522 research outputs found
Anaplastic large-cell lymphoma.
No full textThe concept of anaplastic large-cell lymphoma (ALCL) has changed over the years because of a stream of new information and novel understanding regarding the cell of origin, biology, genetics, and clinical features of these neoplasms. This new information has led to the current classification proposed by the expert reviewers of the World Health Organization. The objective of this review is to present the most updated information on the cytologic and histologic features of these entities, with a special reference to diagnostic algorithms. A detailed description of the genetic aberrations and the pathogenetic mechanisms leading to transformation is presented. The clinical features of ALCL and novel tailored strategies are briefly illustrated
Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study
No full textSummary Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0-3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required
The function and origin of the CD4+ T cell in the classical Hodgkin lymphoma microenvironment
No full textPhDClassical Hodgkin lymphoma (CHL) is a germinal centre B cell malignancy where the bulk of the tumour comprises a non-clonal immune infiltrate enriched for CD4+ T cells. The role of these cells in the pathophysiology of CHL is poorly understood. Biomarkers predictive of clinical outcome in CHL are limited. This thesis examines microenvironment biomarkers with the goal of identifying the 10-20% of patients who are not cured by conventional therapy, and also investigates the function of the CD4+ T cell in CHL.
The prognostic power of FOXP3, a marker of regulatory T cells, CD68, a macrophage marker and CD20, a B cell marker, is validated in a new patient cohort and for the first time CD68 and FOXP3 are combined in a statistically robust scoring system. The data presented challenge the assumption that the microenvironment is Th2-polarised or senescent and demonstrates relative over-expression of T-BET, a Th1 marker and under-expression of PD1, a marker of senescence/exhaustion, with little evidence for Th2 marker expression. A cytokine-enriched in vitro culture system was developed demonstrating superior proliferation and longevity of CHL-derived T cells compared to non-malignant tissue-derived controls. These cells sustain expression of markers associated with proliferation and longevity (e.g. CD27, CD28) and remain functional (express cytokines) for many weeks. A panel of CD4+ T cell-specific markers was determined capable of differentiating CHL-derived from non-malignant or non-Hodgkin lymphoma-derived CD4+ T cells, in which markers of central memory (CD62L and CCR7) and early activation (CD69) are over-represented and markers of senescence (CD57 and PD1) are under-represented. Cytokine profiles were found to resemble Th1 (expression of IL2, IFN- and TNF expression) rather than Th2 (IL4, IL13, IL21, IL10 and IL6) responses.
The data presented confirm a new prognostic biomarker signature and show a Th1 rather than Th2-dominated microenvironment enriched for cytokine-secreting functional effector CD4+ T cells and long-lived, proliferative cells resembling central memory cells rather than hypoproliferative, anergic, non-functional T cells
Molecular mechanisms of follicular lymphoma and its transformation
No full textPhDFollicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma and at least a third of cases undergo aggressive transformation (t-FL), most frequently to diffuse large B-cell lymphoma. This study examined the role of germline and acquired genetic changes in FL and t-FL to determine prognostically significant events and chart the evolution of transformation.
Assessment of germline polymorphic variation in over 200 FL cases demonstrated two SNPs in the HLA region of chromosome 6p (rs10484561 and rs6457327) associate with FL risk in the UK and identified that rs6457327 predicts both time to and risk of transformation independently of clinical variables, including the FLIPI. Mutation and expression studies of the single known gene in linkage disequilibrium with rs6457327 (C6orf15) suggest an alternative mechanism is responsible for this transformation association.
DNA copy number and mutational analysis of FL and t-FL samples then revealed a high prevalence of TNFSRF14 and EZH2 mutations at transformation accompanied by frequent loss and gain of their genomic locations on chromosome 1p and 7q, respectively. In a search for co-operating genetic events, genome-wide profiling identified recurrent losses and gains ranging from 4 kb to 60 Mb with gain 2p16.1-p15 (including REL) predictive of worse survival in FL that transforms.
In >50% of transformed cases, FL DNA contained either copy number aberrations or mutations that were absent from subsequent t-FL. This suggested FL and t-FL might develop non-sequentially from a common cell of origin. To further explore the evolution of FL and t-FL, IGH-V somatic-hypermutation (SHM) analysis was performed in sequential FL / t-FL samples. t-FL clones were detected in FL samples taken many months prior to clinical presentation of transformation and, furthermore, the predicted SHM patterns of putative precursors were detected in both FL and t-FL samples indicating that a (long-lived) common progenitor cell could indeed give rise to both FL and subsequent t-FL by divergent clonal evolution
The impact of molecular alterations and the immune microenvironment on the natural history of Follicular Lymphoma including transformation to Diffuse Large B cell Lymphoma
No full textPhDThe natural history of follicular lymphoma is heterogeneous with numerous relapses
and remissions over many years. A substantial number of patients suffer an
aggressive disease course with death due to disease within 5 years of diagnosis. The
prognosis is significantly worse in patients (10-68%) who transform to an aggressive
histology. The clinical parameters used to stratify patients with this disease have
limited discriminative power and new prognostic biomarkers are required. Insights
into the biology of the disease, with identification of potential therapeutic targets are
also required. Analysis of paraffin embedded diagnostic FL biopsies from
populations of patients at the extremes of overall survival (15 years)
demonstrated that expression of CD4 T lymphocytes and a perifollicular location of
forkhead box protein P3 were significantly more common in diagnostic biopsies
from patients who lived >15 years. Patients with high numbers of intrafollicular CD4
T lymphocytes and higher numbers of CD68 positive macrophages were more likely
to undergo rapid transformation to diffuse large B cell lymphoma (DLBCL).
Analysis of sequential biopsies pre-and post-transformation from patients with FL
who subsequently transformed to DLBCL demonstrated high numbers of CD68
positive macrophages in the majority of cases. The overall survival from
transformation was reduced in patients in whom the number of FOXP3 positive T
cells decreased/remained low compared to patients in whom the number of FOXP3
positive T cells increased/remained high.
Analysis of biopsies pre-and post-transformation from patients with FL who
subsequently transformed, identified mutation of TP53 in 28% of cases suggesting a
limited role in the process of transformation. The immunocytochemical expression of
MDM2, the TP53 regulator, was significantly higher on transformation. The
phenotype of transformed FL was confirmed immunocytochemically as Germinal
Centre type and two potential drug targets, Aurora Kinase B and nm23, were
confirmed as being up-regulated on transformation
Ultra-deep mutational analysis of NPM-ALK and possible implications on target therapy in anaplastic large cell lymphoma of childhood
No full textAnaplastic Large Cell Lymphoma (ALCL) represents a distinct subset of aggressive T-cell non-Hodgkin lymphoma (NHL) accounting for about 3% of adult NHL and 10 to 15% of childhood lymphomas. In the vast majority of the cases, ALCL is associated to chromosomal translocations, the most frequent being the t(2;5)(p23;q35), involving the Anaplastic Lymphoma Kinase (ALK) gene, which lead to aberrant NPM-ALK protein expression and kinase activity. It has been extensively demonstrated that aberrant
NPM-ALK expression contributes to the pathogenesis of ALK-positive ALCL, as it causes cell transformation through activation of several biological pathways related to cell proliferation, cell-cycle control and apoptosis. Although ALK-positive ALCL have a rather benign prognosis when treated with standard chemotherapy, the failure rate at two years is almost 30% for most of these regimens. Notably, most of relapses occur within the first year from the start of therapy, and long-term survival for relapsed disease is less than 50%. Aberrant ALK activity is one of the major oncogenic events not only in ALK-positive ALCL, but also in neuroblastoma, non-small cell lung cancer (NSCLC) and inflammatory myofibroblastic tumour (IMT) bearing ALK activating mutations/rearrangements, and the inhibition of ALK kinase activity was proven to substantially reduce cancer cell proliferation and invasiveness both in vitro and in vivo. Successful clinical experience with crizotinib further support the concept of ALK-specific inhibition as a valuable treatment strategy in ALK-positive ALCL, as well as in other
ALK-addicted tumours. However, similarly to other inhibitors selectively targeting oncogenic kinases, data on relapse to crizotinib due to newly acquired secondary mutations were reported. In this context, although a robust clinical response of ALCL patients to an ALK inhibitor is expected, some of those patients are also anticipated to develop resistance, making the knowledge of NPM-ALK kinase domain (KD) mutational status a valuable and mandatory information to the rational design of ALK-targeted therapies.
