Publications by authors named "Roberto Bugarini"

26 Publications

  • Page 1 of 1

Early thymus and activation-regulated chemokine (TARC) reduction and response following panobinostat treatment in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant.

Leuk Lymphoma 2014 May 5;55(5):1053-60. Epub 2013 Aug 5.

Sir Peter MacCallum Department of Oncology, University of Melbourne , Parkville, Victoria , Australia.

Abstract In a phase 2 trial of panobinostat in 129 patients with relapsed or refractory Hodgkin lymphoma, exploratory analyses of chemokines and cytokines were prospectively performed in 109 patients to determine their association with clinical outcomes. Patients were categorized into two groups (reductions > median and reductions ≤ median) based on percentage change from baseline of log10 transformed measurements. Thymus and activation-regulated chemokine (TARC) was most strongly associated with clinical outcome. Early reduction of TARC was observed in responding patients, with the greatest reduction at cycle 1, day 15 (C1D15). Of 93 patients with C1D15 samples, there were three complete and 25 partial responses. The group with TARC reductions > median at C1D15 had more responders (18 [39%] vs. 10 [21%]), longer progression-free survival (10.6 vs. 4.9 months), shorter time to response and longer overall survival than the group with reductions ≤ median. This study is registered at www.ClinicalTrials.gov , NCT00742027.
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http://dx.doi.org/10.3109/10428194.2013.820287DOI Listing
May 2014

Relationship between quantitative GRB7 RNA expression and recurrence after adjuvant anthracycline chemotherapy in triple-negative breast cancer.

Clin Cancer Res 2011 Nov 20;17(22):7194-203. Epub 2011 Sep 20.

Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Purpose: To conduct an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy.

Experimental Design: RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative reverse transcriptase PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests.

Results: Growth factor receptor bound protein 7 (GRB7) was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn's adjusted P value = 0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR = 2.31; P = 0.04 using the median as the split). The 5-year recurrence rates were 10.5% [95% confidence intervals (CI), 7.8-14.1] in the low and 20.4% (95% CI, 16.5-25.0) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy.

Conclusions: GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-3357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570203PMC
November 2011

Physician survey of the effect of the 21-gene recurrence score assay results on treatment recommendations for patients with lymph node-positive, estrogen receptor-positive breast cancer.

J Oncol Pract 2011 Mar;7(2):94-9

New York University School of Medicine, New York, NY; Division of Hematology-Oncology, Department of Medicine, and Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles; Pardee RAND Graduate School, RAND Corporation, Santa Monica; Genomic Health, Redwood City; Partnership for Health Analytic Research, Los Angeles, CA.

Purpose: To survey the effect of the 21-gene recurrence score (RS) assay results on adjuvant treatment recommendations for patients with lymph node-positive (N+), estrogen receptor-positive (ER+) breast cancer.

Methods: Medical oncologists who ordered the 21-gene RS assay were invited to complete a survey regarding their most recent patient with N+/ER+ breast cancer. We obtained responses from 160 (16%) of the 1,017 medical oncologists.

Results: Most of the respondents were in community (71%) versus academic (25%) settings and had practiced for a median of 11 years. T1, T2, or T3 disease was reported in 62%, 35%, and 3% of patients, respectively. One, two, three, or ≥ 4 nodes were reported in 69%, 18%, 6%, and 3% of patients, respectively. Eighty-six percent of the oncologists made treatment recommendations before obtaining the RS; 51% changed their recommendations after receiving the RS. In 33%, treatment intensity decreased from chemotherapy plus hormonal therapy to hormonal therapy alone. In 9%, treatment intensity increased from hormonal therapy alone to chemotherapy plus hormonal therapy. In 8%, treatment recommendations changed in a way that did not fit the definition of either increased or decreased intensity.

Conclusion: In this survey of physician practice, the RS result was used to guide adjuvant treatment decision making in N+/ER+ breast cancer more often in patients with tumors less than 5 cm in size and one to three positive lymph nodes than in patients with larger tumors and four or more positive nodes and yielded an overall reduction in recommendations for chemotherapy.
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http://dx.doi.org/10.1200/JOP.2010.000046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051869PMC
March 2011

Human immunodeficiency virus protease inhibitors reduce the growth of human tumors via a proteasome-independent block of angiogenesis and matrix metalloproteinases.

Int J Cancer 2011 Jan;128(1):82-93

National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.

Human immunodeficiency virus protease inhibitors (HIV-PIs), such as indinavir and saquinavir, have been shown to block angiogenesis and tumor cell invasion and to induce tumor cell apoptosis and growth arrest, respectively, both in vitro and in vivo. These findings have suggested that HIV-PIs or their analogues can be used as antitumor drugs. To this regard, indinavir and saquinavir were assessed for their ability to inhibit in vivo the growth of highly prevalent human tumors, such as lung, breast, colon and hepatic adenocarcinomas. We show here that both HIV-PIs significantly inhibited the growth of all adenocarcinomas tested in the mice model. This was not mediated by effects on proteasome-dependent cell growth arrest or on apoptosis but by the block of angiogenesis and matrix metalloproteinase activity. Accordingly, therapeutic steadystate concentrations of indinavir or saquinavir were highly effective in inhibiting invasion of tumor cells in vitro. In contrast, growth arrest was induced only by high concentrations of saquinavir that are not reached or are only transiently present in plasma of treated patients, likely through a proteasome-mediated mechanism. These data suggest that HIV-PIs or their analogues, characterized by a better biodistribution and lower toxicity, may represent a new class of antitumor drugs capable of targeting both matrix metalloproteinases and the proteasome for a most effective antitumor therapy.
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http://dx.doi.org/10.1002/ijc.25550DOI Listing
January 2011

Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.

J Clin Oncol 2010 Apr 8;28(11):1829-34. Epub 2010 Mar 8.

Royal Marsden Hospital,Wolfson Institute for Preventive Medicine, Queen Mary University of London London.

PURPOSE To determine whether the Recurrence Score (RS) provided independent information on risk of distant recurrence (DR) in the tamoxifen and anastrozole arms of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial. PATIENTS AND METHODS RNA was extracted from 1,372 tumor blocks from postmenopausal patients with hormone receptor-positive primary breast cancer in the monotherapy arms of ATAC. Twenty-one genes were assessed by quantitative reverse transcriptase polymerase chain reaction, and the RS was calculated. Cox proportional hazards models assessed the value of adding RS to a model with clinical variables (age, tumor size, grade, and treatment) in node-negative (N0) and node-positive (N+) women. RESULTS Reportable scores were available from 1,231 evaluable patients (N0, n = 872; N+, n = 306; and node status unknown, n = 53); 72, 74, and six DRs occurred in N0, N+, and node status unknown patients, respectively. For both N0 and N+ patients, RS was significantly associated with time to DR in multivariate analyses (P < .001 for N0 and P = .002 for N+). RS also showed significant prognostic value beyond that provided by Adjuvant! Online (P < .001). Nine-year DR rates in low (RS < 18), intermediate (RS = 18 to 30), and high RS (RS > or = 31) groups were 4%, 12%, and 25%, respectively, in N0 patients and 17%, 28%, and 49%, respectively, in N+ patients. The prognostic value of RS was similar in anastrozole- and tamoxifen-treated patients. CONCLUSION This study confirmed the performance of RS in postmenopausal HR+ patients treated with tamoxifen in a large contemporary population and demonstrated that RS is an independent predictor of DR in N0 and N+ hormone receptor-positive patients treated with anastrozole, adding value to estimates with standard clinicopathologic features.
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http://dx.doi.org/10.1200/JCO.2009.24.4798DOI Listing
April 2010

Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.

Lancet Oncol 2010 Jan 10;11(1):55-65. Epub 2009 Dec 10.

Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, IL, USA.

Background: The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence.

Methods: The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes.

Findings: There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0.97; HR 1.02, 0.54-1.93), but an improvement in disease-free survival for those with a high recurrence score (score > or =31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival.

Interpretation: The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes.

Funding: National Cancer Institute and Genomic Health.
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http://dx.doi.org/10.1016/S1470-2045(09)70314-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058239PMC
January 2010

Relationship between Topoisomerase 2A RNA Expression and Recurrence after Adjuvant Chemotherapy for Breast Cancer.

Clin Cancer Res 2009 Dec;15(24):7693-7700

Authors' Affiliations: Eastern Cooperative Oncology Group, Brookline, Massachusetts; Sanofi-Aventis, Bridgewater, New Jersey; Genomic Health, Inc., Redwood City, California; North Central Cancer Treatment Group, Rochester, Minnesota; Cancer and Leukemia Group B, Chicago, Illinois; and Southwest Oncology Group, Ann Arbor, Michigan.

