Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial.

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.

Trends in three major histological subtypes of cutaneous melanoma in the Netherlands between 1989 and 2016.

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.

Immunological responses to adjuvant vaccination with combined CD1c myeloid and plasmacytoid dendritic cells in stage III melanoma patients.

We evaluated the immunological responses of lymph-node involved (stage III) melanoma patients to adjuvant dendritic cell vaccination with subsets of naturally occurring dendritic cells (nDCs). Fifteen patients with completely resected stage III melanoma were randomized to receive adjuvant dendritic cell vaccination with CD1c myeloid dendritic cells (cDC2s), plasmacytoid dendritic cells (pDCs) or the combination. Immunological response was the primary endpoint and secondary endpoints included safety and survival.

Autologous monocyte-derived DC vaccination combined with cisplatin in stage III and IV melanoma patients: a prospective, randomized phase 2 trial.

Background: Autologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination.

Methods: This is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin.

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer.

Background: Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs).

Methods: In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs.

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.

Recommendations for the Optimal Radiation Dose in Patients With Primary Cutaneous Anaplastic Large Cell Lymphoma: A Report of the Dutch Cutaneous Lymphoma Group.

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).

Improvement of Gynecological Screening of Female Renal Transplant Recipients by Self-Sampling for Human Papillomavirus Detection.

Objectives: Female renal transplant recipients (RTRs) have increased risk for developing human papillomavirus (HPV)-related (pre)malignancies of the lower genital tract. Annual cervical screening is advised for RTRs, but the participation rate is low. The aim of this study is to investigate whether HPV self-sampling is suitable for gynecological screening of RTRs to increase participation rate.

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients.

Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients.

Experimental Design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines.

Clinical Staging and Prognostic Factors in Folliculotropic Mycosis Fungoides.

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.

Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase.

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells.

Purpose: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c(+) myeloid DCs, naturally circulating in the blood.

Experimental Design: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c(+) myeloid DCs, activated by only brief (16 hours) ex vivo culture and loaded with tumor-associated antigens of tyrosinase and gp100.

Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG.

Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients.

Autologous dendritic cell (DC) therapy is an experimental cellular immunotherapy that is safe and immunogenic in patients with advanced melanoma. In an attempt to further improve the therapeutic responses, we treated 15 patients with melanoma, with autologous monocyte-derived immature DC electroporated with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively active TLR4 (caTLR4) together with mRNA encoding a tumor-associated antigen (TAA; respectively gp100 or tyrosinase). In addition, DC were pulsed with keyhole limpet hemocyanin (KLH) that served as a control antigen.

[A girl with hyperkeratotic patches on the skin].

A 5-year-old girl with generalized verrucous hyperkeratosis consulted the dermatologist for diagnosis and therapy. Further physical and mental development were normal. Gene analysis of keratin 1 and 10 was negative.

Reproducibility of self-reported melanoma risk factors in melanoma patients.

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.

Genital psoriasis awareness program: physical and psychological care for patients with genital psoriasis.

Genital psoriasis is a neglected manifestation of psoriasis, although it affects numerous patients and has major effects on sexual quality of life (SQoL). We aimed to assess the value of specialised care for patients with genital psoriasis. Patients were treated for at least one year at a specialised research outpatient clinic with extensive attention for genital lesions and SQoL.

A variant in FTO shows association with melanoma risk not due to BMI.

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10(-12), per-allele odds ratio for allele A = 1.

Trends in Basal cell carcinoma incidence rates: a 37-year Dutch observational study.

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).

Targeting CD4(+) T-helper cells improves the induction of antitumor responses in dendritic cell-based vaccination.

To evaluate the relevance of directing antigen-specific CD4(+) T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)-restricted epitopes alone or both MHC class I and II (MHC-I/II)-restricted epitopes. We enrolled 33 stage III and IV HLA-A*02:01-positive patients with melanoma in this study, of whom 29 were evaluable for immunologic response. Patients received intranodal vaccinations with cytokine-matured DCs loaded with keyhole limpet hemocyanin and MHC-I alone or MHC-I/II-restricted tumor-associated antigens (TAA) of tyrosinase and gp100, depending on their HLA-DR4 status.

Melanoma of unknown primary origin: a population-based study in the Netherlands.

Aim: Few population-based studies have been published on melanoma of unknown primary origin (MUP). This study's aim is to describe characteristics and survival of MUP patients in the Netherlands, based on nationwide data from the Netherlands Cancer Registry (NCR).

Methods: Patient and tumour characteristics of MUP patients were retrieved from the NCR.

Skin-test infiltrating lymphocytes early predict clinical outcome of dendritic cell-based vaccination in metastatic melanoma.

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.