Proliferation in HHV-8-Positive Primary Effusion Lymphomas Is Associated with Expression of HHV-8 Cyclin but Independent of p27(kip1).
Carbone A, Gloghini A, Bontempo D, Monini P, Tirelli U, Volpe R, Browning PJ, Gaidano G
Divisions of Pathology and Medical Oncology A, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Aviano, Italy. Istituto Superiore di Sanita, Roma, Italy. Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. Department of Medical Sciences, "Amedeo Avogadro" University of Eastern Piedmont, Novara, Italy.
[Record supplied by publisher]
Primary effusion lymphoma (PEL) develops in immunodeficient patients, selectively localizes to the serous body cavities, and harbors infection by human herpesvirus type-8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus. HHV-8 encodes a viral (v)-cyclin homologous to cellular D-type cyclins, a class of positive cell-cycle regulators that are physiologically modulated by the p27(Kip1) cell cycle inhibitor. The aims of the present study were: 1) to establish the expression pattern of p27(Kip1) in PEL; and 2) to address the relationship between p27(Kip1) expression, proliferation index, and expression of cellular cyclin D1 and v-cyclin in PEL. Expression of p27(Kip1) was detected in all (n = 18) PEL samples analyzed by both immunocytochemistry and Western blot. All PELs displayed a high proliferation index as assessed by Ki-67 staining. Expression of cellular cyclin D1 was absent in all PELs tested, which conversely expressed (14 out of 14 samples) v-cyclin by immunocytochemistry and/or Western blot. In contrast to PELs, HHV-8-negative lymphomatous effusions secondary to a tissue-based lymphoma generally failed to express p27(Kip1). Overall, these data show that PELs consistently express p27(Kip1) protein despite the high proliferative rate of the lymphoma clone, suggesting that p27(Kip1) may be unable to drive cell-cycle arrest in PEL cells. The co-existence of p27(Kip1) expression and high proliferative index is a selective feature of PEL among lymphomas involving the serous body cavities, because lymphomatous effusions secondary to a tissue-based lymphoma generally display the inverse relationship between p27(Kip1) positivity and growth fraction observed in normal lymphoid tissues and in most other lymphomas. Expression of p27(Kip1) in PEL associates with expression of HHV-8 v-cyclin, but not of cellular cyclin D1. The fact that HHV-8 v-cyclin is resistant to p27(Kip1)-modulated inhibition, whereas cellular cyclin D1 is sensitive, may explain, at least in part, the co-existence of p27(Kip1) expression and high proliferative index observed in PEL.
PMID: 10751346
Vinorelbine is an effective and safe drug for AIDS-related Kaposi's sarcoma: results of a phase II study.
Nasti G, Errante D, Talamini R, Rizzardini G, Fasan M, Landonio G, Zeroli C, Chichino G, Nigra E, Vaccher E, Tirelli U
Division of Medical Oncology A and Epidemiology Unit, Centro di Riferimento Oncologico, Aviano.
[Medline record in process]
PURPOSE: To assess the safety and efficacy of vinorelbine in patients with AIDS-related Kaposi's sarcoma (KS). PATIENTS AND METHODS: From December 1994 to May 1997, within the Italian Cooperative Group on AIDS and Tumors, we enrolled 36 patients with AIDS-related KS who experienced disease progression after one or more regimens of systemic chemotherapy. Patients were treated with vinorelbine 30 mg/m(2) every 2 weeks by intravenous bolus. RESULTS: Of 35 assessable patients, three (9%) had a clinical complete response and 12 (34%) had a partial remission, for an overall objective response rate of 43% (95% confidence interval, 26% to 61%). For the 15 patients with objective responses, the median duration of response from the beginning of therapy until the development of progression was 176 days, whereas the median progression-free survival and the median survival durations for 35 assessable patients were 151 days and 216 days, respectively. Vinorelbine also induced responses in patients who had become resistant to regimens that included other vinca alkaloids. Overall, vinorelbine was well tolerated. Toxicity, including neurologic toxicity, was mild and reversible. Neutropenia was the most frequent dose-limiting toxicity. CONCLUSION: Vinorelbine is safe and effective in the treatment of patients with advanced KS who have been previously treated with one or more chemotherapy regimens.
PMID: 10735904, UI: 20200509
Role of brain biopsy in the management of focal brain lesions in HIV-infected patients. Gruppo Italiano Cooperativo AIDS & Tumori.
Antinori A, Ammassari A, Luzzati R, Castagna A, Maserati R, Rizzardini G, Ridolfo A, Fasan M, Vaccher E, Landonio G, Scerrati M, Rocca A, Butti G, Nicolato A, Lazzarin A, Tirelli U
Department of Infectious Diseases, IRCCS L. Spallanzani, Rome, Italy.
In this multicenter, retrospective study of 160 brain biopsies in the assessment of HIV-related focal brain lesions, diagnostic sensitivity was acceptable (87%), but the procedure carried considerable morbidity (7.5%) and mortality (3.1%). Moreover, it is not always possible to initiate the changes in therapy indicated by the results, and overall survival remains poor, with a median of 2 months. Criteria for brain biopsy for the diagnosis of focal brain lesions should be redefined to include selected patients for whom a less invasive approach does not yield a definitive diagnosis.
Publication Types:
Clinical trial
Multicenter study
PMID: 10691003, UI: 20152862
Molecular profile of epstein-barr virus infection in HHV-8-positive primary effusion lymphoma.
Fassone L, Bhatia K, Gutierrez M, Capello D, Gloghini A, Dolcetti R, Vivenza D, Ascoli V, Coco FL, Pagani L, Dotti G, Rambaldi A, Raphael M, Tirelli U, Saglio G, Magrath IT, Carbone A, Gaidano G
Division of Internal Medicine, Department of Medical Sciences, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
[Medline record in process]
Primary effusion lymphoma (PEL) selectively involves the serous body cavities, occurs predominantly in immunodeficient patients and is infected consistently by human herpesvirus type-8. PEL is also frequently infected by Epstein-Barr virus (EBV). The precise pathogenetic role of EBV coinfection in PEL is not fully understood. The lymphoma fails to express the EBV transforming proteins EBNA-2 and LMP-1, whereas it expresses EBNA-1 (latency I phenotype). Some studies have hypothesized that other EBV-positive lymphomas expressing the latency I phenotype may associate with specific molecular variants of EBNA-1, although this issue has not been addressed in PEL. On this basis, this study is aimed at a detailed molecular characterization of EBV in PEL. Fifteen EBV positive PEL (12 AIDS-related, one post-transplant, two arising in immunocompetent hosts) were subjected to molecular characterization of the viral genes EBNA-1 and LMP-1, as well as definition of EBV type-1/type-2. The EBNA-1 gene displayed a high degree of heterogeneity in different cases of PEL, with seven distinct recognizable variants and subvariants. A wild-type LMP-1 gene was detected in 10/15 cases, whereas in 5/15 cases the LMP-1 gene harbored a deletion spanning codons 346-355. EBV type-1 occurred in 11/15 PEL whereas EBV type-2 occurred in 4/15 cases. Despite a high degree of genetic variability of the virus in different PEL cases, each single PEL harbored only one EBV variant, consistent with monoclonality of infection and suggesting that infection preceded clonal expansion. Overall, our results indicate that: (1) individual PEL cases consistently harbor a single EBV strain; (2) EBNA-1 displays a high degree of heterogeneity in different PEL cases; (3) no specific EBV genotype preferentially associates with PEL. Leukemia (2000) 14, 271-277.
PMID: 10673744, UI: 20139548
Lung carcinoma in 36 patients with human immunodeficiency virus infection.
Tirelli U, Spina M, Sandri S, Serraino D, Gobitti C, Fasan M, Sinicco A, Garavelli P, Lisa A, Vaccher E
Division of Medical Oncology A, Aviano Cancer Center, Aviano, Italy.
[Medline record in process]
BACKGROUND: The current study describes the clinicopathologic characteristics of 36 patients with lung carcinoma and human immunodeficiency virus (HIV) infection observed within the Italian Cooperative Group on AIDS and Tumors (GICAT).