PURPOSE: To perform an exploratory analysis of the relationship between gene expression and recurrence in operable hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-normal breast cancer patients treated with adjuvant doxorubicin-containing chemotherapy. EXPERIMENTAL DESIGN: RNA was extracted from archived tumor samples derived from 378 patients with stage I to III HR-positive, HER2-normal breast cancer and analyzed by reverse transcription-PCR for a panel of 374 genes, including the 21-gene recurrence score (RS). Patients were randomized to receive adjuvant doxorubicin plus cyclophosphamide or docetaxel in trial E2197, with no difference in recurrence seen in the treatment arms. All available recurrent cases were selected plus a nonrecurrent cohort. Cox proportional hazard models were used to identify relationships between gene expression and recurrence. RESULTS: TOP2A expression exhibited the strongest association with increased recurrence risk (P = 0.01), and was significantly associated with recurrence (P = 0.008) in a multivariate analysis adjusted for clinicopathologic features. Elevated TOP2A expression above the median was associated with a 2.6-fold increase (95% confidence interval, 1.3-5.2; P = 0.008) in risk of recurrence if the RS was <18, and a 2.0-fold increase (95% confidence interval, 1.2-3.2, P = 0.003) if there was an intermediate RS of 18 to 30. CONCLUSIONS: In patients with HR-positive, HER2-normal breast cancer, a population known to have a low incidence of TOP2A gene alterations thought to be predictive of anthracycline benefit, there is a range of TOP2A RNA expression that is strongly associated with recurrence after adjuvant anthracyclines, which provides information complementary to RS, indicating that it merits further evaluation as a prognostic and predictive marker. (Clin Cancer Res 2009;15(24):7693-700).
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http://dx.doi.org/10.1158/1078-0432.CCR-09-1450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396025PMC
December 2009

Safety and immunogenicity of a novel influenza subunit vaccine produced in mammalian cell culture.

J Infect Dis 2009 Sep;200(6):841-8

Center for Clinical Pharmacology Research, Monipol, Krakow, Poland.

Background: Immunization remains the best prevention strategy for influenza, but production constraints for egg-based influenza vaccines have prompted the development of innovative cell culture manufacturing processes. Here, we describe a novel cell culture-derived influenza vaccine (CCIV) produced in Madin-Darby canine kidney cells.

Methods: This phase 3, observer-blind, randomized, multicenter study in Poland compared the immunogenicity of a CCIV and a conventional egg-based vaccine. Participants, stratified by age (adults 18-60 years, n = 1300; elderly persons > or = 61 years, n = 1354), received a single intramuscular vaccination. Immunogenicity was assessed 21 days later by hemagglutination inhibition assay. Reactogenicity was assessed using self-completed diary cards.

Results: The immunogenicity of CCIV was noninferior to that of the conventional vaccine for all 3 vaccine strains in both age groups, regardless of underlying health status. Both vaccines fulfilled European Union registration criteria and were well tolerated, with similar incidences of solicited local and systemic reactions in both age groups; the only significant difference was an increased frequency of mild or moderate pain with CCIV than the conventional vaccine among adult (22% vs 17%; P < .05) and elderly (9% vs 5%; P < .001) vaccinees.

Conclusions: CCIV was well tolerated and highly immunogenic in adults 18 years of age or older. Cell culture may offer greater flexibility of supply during periods of high demand for both seasonal and pandemic vaccines.
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http://dx.doi.org/10.1086/605505DOI Listing
September 2009

A novel mammalian cell-culture technique for consistent production of a well-tolerated and immunogenic trivalent subunit influenza vaccine.

Vaccine 2009 Oct 8;27(43):6022-9. Epub 2009 Aug 8.

Vilnius University, Vilnius, Lithuania.

Conventional influenza vaccine production methods have limitations due to their reliance on chicken eggs. We evaluated whether a mammalian cell-culture system could reliably produce an influenza vaccine with favourable tolerability and immunogenicity profiles. Adult subjects (n=1200; 18-60 years of age) were randomized (2:2:2:1) to receive either one of three lots of a cell-culture-derived influenza vaccine (CCIV) or an egg-based trivalent inactivated influenza vaccine (TIV). Safety and reactogenicity were assessed using solicited indicators for 7 days post-vaccination, all other adverse events (AEs) were recorded for 21 days post-vaccination, and all serious AEs and AEs necessitating a physician's visit, and/or resulting in subject's withdrawal from the study, were collected for up to 6 months post-vaccination. Antibody titres were measured by haemagglutination inhibition (HI) assay using egg-based viral antigens. All three lots of CCIV had similar safety and tolerability profiles, analogous to those of the TIV. Lot-to-lot consistency was statistically demonstrated through bioequivalence for immunogenicity. Antibody titres assessed at 6 months demonstrated good persistence. This Phase III trial is the first to demonstrate lot-to-lot bioequivalence of a CCIV and persistence of immunogenicity in comparison with a TIV.
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http://dx.doi.org/10.1016/j.vaccine.2009.07.083DOI Listing
October 2009

