Expression of Hepatitis C Virus cDNA in Human Hepatoma Cell Line Mediated by a Hybrid Baculovirus–HCV Vector

AbstractAlthough great progress has been made in the characterization of the biochemical and biological features of hepatitis C virus (HCV) gene expression, the elucidation of the HCV life cycle and the evaluation of novel antiviral strategies have been hindered by the lack of a suitable cell culture system. In this context, the development of an efficient HCV cDNA delivery method would contribute to the understanding of HCV replication. To assess the functionality of baculovirus mediated gene delivery for HCV expression, we have constructed recombinant baculoviruses encoding HCV cDNA under the control of the cytomegalovirus promoter. Transduction of the human hepatoma cell line Huh-7 with Bac–HCV vectors was efficient and HCV cDNA expression was enhanced by treatment of the infected cells with dexamethasone. HCV structural and nonstructural polypeptides were processed correctly and were found to localize in the cytoplasm in a pattern characteristic of the endoplasmic reticulum. The expression of the HCV proteins was detected for 49 days after infection. Thus, these results indicate that the recombinant Bac–HCV vectors are a useful tool for the delivery of HCV cDNA and can facilitate the analysis of structural and functional properties of the HCV proteins. In addition, the Bac–HCV vectors can provide important information on the evaluation of novel anti-HCV antiviral strategies

Transformed Follicular Lymphoma: Not all fit in one

Follicular Lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for approximately 10-20% of all lymphomas in Western Countries. Histologic transformation (HT) is a frequent event in the clini-cal course of patients with indolent lymphoma that is often accompanied by a dramatic change in the clinical fea-tures of the disease towards a more aggressive course. Although the transformation of Follicular Lymphoma (tFL) was described several decades ago, there is a strong need for a better understanding of both the dynamics of the tumor clonal evolution and the genetic events leading to ()transformation. In addition, the management of patients with tFL is challenged by the heterogeneity of the previous treatments. The present review describes the state of art of tFL, outlining recent advances in the understanding of genetic basis and the evolutionary pro-cess governing the initiation and persistence of tumor evolution. It will be also addressed the key questions pend-ing on this incurable disease, such as a lack of a standard therapeutic strategy for tFL patients as well as its out-come in the Rituximab (R) era

Autologous stem-cell transplantation as consolidation of first-line chemotherapy in patients with peripheral T-cell lymphoma: a multicenter GELTAMO/FIL study

Autologous stem-cell transplantation; Chemotherapy; T-cell lymphomaTrasplante autólogo de células madre; Quimioterapia; Linfoma de células TTrasplantament autòleg de cèl·lules mare; Quimioteràpia; Limfoma de cèl·lules TPeripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P=0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study

Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study

To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years (P=.0002), equal to or more than 2 extranodal sites (P=.0002), lactic dehydrogenase (LDH) value at normal levels or above (P<.0001), performance status (PS) equal to or more than 2 (Pless than or equal to.0001), stage III or higher (P=.0001), and bone marrow involvement (P=.0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P<.0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P<.0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P<.0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P=.026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4,3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively (Pless than or equal to.0001; log-rank, 66.79)

Prognostic relevance of serum beta2 microglobulin in patients with follicular lymphoma treated with anthracycline-containing regimens. A GISL study.

Background and ObjectivesAlthough serum b2 microglobulin (b2M) is an easy parameter to measure, and overexpressedin a large number of lymphoproliferative diseases, its prognostic value hasbeen largely underestimated. The present study examined the influence of b2M levelson overall survival (OS) of patients with follicular lymphoma (FL).Design and MethodsThe prognostic role of b2M was evaluated in 236 patients with FL identified from thedatabases of the Gruppo Italiano per lo Studio dei Linfomi (GISL) and treated withanthracycline-based regimens from 1993 to 2003.ResultsElevated serum b2M levels were found in 82 patients (35%). According to multivariatelogistic regression analysis, elevated b2M levels were associated with elevatedlactate dehydrogenase (LDH) (p=0.021), age (p=0.029), and number of involvednodal areas (p<0.001). The percentage of elevated b2M levels increased progressivelywith increasing FLIPI scores (17%, 38%, and 63% in the low-, intermediate-, andhigh-risk groups, respectively). Five-year OS was 61% (95% CI, 47-73%) and 89% (95%CI, 82-93%) for patients with elevated vs normal b2M levels respectively (p<0.001).Cox regression analysis showed that b2M level had an independent and stable prognosticvalue (HR=3.0; 95%CI, 1.6-5.7). In a multivariate analysis the impact of b2Mlevel on survival was independent of FLIPI score, with a HR of 2.94 (95% CI, 1.54-5.62).Interpretation and ConclusionsOur results demonstrate that in patients treated in the pre-rituximab era, b2M levelwas an independent prognostic marker in addition to FLIPI score. We thus suggestthat b2M be routinely assessed and tested in future prognostic studies of FL patientstreated with combination chemotherapy and anti-CD20 agents

The outcome of peripheral t-cell lymphoma patients failing first-line therapy: A report from the prospective, international t-cell project

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation. (Registered at clinicaltrials.gov identifier: 01142674)

T-cell lymphoma in South America and Europe.

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cell, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneos. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year oversall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies

Long‐term overall survival and toxicities of ABVD vs BEACOPP in advanced Hodgkin lymphoma: A pooled analysis of four randomized trials

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T-Cell Lymphomas in South America and Europe

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.424