To detect somatic tumour mutations with potential utility for predicting treatment response in ALK-positive ALCL patients, we performed ultra-deep sequencing analysis on ALK exons 22-25, corresponding to the entire KD coding region, in 37 ALCL pediatric patients. Two low frequent point mutations were identified in two distinct cases, corresponding to the R1275Q and R1231Q amino acid changes. The R1275Q mutation has been already reported as one of the most frequent activating mutations in neuroblastoma, while the R1231Q amino acid substitution represents a novel ALK point mutation, which to our knowledge has never been reported neither in ALK receptor nor in other ALK-translocated kinases. The molecular implications of R1275Q and R1231Q point substitutions on NPM-ALK function and sensitivity to ALK-specific inhibition are still under our investigation. In addition to point mutation, oncokinase alternative spliced transcripts have been previously reported in patients with Bcr-Abl positive chronic myeloid leukemia and more recently ALK receptor isoforms were described in neuroblastoma. To our knowledge, however, NPM-ALK alternative splicing events have never been described. For the first time, we identified and characterized 9 NPM-ALK INDEL mutations, resulting from KD whole exons skipping or alternative canonical splicing sites recognition. To investigate the effect of INDEL mutations on the structure and activity of NPM-ALK, we performed molecular homology modelling and in vitro functional analysis. While all these mutants were shown to be kinase dead, we demonstrated that, when coespressed with wild-type NPM-ALK, these INDELs do interact with wild-type monomers and are likely to inhibit ALK kinase activity and increase sensitivity to treatment with crizotinib. This work demonstrates that NPM-ALK KD point mutations are extremely rare in newly diagnosed ALCL patients, but positive selection of mutated cells could not be excluded in case of an ALK-targeting therapy. Conversely, our results suggest that alternative splicing in NPM-ALK may represent a common event. A clear correlation between the presence of these variants and outcome could not be detected, possibly because of the restricted cohort of patients analyzed. However, we hypothesize that a significant impact of these mutations could be observed if an ALK-specific treatment is used. Patients bearing a consistent level of inactive NPM-ALK are therefore expected to respond differently to ALK kinase inhibitors; whether such a response will be increased or decreased, it remains to be elucidated
Discovery of novel molecular and biochemical predictors of response and outcome in diffuse large B-cell lymphoma
No full textPhDDiscovery of Novel Molecular and Biochemical Predictors
of Response and Outcome in Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the commonest form of non-Hodgkin
lymphoma and responds to treatment with a 5-year overall survival (OS) of 40-50%.
Predicting outcome using the best available method, the International Prognostic Index
(IPI), is inaccurate and unsatisfactory. This thesis describes research undertaken to
discover, explore and validate new molecular and biochemical predictors of response
and long-term outcome with the aims of improving on the inaccurate IPI and of
suggesting novel therapeutic approaches. Two strategies were adopted: a rational and
an empirical approach. The rational strategy used gene expression profiling to identify
transcriptional signatures that correlated with outcome to treatment and from which a
model of 13-genes accurately predict long-term OS. Two components of the 13-gene
model, PKC and PDE4B, were studied using inhibitors in lymphoma cell-lines and
primary cell cultures. PKC inhibition using SC-236 proved to be cytostatic and
cytotoxic in the cell-lines examined and to a lesser extent in primary tumours. PDE4
inhibition using piclamilast and rolipram had no effect either alone or in combination
with chemotherapy. The empirical approach investigated the trace element selenium in
presentation serum and found that it was a biochemical predictor of response and
outcome to treatment. In an attempt to provide evidence of a causal relationship as an
explanation for the associations between presentation serum selenium, response and
outcome, two selenium compounds, methylseleninic acid (MSA) and
selenodiglutathione (SDG) were studied in vitro in the same lymphoma cell-lines and
primary cell cultures. Both MSA and SDG exhibited cytostatic and cytotoxic activity
and caspase-8 and caspase-9 driven apoptosis. For SDG reactive oxygen species
generation was important for its activity in three of the four cell-lines. In conclusion,
molecular and biochemical predictors of response and survival were discovered in
DLBCL that led to viable targets for drug intervention being validated in vitro
Anaplastic lymphoma kinase in human cancer.