METHODS: Patients with lung carcinoma and HIV infection collected by the GICAT between 1986-1998 were evaluated retrospectively. As a control group, the authors analyzed 102 patients age < 60 years with lung carcinoma but without HIV infection who were seen at the CRO, National Cancer Institute, Aviano, Italy between 1995-1996. RESULTS: Patients with lung carcinoma and HIV infection were younger (38 years vs. 53 years) and previously smoked more cigarettes per day (40 vs. 20) than the control group. The main histologic subtype was adenocarcinoma. TNM Stage III-IV disease was observed in 53% of the patients.
The median CD4 cell count was 150/mm(3). The median overall survival was significantly shorter in the patients with HIV compared with the control group (5 months vs. 10 months; P = 0.0001). CONCLUSIONS: The results of the current study demonstrate that lung carcinoma in the HIV setting affects mainly young individuals with a history of heavy tobacco smoking and a moderately advanced immunodeficiency status. Lung carcinoma is associated with a more adverse outcome in HIV patients and represents the cause of death in the majority of these patients. Copyright 2000 American Cancer Society.
PMID: 10649248, UI: 20115359
Mutation of BAX occurs infrequently in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.
Gaidano G, Vivenza D, Forconi F, Capello D, Gloghini A, Bhatia K, Gutierrez M, Gallicchio M, Avanzi GC, Fassone L, Ariatti C, Buonaiuto D, Cingolani A, Saglio G, Tirelli U, Larocca LM, Dalla-Favera R, Carbone A
Division of Internal Medicine, Department of Medical
Sciences, Amedeo Avogadro
University of Eastern Piedmont, Novara, Italy. gaidano@med.no.unipmn.it
Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) consistently derive from B cells, are histologically heterogeneous, and are associated with distinct molecular pathways depending upon histology.
Recently, it has been proposed that inactivating mutations
of the bax death agonist may contribute to the pathogenesis of human tumors. In
particular, among B-cell malignancies, BAX mutations have been detected at a certain
frequency in Burkitt lymphomas. This study is aimed at defining the status of the BAX gene
throughout the clinicopathologic spectrum of AIDS-NHL (n = 54), including AIDS-related
Burkitt lymphoma (n = 14), AIDS-related Burkitt-like lymphoma (n = 8), AIDS-related
diffuse large cell lymphoma (n = 15), AIDS-related primary central nervous system lymphoma
(n = 6), and AIDS-related primary effusion lymphoma (n = 11). All 6 BAX exons and flanking
sequences were subjected to mutational analysis by polymerase chain reaction-single strand
conformation polymorphism followed by DNA direct sequencing of positive cases. Mutations
of BAX among AIDS-NHL were restricted to a cell line of AIDS-related primary effusion
lymphoma, which harbored a frameshift mutation causing the introduction of a proximal stop
codon. All other AIDS-NHL displayed wild-type BAX alleles. In order to investigate whether
BAX inactivation in AIDS-NHL may occur through mechanisms other than gene mutation, bax
protein expression was investigated by Western blot analysis or immunohistochemistry in
selected cases. All AIDS-NHL analyzed expressed normal bax proteins. Overall, this study
indicates that deregulation of apoptotic control in AIDS-NHL is not caused by BAX
alterations.
Genes Chromosomes Cancer 27:177-182, 2000. Copyright 2000 Wiley-Liss, Inc.
PMID: 10612806, UI: 20080733
Idiopathic chronic fatigue and chronic fatigue syndrome: a comparison of two case-definitions.
Arpino C, Carrieri MP, Valesini G, Pizzigallo E, Rovere P, Tirelli U, Conti F, Dialmi P, Barberio A, Rusconi N, Bosco O, Lazzarin A, Saracco A, Moro ML, Vlahov D
Laboratorio di Epidemiologia e Biostatistica, Istituto Superiore di Sanita, Rome, Italy.
The aim of the study was to compare the signs and symptoms of individuals meeting two different definitions of chronic fatigue syndrome (CFS). Ninety-four patients fitting the eligibility criteria for idiopathic fatigue were enrolled into the study. Of the 94 patients, 48 met the 1988 definition of CFS, 20 the 1994 (but not the 1988) definition of CFS, and 26 met neither definition. The 1994 defined cases were more likely than 1988 defined cases, and non-syndromal individuals to be male, married, and high school educated. The 1994 cases were less likely than 1988 cases to present acute onset, self reported sore throat, mild fever lymphadenopathy, pharyngitis. In conclusion, the 1994 criteria increased the number of patients classified as CFS; however, those who fit only the 1994 criteria were less likely to have an acute symptomatic onset and signs and symptoms suggestive of an infectious process.
Publication Types:
Multicenter study
PMID: 10721210, UI: 20185988
HAART is effective as anti-Kaposi's sarcoma therapy only after remission has been induced by chemotherapy.
Vaccher E, di Gennaro G, Nasti G, Juzbasic S, Tirelli U
Publication Types:
Letter
PMID: 10634205, UI: 20097671
Neoplastic complications of HIV infection.
Spina M, Vaccher E, Carbone A, Tirelli U
Division of Medical Oncology A, Istituto Nazionale Tumori, Aviano, Italy.
Publication Types:
Review
Review, academic
PMID: 10631453, UI: 20097028
Therapy of non-small-cell lung cancer (NSCLC) in patients with HIV infection.
GICAT. Cooperative Group on AIDS and Tumors.
Spina M, Sandri S, Serraino D, Gobitti C, Fasan M, Sinicco A, Garavelli PL, Ridolfo A, Tirelli U
Division of Medical Oncology, Aviano Cancer Center, Italy.
Incidence and mortality of AIDS patients have significantly
declined in the developed countries due to the very active anti-HIV combination therapy
available today. Because of the prolongation of the survival expectancy of these patients,
other non-AIDS defining tumours have been recently reported in several cohort studies with
increased frequency. We want to report the clinico-pathological features and the outcome
of 39 patients with lung cancer and HIV infection, collected by the Italian Cooperative
Group on AIDS and Tumors (GICAT) between 1986 and December 1997. As a control group, we
decided to evaluate patients, less than 60 years of age, with lung cancer but without HIV
infection seen at the CRO, Aviano, during 1995 and 1996. The median age of the study group
patients was 38 years (range 28-58) and 90% of them were males.
Sixty-nine percent of patients were intravenous drug users and HIV infection was
asymtomatic in 41% of patients. NSCLC was observed in 78% of patients, SCLC in 13% and
mesothelioma in 8%. Among NSCLC, adenocarcinoma was the most frequently observed
histological subtype (48%). No differences were found as regards the stage of disease at
diagnosis and the histologic subtype in comparison with the control group. The median
overall survival was significantly shorter for patients with HIV infection when compared
to that of the control group (5 months vs. 10 months, P < 0.0001). In conclusion, the
outcome of patients with SNCLC and HIV infection seems worse than that of the general
population, suggesting a synergistic and/or addictive adverse effect of HIV on the outcome
of lung cancer.
PMID: 10582147, UI: 20048860
Interactions of Antineoplastic Chemotherapy with Zidovudine Pharmacokinetics in Patients with HIV-Related Neoplasms.
Toffoli G, Errante D, Corona G, Vaccher E, Bertola A, Robieux I, Aita P, Sorio R, Tirelli U, Boiocchi M
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
[Record supplied by publisher]
To evaluate the perturbations in zidovudine (ZDV)
pharmacokinetics as a consequence of antineoplastic chemotherapeutic treatments, we
performed a prospective crossover study in 13 HIV-infected patients with cancer. The
subjects received 2-day regimens of ZDV (250 mg x 2/day). On the first day ZDV was
administered alone, whereas on the second day it was combined with antitumor
chemotherapies specific for the histological type (ZDV + chemotherapy). Blood sample and
urine collections were performed over a 12-hour period following oral administration of
the antiretroviral agent. ZDV was measured with high-performance liquid chromatography.
Pharmacokinetic parameters of ZDV were calculated by a noncompartmental model. The mean
ZDV area under curve (AUC) was not significantly different in the patients treated with
ZDV alone and ZDV + chemotherapy. Comparison of plasma elimination half-life (t((1/2))),
apparent systemic clearance (CL/F), and apparent volume of distribution (Vd/F) of ZDV did
not show any significant difference before and after chemotherapy. Conversely, some
significant differences were observed for both mean peak concentration (C(max)) of ZDV and
the corresponding time (T(max)). There was a 57% reduction in C(max) (p < 0.05) and a
66% increase in T(max) (p < 0.05) after chemotherapy compared with treatment with ZDV
alone. No differences were observed in the urinary excretion of ZDV and ZDV glucuronide
and urinary metabolic ratio, as a consequence of antineoplastic treatment. In conclusion,
this study demonstrates that some minor perturbations in ZDV pharmacokinetics (i.e. C(max)
and T(max)) derived from antineoplastic chemotherapy. Based on the observation that
antineoplastic chemotherapy had no significant effect on plasma ZDV concentration
expressed as AUC, the observed pharmacokinetic interaction would not warrant by itself a
change in the ZDV dosage during chemotherapy. Copyright
Copyright 1999 S.Karger AG, Basel
PMID: 10567772
Hodgkin's disease in HIV-infected individuals.
Spina M, Sandri S, Tirelli U
Division of Medical Oncology A Aviano Cancer Center, Italy.
The clinical and pathologic characteristics of Hodgkin's disease as they are diagnosed in patients with HIV infection differ from those of the general population. In fact, a higher frequency of unfavorable histologic subtypes, advanced stage, and poor therapeutic outcome have been reported in the HIV setting. Complete response rate after chemotherapy ranges from approximately 45% to 70%, although the disease-free survival is very short, and the median overall survival is only 18 months. The survival of these patients may be improved by the optimal combination of antineoplastic and antiretroviral treatment with the support of hematologic growth factors. However, new strategies of therapeutic intervention must be explored.
Publication Types:
Review
Review, tutorial
PMID: 10550018, UI: 20016211
Combination therapy with alpha interferon and lamivudine in patients with chronic hepatitis B and HIV infection.
Nasti G, di Gennaro G, Donada C, Donadon V, Tirelli U
Publication Types:
Letter
PMID: 10546877, UI: 20012368
Kinetics of lymphokine production in HIV+ patients treated with highly active antiretroviral therapy and interleukin 2.
De Paoli P, Zanussi S, Caggiari L, Bortolin MT, D'Andrea M, Simonelli C, Tirelli U
Department of Microbiology, Immunology and Virology, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
This study presents the kinetics of CD4/CD25 cell numbers, serum sCD25 levels, and intracellular production and release of interleukin-2 (IL-2) and interleukin-16 (IL-16) in 11 HIV+ patients treated with six cycles of highly active antiretroviral therapy (HAART) plus six MUI of subcutaneous IL-2 compared to 10 HIV+ patients treated with HAART alone. IL-2 therapy induced moderate effects on CD4 T cell recovery and increased CD4/CD25+ cells and sCD25 levels after 2 weeks, while intracellular and secreted IL-2 was reduced and IL-16 was increased at the same time point. After 24 weeks, while HAART-treated patients had increased IL-2 production, in IL-2 treated patients, cytokine production was unaltered compared to pretreatment values. Decreased in vitro IL-2 production may depend on a feedback inhibition by IL-2 infusion. Because of its known antiviral effects, the increased IL-16 production seen after 2 weeks in IL-2-treated individuals may produce beneficial effects on HIV disease. The kinetics of cytokine production may serve to define better the use IL-2 in clinical trials.
Publication Types:
Clinical trial
Randomized controlled trial
PMID: 10535609, UI: 20004267
Debate on Di Bella therapy.
Tirelli U, Di Filippo F
Publication Types:
Comment
Letter
Comments:
Comment on: Lancet 1999 Apr 17;353(9161):1310-4
PMID: 10408510, UI: 99334995