Immunophenotype of HIV+ patients during CD4 cell-monitored treatment interruption: role of the IL-7/IL-7 receptor system.

AIDS 2006 Oct;20(16):2021-32

Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Objective: To investigate immunological changes during CD4-guided therapy interruption in HIV(+) patients who suspended HAART.

Patients: Seventeen patients aged > 18 years, who had received HAART for at least 12 months, and had a pre-interruption CD4+ cell count > 500 cells/microl, interrupted treatment. Median nadir CD4(+) cell count was 288 cells/microl. HIV plasma viral load at discontinuation was < 50 or > 50 copies/ml. Criteria for restarting treatment were: a CD4(+) T-lymphocyte count < 350 cells/microl on two separate occasions, a clinical manifestation of AIDS, and the patient's desire to resume HAART. Eleven patients were still off therapy after 12 months (group A); according to the first criterion, six patients restarted therapy within 12 months (group B).

Methods: Haematological, viro-immunological, cytofluorimetic and molecular assays were performed at baseline and every 2 months following standard methods. Statistical analysis was performed under Stata 7.0.

Results: In the first 2 months of treatment interruption, a significant increase in viral load and CD8(+) lymphocyte activation occurred. Then such parameters decreased and remained stable. In all patients, a decrease in CD4(+) lymphocytes took place as well, that affected in a similar manner naive, central memory, effector memory and terminally differentiated cells. Group B always presented lower amounts of CD4(+) effector memory lymphocytes. The expression of CD127 was always higher in group A.

Conclusions: The loss of CD4(+) lymphocytes upon viral rebound is equal among naive and memory subsets. Patients with higher expression of CD127, who are likely to exert a better capacity to utilize endogenous interleukin-7 by T cells, could remain off therapy for longer periods.
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http://dx.doi.org/10.1097/01.aids.0000247575.41622.b1DOI Listing
October 2006

Vaccines with the MF59 adjuvant do not stimulate antibody responses against squalene.

Clin Vaccine Immunol 2006 Sep;13(9):1010-3

Research Center, Novartis Vaccines, Via Fiorentina 1, 53100 Siena, Italy.

Squalene is a naturally occurring oil which has been used in the development of vaccine adjuvants, such as the oil-in-water emulsion MF59. In past years, by use of noncontrolled and nonvalidated assays, a claim was made that antisqualene antibodies were detectable in the sera of individuals with the so-called Gulf War syndrome. Using a validated enzyme-linked immunosorbent assay for the quantitation of immunoglobulin G (IgG) and IgM antibodies against squalene, we demonstrated that antisqualene antibodies are frequently detectable at very low titers in the sera of subjects who were never immunized with vaccines containing squalene. More importantly, vaccination with a subunit influenza vaccine with the MF59 adjuvant neither induced antisqualene antibodies nor enhanced preexisting antisqualene antibody titers. In conclusion, antisqualene antibodies are not increased by immunization with vaccines with the MF59 adjuvant. These data extend the safety profile of the MF59 emulsion adjuvant.
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http://dx.doi.org/10.1128/CVI.00191-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1563566PMC
September 2006

Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers.

J Virol 2006 May;80(10):4962-70

Infectious Diseases Unit, Leicester Royal Infirmary, Leicester LE1 5WW, United Kingdom.

Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-microg doses of hemagglutinin from each virus strain with either 3, 10, or 30 microg of heat-labile Escherichia coli enterotoxin (LTK63) and 990 microg of a supramolecular biovector; one intranasally vaccinated group was given 7.5-microg doses of hemagglutinin with 30 microg of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 microg hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of 1 week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 microg LTK63 with the biovector, occurring in 7/15 (47%; P=0.0103), 8/15 (53%; P=0.0362), and 14/15 (93%; P=0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 microg LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P=0.0491) and B/Guandong (P=0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated.
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http://dx.doi.org/10.1128/JVI.80.10.4962-4970.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472052PMC
May 2006

An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine.

