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The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level.

Primary cutaneous marginal zone B-cell lymphoma is considered the cutaneous counterpart of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Although its molecular pathogenesis is currently unknown, an etiological link with Borrelia burgdorferi infection has been identified in European, but not in American or Asian cases. To better understand the pathogenesis and the geographical differences of cutaneous marginal zone B-cell lymphoma, 60 cases from the East Asia, Germany, and the United States at their initial presentation were subjected to the following analyses; (1) clinicopathological comparison between the geographical regions, (2) detection of B. burgdorferi DNA, (3) detection of the API2–MALT1 fusion transcript, a gene alteration specific to mucosa-associated lymphoid tissue lymphoma, and (4) inactivation of tumor suppressor genes (death-associated protein kinase ( DAPK ), p16 INK4a , p14 ARF , MGMT , TIMP3 , CDH1 , and RARB ) by hypermethylation of the CpG islands. Cases from the three geographical regions showed similar clinicopathological features. However, moderate/marked tissue eosinophilia was found in 9/25 Asian cases, but only 1/23 German cases ( P =0.011) and 0/12 American cases ( P =0.015). All 60 cases were negative for either Borrelia DNA or API2–MALT1 fusion. Tumors from the three regions were highly methylated for DAPK (38–50% of the cases, mean 43%) and p16 INK4a (42–70%, mean 49%), and the positivities were significantly higher than those of nonneoplastic skin (8%, P =0.0010 and 14%, P =0.0032, respectively). Methylation of these genes had no significant association with progressive features of the tumor. Primary cutaneous marginal zone B-cell lymphomas from the three geographical regions have common clinicopathological features, however, moderate/marked tissue eosinophilia is a feature found almost exclusively in Asian cases. Borrelia infection and API2–MALT1 fusion are not significant in this tumor. Methylation of DAPK and p16 INK4a genes is a frequent event in this lymphoma at its initial presentation, but may not be associated with tumor progression.

The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy. Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome. LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days. Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35% vs. compensated 78%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14%, mild 27%, intermediate 67%, and severe 64%). Mid-septum LSsys<11% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival. Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy.

Background Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all -trans -RA (ATRA), 9 cis- RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9 cis- RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as type II enteropathy associated T-cell lymphoma (type II EATL), is a rare, aggressive primary intestinal T-cell lymphoma with a poor prognosis and an incompletely understood pathogenesis. We collected 40 cases of MEITL and 27 cases of EATL, formerly known as type I EATL, and comparatively investigated the T-cell receptor (TCR) itself and associated signaling molecules using immunohistochemistry, amplicon deep sequencing and bisulfite pyrosequencing. The TCR showed both an α β -T-cell origin (30%) and a γ δ -T-cell derivation (55%) resulting in a predominant positive TCR phenotype in MEITL compared with the mainly silent TCR phenotype in EATL (65%). The immunohistochemical expression of the spleen tyrosine kinase (SYK) turned out to be a distinctive feature of MEITL (95%) compared with EATL (0%). Aberrant SYK overexpression in MEITL is likely caused by hypomethylation of the SYK promoter, while no common mutations in the SYK gene or in its promoter could be detected. Using amplicon deep sequencing, mutations in DNMT3A , IDH2 , and TET2 were infrequent events in MEITL and EATL. Immunohistochemical expression of linker for activation of T-cells (LAT) subdivided MEITL into a LAT expressing subset (33%) and a LAT silent subset (67%) with a potentially earlier disease onset in LAT-positive MEITL.

The expression of IgG4 in malignant B-cell lymphomas has only partially been studied. Recent reports described single cases of marginal zone lymphomas arising in the ocular adnexae that express IgG4. Moreover, a subset of dura-associated marginal zone lymphomas appear to express IgG4 as well. We investigated IgG4 expression in a more systematic manner in a large cohort of marginal zone lymphoma specimens derived from the archive of our institute. Overall, we examined 169 marginal zone lymphomas of various primary sites that displayed a distinct plasmacytic differentiation and light chain restriction, allowing for a detailed investigation of the immunoglobulin heavy chain expression in these tumors by immunohistochemistry. Unexpectedly, primary cutaneous marginal zone lymphomas showed frequent IgG4 expression. Although only 1 out of 120 noncutaneous marginal zone lymphomas, located in the ocular adnexae, expressed IgG4, 19 of 49 (39%) primary cutaneous marginal zone lymphomas showed this feature, constituting the highest expression rate of IgG4 reported to date in any B-cell lymphoma. None of the IgG4-positive cutaneous marginal zone lymphomas with available clinical data showed evidence of a preexisting systemic IgG4-related disease, suggesting a localized immunologic IgG4-driven pathogenetic process at early stages of the disease. IgG4-positive and IgG4-negative primary cutaneous marginal zone lymphomas did not significantly differ in architectural features of the infiltrate or the composition of the reactive T-cell infiltrate as determined by analysis of T-cell content, CD4/CD8 ratio, and content of FOXP3- and PD1-positive T cells. Although the pathogenetic role of IgG4 expression in a significant subset of primary cutaneous marginal zone lymphomas with plasmacytic differentiation remains unclear at present, the demonstration of IgG4 expression in a marginal zone lymphoma involving the skin might be a helpful clue in the routine diagnostic setting, as these tumors will almost invariably be of primary cutaneous origin with an extremely low risk of spread to noncutaneous sites and an excellent prognosis.

Primary involvement of skeletal muscle is a very rare event in ALK-1 positive anaplastic large cell lymphoma (ALCL). We describe a case of a 10-year old boy presenting with a three week history of pain and a palpable firm swelling at the dorsal aspect of the left thigh. Histological examination of the lesion revealed a tumoral and diffuse polymorphic infiltration of the muscle by large lymphoid cells. Tumor cells displayed eccentric, lobulated \"horse shoe\" or \"kidney-shape\" nuclei. The cells showed immunohistochemical positivity for CD30, ALK-1, CD2, CD3, CD7, CD8, and Perforin. Fluorescence in situ hybridization analysis revealed a characteristic rearrangement of the ALK-1 gene in 2p23 leading to the diagnosis of ALK-1 positive ALCL. Chemotherapy according to the ALCL-99-NHL-BFM protocol was initiated and resulted in a complete remission after two cycles. This case illustrates the unusual presentation of a pediatric ALCL in soft tissue with a good response to chemotherapy.

Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling—together with epigenetic dysregulation—may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.

To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells.