Factores preditivos de linfoma no síndrome de Sjögren : a propósito de um caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Multiple indicators of ambient and personal ultraviolet radiation exposure and risk of non-Hodgkin lymphoma (United States)

Recent epidemiologic studies have suggested that ultraviolet radiation (UV) may protect against non-Hodgkin lymphoma (NHL), but few, if any, have assessed multiple indicators of ambient and personal UV exposure. Using the US Radiologic Technologists study, we examined the association between NHL and self-reported time outdoors in summer, as well as average year-round and seasonal ambient exposures based on satellite estimates for different age periods, and sun susceptibility in participants who had responded to two questionnaires (1994–1998, 2003–2005) and who were cancer-free as of the earlier questionnaire. Using unconditional logistic regression, we estimated the odds ratio (OR) and 95% confidence intervals for 64,103 participants with 137 NHL cases. Self-reported time outdoors in summer was unrelated to risk. Lower risk was somewhat related to higher average year-round and winter ambient exposure for the period closest in time, and prior to, diagnosis (ages 20–39). Relative to 1.0 for the lowest quartile of average year-round ambient UV, the estimated OR for successively higher quartiles was 0.68 (0.42–1.10); 0.82 (0.52–1.29); and 0.64 (0.40–1.03), p-trend = 0.06), for this age period. The lower NHL risk associated with higher year-round average and winter ambient UV provides modest additional support for a protective relationship between UV and NHL.

Serum YKL-40 and Interleukin 6 Levels in Hodgkin Lymphoma

Purpose Serum levels of the inflammatory markers YKL-40 and IL-6 are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma (HL), a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis HL. Experimental Design We analyzed Danish and Swedish patients with incident HL (N=470) and population controls from Denmark (N= 245 for YKL-40; N= 348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analysed by linear regression, adjusting for age and sex. Results Serum levels of YKL-40 and IL-6 were increased in HL patients compared to controls (YKL-40: 3.6-fold, IL-6: 8.3-fold; both p<0.0001). In samples from pre-treatment HL patients (N=176), levels were correlated with more advanced stages (ptrend 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms, but levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (<45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pre-treatment patients, but even >6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased, compared to controls. In patients who died (N=12), pre-treatment levels for both YKL-40 and IL-6 were higher than in survivors, although not statistically significantly. Conclusions Serum YKL-40 and IL-6 levels were increased in untreated HL patients and those with more advanced stages but did not differ significantly by HL histology. Following treatment, serum levels were significantly lower.

Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS

In persons with HIV/AIDS (PWHAs), Hodgkin lymphoma (HL) risk is increased. However, HL incidence in PWHAs has unexpectedly increased since highly active antiretroviral therapy (HAART) was introduced. We linked nationwide HIV/AIDS and cancer registry data from 1980 through 2002. Immunity was assessed by CD4 T-lymphocyte counts at AIDS onset. Annual HL incidence rates were calculated for 4 through 27 months after AIDS onset. During 477 368 person years (py's) of follow-up in 317 428 persons with AIDS (PWAs), 173 HL cases occurred (36.2 per 105 py's). Incidence was significantly higher in 1996 to 2002 than earlier. Incidence in PWAs with 150 to 199 CD4 cells/μL was 53.7 per 105 py's, whereas in PWAs with fewer than 50 CD4 cells/μL, it was 20.7 per 105 py's (Ptrend = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. We conclude that HL incidence is lower with severe immunosuppression than with moderate immunosuppression, and HAART-related improvements in CD4 counts likely explain the increasing HL incidence in PWHAS observed since 1996. With more severe immunosuppression, nodular sclerosing HL becomes infrequent, explaining the higher proportion of mixed cellularity HL found in PWAs. Pathogenesis implications are discussed.

High-resolution loss of heterozygosity screening implicates PTPRJ as a potential tumor suppressor gene that affects susceptibility to non-Hodgkin's Lymphoma

We employed a Hidden-Markov-Model (HMM) algorithm in loss of heterozygosity (LOH) analysis of high-density single nucleotide polymorphism (SNP) array data from Non-Hodgkin’s lymphoma (NHL) entities, follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region 11p11.2, containing the gene encoding the protein tyrosine phosphatase receptor type J (PTPRJ). Although PTPRJ regulates components of key survival pathways in B-cells (i.e., BCR, MAPK, and PI3K signaling), its role in B-cell development is poorly understood. LOH of PTPRJ has been described in several types of cancer but not in any hematological malignancy. Interestingly, FL cases with LOH exhibited down-regulation of PTPRJ, in contrast no significant variation of expression was shown in DLBCLs. In addition, sequence screening in Exons 5 and 13 of PTPRJ identified the G973A (rs2270993), T1054C (rs2270992), A1182C (rs1566734), and G2971C (rs4752904) coding SNPs (cSNPs). The A1182 allele was significantly more frequent in FLs and in NHLs with LOH. Significant over-representation of the C1054 (rs2270992) and the C2971 (rs4752904) alleles were also observed in LOH cases. A haplotype analysis also revealed a significant lower frequency of haplotype GTCG in NHL cases, but it was only detected in cases with retention. Conversely, haplotype GCAC was over-representated in cases with LOH. Altogether, these results indicate that the inactivation of PTPRJ may be a common lymphomagenic mechanism in these NHL subtypes and that haplotypes in PTPRJ gene may play a role in susceptibility to NHL, by affecting activation of PTPRJ in these B-cell lymphomas.

Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin's lymphoma

Recent developments in genomic technologies have resulted in increased understanding of pathogenic mechanisms and emphasized the importance of central survival pathways. Here, we use a novel bioinformatic based integrative genomic profiling approach to elucidate conserved mechanisms of lymphomagenesis in the three commonest non-Hodgkin's lymphoma (NHL) entities: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. By integrating genome-wide DNA copy number analysis and transcriptome profiling of tumor cohorts, we identified genetic lesions present in each entity and highlighted their likely target genes. This revealed a significant enrichment of components of both the apoptosis pathway and the mitogen activated protein kinase pathway, including amplification of the MAP3K12 locus in all three entities, within the set of genes targeted by genetic alterations in these diseases. Furthermore, amplification of 12p13.33 was identified in all three entities and found to target the FOXM1 oncogene. Amplification of FOXM1 was subsequently found to be associated with an increased MYC oncogenic signaling signature, and siRNA-mediated knock-down of FOXM1 resulted in decreased MYC expression and induced G2 arrest. Together, these findings underscore genetic alteration of the MAPK and apoptosis pathways, and genetic amplification of FOXM1 as conserved mechanisms of lymphomagenesis in common NHL entities. Integrative genomic profiling identifies common central survival mechanisms and highlights them as attractive targets for directed therapy.

Association between xenobiotic gene polymorphisms and non-Hodgkin's lymphoma risk

The last four decades have seen a significant increase in the incidence of non-Hodgkin's lymphoma (NHL) as a possible result of increasing environmental carcinogen exposure, particularly pesticides and solvents. Based on the increasing evidence for an association between carcinogen exposure-related cancer risk and xenobiotic gene polymorphisms, we have undertaken a case-control study of xenobiotic gene polymorphisms in individuals with a diagnosis of NHL. Polymorphisms of six xenobiotic genes (CYP1A1, GSTT1, GSTM1, PON1, NAT1, NAT2) were characterized in 169 individuals with NHL and 205 normal controls using polymerase chain reaction-based methods. Polymorphic frequencies were compared using Fisher's exact tests, and odds ratios for NHL risk were calculated. Among the NHL group, the incidence of GSTT1 null and PON1 BB genotypes were significantly increased compared with controls, 34% vs 14%, and 24% vs 11% respectively. Adjusted odds ratios calculated from multivariate analyses demonstrated that GSTT1 null conferred a fourfold increase in NHL risk (OR = 4.27; 95% CI, 2.40-7.61, P < 0.001) and PON1 BB a 2.9-fold increase (OR = 2.92; 95% CI, 1.49-5.72, P = 0.002). Furthermore, GSTT1 null combined with PON1 BB or GSTM1 null conferred an additional risk of NHL. This is the first time that a PON1 gene polymorphism has been shown to be associated with cancer risk. We conclude that the two polymorphisms, GSTT1 null and PON1 BB, are common genetic traits that pose low individual risk but may be important determinants of overall population NHL risk, particularly among groups exposed to NHL-related carcinogens.

Resistance Mechanisms of Non-Hodgkin Lymphomas against Rituximab Treatment

Rituximab, a monoclonal antibody against B-cell specific CD20 antigen, is used for the treatment of non-Hodgkin lymphomas (NHL) and chronic lymphatic leukemia. In combination with chemotherapeutics rituximab has remarkably improved the outcome of NHL patients, but a vast variation in the lengths of remissions remains and the outcome of individual patients is difficult to predict. This thesis has searched for an explanation for this by studying the effector mechanisms of rituximab and by comparing gene expression in lymphoma tissue samples of patients with long- and short-term survival. This work demonstrated that activation of complement (C) system is in vitro more efficient effector mechanism of rituximab than cellular mechanisms or apoptosis. Activation of the C system was also shown in vivo during rituximab treatment. However, intravenously administered rituximab could not enter the cerebrospinal fluid, and neither C activation nor removal of lymphoma cells was observed in central nervous system. In vitro cytotoxicity assays showed that rituximab-induced cell killing could be markedly improved with simultaneous neutralization of the C regulatory proteins CD46 (Membrane cofactor protein), CD55 (Decay-accelerating factor), and CD59 (protectin). In a retrospective study of follicular lymphoma (FL) patients, low lymphoma tissue mRNA expressions of CD59 and CD55 were associated with a good prognosis and in a progressive flow cytometry study high expression of CD20 relative to CD55 was correlated to a longer progression free survival. Gene expression profile analysis revealed that expression of certain often cell cycle, signal transduction or immune response related genes correlate with clinical outcome of FL patients. Emphasizing the role of tumor microenvironment the best differentiating genes Smad1 and EphA1 were demonstrated to be mainly expressed in the non-malignant cells of tumors. In conclusion, this thesis shows that activation of the C system is a clinically important effector mechanism of rituximab and that microenvironment factor in tumors and expression of C regulatory proteins affect markedly the efficacy of immunochemotherapy. This data can be used to identify more accurately the patients for whom immunochemotherapy is given. It may also be beneficial in development of rituximab-containing and other monoclonal antibody therapies against cancer.

Genetic and epigenetic variants in the MTHFR gene are not associated with non-Hodgkin lymphoma

The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme which plays a key role in the pathway of folate and methionine metabolism. Polymorphisms of genes in this pathway affect its regulation and have been linked to lymphoma. In this study we examined whether we could detect an association between two common non-synonomous MTHFR polymorphisms, 677C>T (rs1801133) and 1298A>C (rs1801131), and susceptibility to non-Hodgkin lymphoma (NHL) in an Australian case-control cohort. We found no significant differences between genotype or allele frequencies for either polymorphisms between lymphoma cases and controls. We also explored whether epigenetic modification of MTHFR, specifically DNA methylation of a CpG island in the MTHFR promoter region, is associated with NHL using blood samples from patients. No difference in methylation levels was detected between the case and control samples suggesting that although hypermethylation of MTHFR has been reported in tumour tissues, particularly in the diffuse large B-cell lymphoma subtype of NHL, methylation of this MTHFR promoter CpG island is not a suitable epigenetic biomarker for NHL diagnosis or prognosis in peripheral blood samples. Further studies into epigenetic variants could focus on genes that are robustly associated with NHL susceptibility.

Energy and information in Hodgkin-Huxley neurons

[EN]The generation of spikes by neurons is energetically a costly process and the evaluation of the metabolic energy required to maintain the signaling activity of neurons a challenge of practical interest. Neuron models are frequently used to represent the dynamics of real neurons but hardly ever to evaluate the electrochemical energy required to maintain that dynamics. This paper discusses the interpretation of a Hodgkin-Huxley circuit as an energy model for real biological neurons and uses it to evaluate the consumption of metabolic energy in the transmission of information between neurons coupled by electrical synapses, i.e., gap junctions. We show that for a single postsynaptic neuron maximum energy efficiency, measured in bits of mutual information per molecule of adenosine triphosphate (ATP) consumed, requires maximum energy consumption. For groups of parallel postsynaptic neurons we determine values of the synaptic conductance at which the energy efficiency of the transmission presents clear maxima at relatively very low values of metabolic energy consumption. Contrary to what could be expected, the best performance occurs at a low energy cost.

The propagation of nerve pulses: From the Hodgkin-Huxley model to the soliton theory

The present project aims to describe and study the nature and transmission of nerve pulses. First we review a classical model by Hodgkin-Huxley which describes the nerve pulse as a pure electric signal which propagates due to the opening of some time- and voltage-dependent ion channels. Although this model was quite successful when introduced, it fails to provide a satisfactory explanation to other phenomena that occur in the transmission of nerve pulses, therefore a new theory seems to be necessary. The soliton theory is one such theory, which we explain after introducing two topics that are important for its understanding: (i) the lipid melting of membranes, which are found to display nonlinearity and dispersion during the melting transition, and (ii) the discovery and the conditions required for the existence of solitons. In the soliton theory, the pulse is presented as an electromechanical soliton which forces the membrane through the transition while propagating. The action of anesthesia is also explained in the new framework by the melting point depression caused by anesthetics. Finally, we present a comparison between the two models.

Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage hodgkin's disease: the H6 twin randomized trials from the european organization for research and treatment of cancer lymphoma cooperative group

info:eu-repo/semantics/published

Fertility preservation: Successful transplantation of cryopreserved ovarian tissue in a young patient previously treated for Hodgkin's disease

Cryopreservation of ovarian tissue is now offered as an experimental procedure to preserve the fertility of young patients with a high risk for premature ovarian failure resulting from cancer therapy. This is the only available option to preserve the fertility of prepubertal patients treated with gonadotoxic chemotherapy. At present, thousands of patients all over the world have undergone this procedure with the hope of later restoring their fertility. Although the efficiency of the transplantation of cryopreserved ovarian tissue to restore ovarian function has been established, reports of pregnancy are still very scarce. Here, we describe the second published full-term spontaneous pregnancy after an orthotopic and heterotopic transplantation of cryopreserved ovarian tissue in a 31-year-old woman previously treated by conditioning therapy for bone marrow transplantation for Hodgkin's disease. This birth gives compelling evidence for the graft origin of the gamete and confirms the efficacy of ovarian tissue transplantation in restoring human natural fertility after oncological treatment. This case report stresses the importance of proposing the ovarian tissue cryopreservation procedure to all young patients who require potentially sterilizing treatment, with all alternative options to preserve fertility being duly taken into consideration.

Hodgkin lymphoma treatment with ABVD in the US and the EU: neutropenia occurrence and impaired chemotherapy delivery.

BACKGROUND: In newly diagnosed patients with Hodgkin lymphoma (HL) the effect of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD)-related neutropenia on chemotherapy delivery is poorly documented. The aim of this analysis was to assess the impact of chemotherapy-induced neutropenia (CIN) on ABVD chemotherapy delivery in HL patients. STUDY DESIGN: Data from two similarly designed, prospective, observational studies conducted in the US and the EU were analysed. One hundred and fifteen HL patients who started a new course of ABVD during 2002-2005 were included. The primary objective was to document the effect of neutropenic complications on delivery of ABVD chemotherapy in HL patients. Secondary objectives were to investigate the incidence of CIN and febrile neutropenia (FN) and to compare US and EU practice with ABVD therapy in HL. Pooled data were analysed to explore univariate associations with neutropenic events. RESULTS: Chemotherapy delivery was suboptimal (with a relative dose intensity < or = 85%) in 18-22% of patients. The incidence of grade 4 CIN in cycles 1-4 was lower in US patients (US 24% vs. EU 32%). Patients in both the US and the EU experienced similar rates of FN across cycles 1-4 (US 12% vs. EU 11%). Use of primary colony-stimulating factor (CSF) prophylaxis and of any CSF was more common in the US than the EU (37% vs. 4% and 78% vs. 38%, respectively). The relative risk (RR) of dose delays was 1.54 (95% confidence interval [CI] 1.08-2.23, p = 0.036) for patients with vs. without grade 4 CIN and the RR of grade 4 CIN was 0.35 (95% CI 0.12-1.06, p = 0.046) for patients with vs. without primary CSF prophylaxis. CONCLUSIONS: In this population of HL patients, CIN was frequent and FN occurrence clinically relevant. Chemotherapy delivery was suboptimal. CSF prophylaxis appeared to reduce CIN rates.