No full textThe receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. Their pivotal function has been firmly established in the pathogenesis of many cancers as well. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)–ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. In this review, we describe the expression of the ALK–RTK, its related fusion proteins, and their molecular mechanisms of activation. Novel tailored strategies are briefly illustrated for the treatment of ALK-positive neoplasms.</jats:p
Mucosa associated lymphoid tissue lymphoma of the thyroid gland: a case report and literature review = MALT linfoma della tiroide: caso clinico e revisione della letteratura
No full textMucosa associated lymphoid tissue (MALT) lymphomas are low-grade, non-Hodgkin’s B cell lymphomas, mainly occurring in the gastrointestinal tract, but also in other tissues. We describe the management of a patient with hypothyroidism, tracheoesophageal compressive symptoms and chest tightness affected by a thyroid MALT lymphoma. The patient underwent debulking thyroidectomy and temporary tracheostomy in order to reduce dysphonia and dysphagia, followed by adjuvant chemotherapy and subsequently radiation therapy. A CT scan performed at the end of radiotherapy 6 months after surgery revealed remnants of residual tissue from the thyroidectomy without any pathological findings.
I linfomi MALT sono dei linfomi non-Hodgkin a cellule B a basso grado che in genere insorgono a livello del tratto gastrointestinale, ma anche in altri tessuti. Descriviamo in questo articolo il management clinico-chirurgico di un paziente con ipotiroidismo, sintomi da compressione
tracheo-esofagea e senso di oppressione toracica, affetto da linfoma MALT della tiroide. Il paziente è stato sottoposto a parziale asportazione della massa tiroidea e tracheostomia allo scopo di ridurre i sintomi compressivi ed in seguito a trattamento chemioterapico e radioterapico. L’esame TC effettuato una volta conclusa la radioterapia,
circa 6 mesi dopo l’intervento, ha evidenziato gli esiti della tiroidectomia parziale in assenza di altri reperti patologici
The potential therapeutic role of selenium in diffuse large B-cell lymphoma
No full textPhDThe clinical background to this work confirms the very poor outcome of patients with recurrent diffuse large B-cell lymphoma (DLBCL) and highlights the need for better therapies. One such potential option would be to add selenium (Se) to conventional chemotherapy. Previous work has demonstrated the ability of non-toxic concentrations of Se to sensitise DLBCL cell lines to chemotherapy and to protect normal cells from chemotherapy-induced toxicity. The aims of this study were therefore to identify mechanisms of Se action and potential biomarkers of Se activity. The form of Se used was methylseleninic acid (MSA), a precursor of methylselenol, which is the metabolite thought to be responsible for the anti-tumour effects of organic Se compounds. DLBCL cell lines differed in their sensitivity to MSA, which may relate to differences in intracellular glutathione depletion by MSA. MSA sensitivity, however, was not related to the induction of DNA damage or to the p53 status of lymphoma cell lines. Although cytotoxic concentrations of MSA induced apoptosis, chemo-sensitising concentrations did not enhance apoptosis or alter pro-apoptotic pathways. MSA induced endoplasmic reticulum (ER) stress in a concentration-dependent manner, however, in an MSA-resistant cell line, this led to autophagy and cell survival. Thus, ER stress induction is not a mechanism of chemo-sensitisation. MSA inhibited HDAC activity in DLBCL cell lines but only in a cell-based assay, suggesting that a metabolite of MSA is responsible for this effect. In addition, MSA inhibited the hypoxia-induced induction of HIF-1α in DLBCL cell lines.
Peripheral blood mononuclear cells (PBMCs) were relatively resistant to MSA and this was associated with increased expression of two pro-survival proteins, GRP78 and NF-κB. In addition, the metabolism of MSA differed between PBMCs and DLBCL cell lines, suggesting that methylselenol is formed more efficiently in the latter. In contrast, keratinocytes and fibroblasts were relatively sensitive to MSA, but MSA was unable to protect keratinocytes from the toxicity of chemotherapeutic agents. These results differ
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from those obtained in DLBCL cell lines in which MSA enhances the activity of chemotherapeutic agents. Combining MSA and bortezomib in mantle cell lymphoma cell lines unexpectedly resulted in an antagonistic interaction. This was associated with the induction of ER stress and autophagy and increased expression of two pro-survival proteins, Bcl-2 and Mcl-1. A proteomics approach identified novel protein changes induced by chemo-sensitising concentrations of MSA in two DLBCL cell lines. Several potential biomarkers of Se activity were identified; GRP78, NF-κB, vascular endothelial growth factor and acetylated histone H3. In conclusion, Se in the form of MSA affects many intracellular pathways in DLBCL cell lines, such that it has not been possible to identify a single unifying mechanism of Se action. However, differences have been observed between PBMCs and DLBCL cell lines and this work has identified novel protein changes and mechanisms of Se actionKatherine Priestly Trust Fund
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