Variable heavy-chain gene analysis of follicular lymphomas: subclone selection rather than clonal evolution over time

To investigate B-cell receptor evolution in follicular lymphomas (FLs), immunoglobulin variable heavy chain (V(H)) gene regions of 3 FLs were analyzed at different time points. One FL with a high somatic mutation load and intraclonal V(H) gene diversity was investigated in situ. V(H) gene transcripts were amplified and sequenced from samples of approximately 50 tumor cells isolated from frozen tissue sections by laser microdissection. Interestingly, the mutation pattern of the prevalent subclone in the relapse biopsy was virtually identical to that of a subclone isolated by microdissection from the presentation biopsy 9 years earlier. In a second FL, proof was obtained that the subclone that dominated the relapse sample had already been present in the initial biopsy. The finding that subclones found in the relapses of these FLs had not evolved over time but were preexistent, challenges the concept of antigen-driven B-cell receptor evolution during disease cours

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation

Increased Incidence of T-Cell Malignancies in Patients with Chronic Lymphocytic Leukemia

We present a patient with chemotherapy-refractory Chronic Lymphocytic Leukemia (CLL) in whom postmortem examination showed hepatosplenomegaly, with both multiple small-cellular CLL lesions and large-cellular, monoclonal T-cell infiltrates. Following this case, the co-incidence of T-cell malignancies and CLL was studied using Dutch and American cancer registry databases. Analysis showed an excess risk for T-cell malignancies in CLL patients, with increased standardized incidence ratios compared with the general population and all cancer survivors in the databases. We hypothesize that CLL cells interact with T-cells in the microenvironment, facilitating malignant transformatio

Multiple tumors due to mosaic genome-wide paternal uniparental disomy

Mosaic genome-wide paternal uniparental disomy is an infrequently described disorder in which affected individuals have signs and symptoms that may resemble Beckwith–Wiedemann syndrome. In addition, they can develop multiple benign and malignant tumors throughout life. Routine molecular diagnostics may not detect the (characteristic) low level of mosaicism, and the diagnosis is likely to be missed. Genetic counseling and a life-long alertness for the development of tumors is indicated. We describe the long diagnostic process of a patient who already had a tumor at birth and developed multiple tumors in childhood and adulthood. Furthermore, we offer clues to recognize the entit

Neuroblastoma stage 4S: Tumor regression rate and risk factors of progressive disease

Background: The clinical course of neuroblastoma stage 4S or MS is characterized by a high rate of spontaneous tumor regression and favorable outcome. However, the clinical course and rate of the regression are poorly understood. Methods: A retrospective cohort study was performed, including all patients with stage 4S neuroblastoma without MYCN amplification, from two Dutch centers between 1972 and 2012. We investigated the clinical characteristics, the biochemical activity reflected in urinary catecholamine excretion, and radiological imaging to describe the kinetics of tumor regression, therapy response and outcome. Results: The cohort of 31 patients reached a 10-year overall survival of 84% ± 7% (median follow-up 16 years; range, 3.3-39). During the regressive phase, liver size normalized in 91% of the patients and catecholamine excretion in 83%, both after a median of two months (liver size: range, 0-131; catecholamines: range, 0-158). The primary tumors completely regressed in 69% after 13 months (range, 6-73), and the liver architecture normaliz

Loss of SMAD4 Alters BMP Signaling to Promote Colorectal Cancer Cell Metastasis via Activation of Rho and ROCK

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas