be useful in research settings. The reproducibility is slightly better in young patients and patients with a higher education level, which can be taken into account when interpreting results from epidemiological studies.

Basal cell carcinoma (BCC) incidence rates are increasing. From 1973 to 2009, data on all first histologically confirmed BCCs were gained from the Eindhoven Cancer Registry to estimate trends in patient-based BCC incidence rates by sex, age group, and site in the southeast Netherlands. Trends in European age-standardized rates and age- and site-specific incidence rates were assessed by calculating the estimated annual percentage change (EAPC). Between 1973 and 2009, the European standardized rate quadrupled from 40 to 165 per 100,000 person-years for men and from 34 to 157 for women, significantly increasing since 1973 in both sexes, but accelerating from 2002 until 2009 with an EAPC of 6.8% (95% confidence interval (CI), 5.3-8.3) for men and 7.9% (95% CI, 6.2-9.7) for women. Women below the age of 40 years exhibited a constant linear increase of 6.3% since 1973. The head and neck region was most often affected in both sexes, but the steepest increase was seen for the trunk (EAPC men 13%, women 15%). In the absence of reliable tumor-based rates, these alarming patient-based rates are probably an interesting indicator for the impact of more intensive UV exposure in a prosperous European population.

The identification of responding patients early during treatment would improve the capability to develop effective new immunotherapies more rapidly. Here, we describe a bioassay that may link early T-cell-mediated immune responses to later clinical benefits. This bioassay rests upon the tenet of immunotherapy that tumor-specific effector T cells capable of invading peripheral tissue can recognize tumor antigens and exert cytotoxic functions there. To show its utility, we conducted a retrospective study of a large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic cell (DC)-based vaccination protocols to examine a hypothesized correlation of posttreatment skin-infiltrating lymphocytes (SKIL) with overall survival (OS). Stringent immunologic criteria were defined to identify long-term survivors. The presence of tumor-associated antigen (TAA)-specific CD8(+) T cell populations within SKILs (criterion I) was highly predictive for long-term survival. Further restriction by selecting for the presence of TAA-specific CD8(+) T cells specifically recognizing tumor peptide (criterion II) was also associated with improved OS. Recognition of naturally processed antigen (criterion III) maximized the accuracy of the test, with a median OS of 24.1 versus 9.9 months (P = 0.001). Our results show that detailed characterization of SKILs can permit an accurate selection of metastatic melanoma patients who benefit most from DC-based vaccination. This simple and robust bioassay integrates multiple aspects of cellular functions that mediate effective immune responses, thereby offering an effective tool to rapidly identify patients who are responding to immunotherapy at an early stage of treatment.

Background: Primary cutaneous CD30+ anaplastic large-cell lymphoma is a rare form of non-Hodgkin's lymphoma, which is restricted to the skin., Case Description: A 50-year-old man presented with an asymptomatic tumorous area in the groin that had appeared within the previous week, and a longer history of a transient red, flaking area in the popliteal space. Histopathological findings were consistent with CD30+ anaplastic large-cell lymphoma. Staging demonstrated no extracutanous spread. The skin lesions disappeared without treatment within 3 months., Conclusion: Primary cutaneous CD30+ anaplastic large-cell lymphoma is a rare condition. It has a histopathological picture of a diffuse proliferation of large atypical anaplastic cells, suggesting an unfavourable disease course. However, this condition is characterised by a indolent course and favourable prognosis since spontaneous complete regression can occur.

Eight cases of the acanthosis nigricans form of epidermal nevus have been described in literature. The present case is impressive and has an extensive segmental distribution. Although etiological factors, such as mutations in the FGFR3 gene, are becoming recognized, treatment options remain limited. We present a case of a 14-year-old male with multiple hyperpigmented, hyperkeratotic plaques on the upper body, axillae, and groin with a segmental distribution following Blaschko lines. Histopathological investigation showed aspects of both acanthosis nigricans and epidermal nevus. So far, screening has not revealed any internal abnormalities. As previous cases show a clear association with internal diseases, repetitive screening for internal diseases and syndromes is suggested in the case of the acanthosis nigricans form of epidermal nevus. Treatment of the condition remains a challenge.

Summary: Immunosuppressive therapy in renal transplant recipients (RTRs) is associated with an increased risk for the development of (pre)malignancies involving the skin and the female lower genital tract. We assessed whether yearly cervical screening was performed and evaluated the development of skin cancer and gynaecological (pre)malignancies in RTRs. Female RTRs (n = 224), transplanted between 1991 and 1995, were analysed retrospectively. Sociodemographic patient characteristics, frequency and results of cervical smears and prevalence of cutaneous, cervical, vaginal or vulvar (pre)malignancies were investigated and compared with that in the general population. A mean of 0.2 cervical smears per patient per year was found to have been performed in RTRs, which is significantly less than the recommended screening ratio of 1.0 for female RTRs (P < 0.001). The risk for RTRs to develop malignancies of the female lower genital tract was increased: twofold to sixfold for cervical intraepithelial neoplasia, threefold for cervical carcinoma and 50-fold for vulvar carcinoma. Cervical screening is not performed in accordance with the advised yearly intervals, and the risk for RTRs to develop vulvar and cervical (pre)malignancies is increased. More attention should be paid to the vulvar and cervical surveillance of RTRs by both medical specialists and general physicians.

In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.

Purpose: The success of immunotherapy with dendritic cells (DC) to treat cancer is dependent on effective migration to the lymph nodes and subsequent activation of antigen-specific T cells. In this study, we investigated the fate of DC after intradermal (i.d.) or intranodal (i.n.) administration and the consequences for the immune activating potential of DC vaccines in melanoma patients., Experimental Design: DC were i.d. or i.n. administered to 25 patients with metastatic melanoma scheduled for regional lymph node resection. To track DC in vivo with scintigraphic imaging and in lymph nodes by immunohistochemistry, cells were labeled with both [(111)In]-indium and superparamagnetic iron oxide., Results: After i.d. injection, maximally 4% of the DC reached the draining lymph nodes. When correctly delivered, all DC were delivered to one or more lymph nodes after i.n. injection. Independent of the route of administration, large numbers of DC remained at the injection site, lost viability, and were cleared by infiltrating CD163+ macrophages within 48 hours. Interestingly, 87 +/- 10% of the surviving DC preferentially migrated into the T-cell areas, where they induced antigen-specific T-cell responses. Even though more DC reached the T-cell areas, i.n. injection of DC induced similar antigen-specific immune responses as i.d. injection. Immune responses were already induced with <5 x 10(5) DC migrating into the T-cell areas., Conclusions: Monocyte-derived DC have high immune activating potential irrespective of the route of vaccination. Limited numbers of DC in the draining lymph nodes are sufficient to induce antigen-specific immunologic responses.