Vaccine 2006 Apr 19;24(16):3063-5. Epub 2006 Jan 19.

Chiron Vaccines, Research Center and Clinical Research, Via Fiorentina 1, 53100 Siena, Italy.

To test whether inactivated influenza vaccines distributed during the 2003-2004 influenza season in the northern hemisphere were able to confer protection against the mismatched variant A/Fujian/411/2002 virus strain, we measured haemagglutination inhibiting (HI) antibodies in elderly subjects vaccinated with three inactivated vaccines against the homologous A/H3N2 vaccine strain (A/Panama) and against the mismatched A/Fujian strain. The results showed that, while 76 to 80% of elder people vaccinated with conventional vaccines had protected levels of antibodies against the A/Fujian heterovariant strain, those vaccinated with the MF59-adjuvanted vaccine have protective levels of antibodies in >98% of the cases. We conclude that MF59-adjuvanted vaccines confer protection also against influenza virus strains which are not fully matched with those included in the vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2006.01.015DOI Listing
April 2006

Effect of treatment interruption monitored by CD4 cell count on mitochondrial DNA content in HIV-infected patients: a prospective study.

AIDS 2005 Oct;19(15):1627-33

Clinic of Infectious and Tropical Diseases, University of Modena and Reggio Emilia, Modena, Italy.

Background: HIV infection per se and HAART can alter mitochondrial functionality, leading to a decrease in mitochondrial DNA content.

Objective: To evaluate whether treatment interruption monitored by CD4 cell count can restore mitochondrial DNA content in peripheral blood lymphocytes.

Methods: Mitochondrial DNA content was measured in platelet-free CD4 and CD8 T cells by real-time polymerase chain reaction; flow cytometry was used to identify and quantify activated CD4 and CD8 T lymphocytes.

Results: The 30 patients had been treated for a mean of 107 months (range, 27-197). Median CD4 cell count at discontinuation was 702 cells/microl (range, 547-798). Median observational time from HAART discontinuation was 11.3 months (range, 4-26). Discontinuation of treatment provoked significant increases in mitochondrial DNA in CD8 T cells, which started only 6 months after therapy discontinuation [5.12 copies/cell per month from 0 to 6 months (P = 0.37) and 26.96 copies/cell per month from 6 to 12 months (P < 0.0001)].

Conclusions: This study is the first showing that mitochondrial DNA content can increase in peripheral blood lymphocytes during treatment interruption, but only after at least 6 months of interruption. Consequently, interruptions of shorter periods, whether by clinician or patient decision, are unlikely to allow restoration of mitochondrial DNA and so decrease HAART-related toxicity.
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http://dx.doi.org/10.1097/01.aids.0000186019.47297.0dDOI Listing
October 2005

Genetic polymorphisms of Fas (CD95) and Fas ligand (CD178) influence the rise in CD4+ T cell count after antiretroviral therapy in drug-naïve HIV-positive patients.

Immunogenetics 2005 Oct 18;57(9):628-35. Epub 2005 Oct 18.

Department of Biomedical Sciences, Chair of Immunology, University of Modena and Reggio Emilia, via Campi 287, Modena, 41100, Italy.

Fas and Fas ligand (FasL) are the main genes that control cell death in the immune system. Indeed, they are crucial for the regulation of T lymphocyte homeostasis because they can influence cell proliferation. A strong debate exists on the importance of Fas/FasL system during HIV infection, which is characterized by the loss of CD4+ T cells directly, or indirectly, caused by the virus. To investigate whether the genetic background of the host plays a role in the immunoreconstitution, we studied the influence of different Fas and FasL polymorphisms on CD4+ T lymphocyte count and plasma viral load following initiation of highly active antiretroviral therapy (HAART) in drug-naïve HIV+ patients. We studied 131 individuals, who were compared to 136 healthy donors. Statistical analysis was performed by using Chi2 test, Fischer's Exact Test, and analysis for repeated measurements. The group of HIV+ patients had an unexpected lower frequency of FasLnt169 polymorphism (delT allele) than healthy controls (p = 0.039). We then observed no significant differences in the immune reconstitution, in terms of CD4+ T cell increase, when the influence of single alleles of the gene Fas or FasL was considered. However, the combination of some polymorphisms of Fas or FasL significantly influenced CD4+ T cell production and viral load decrease, showing that these genes can play a role in the immunoreconstitution triggered by antiretroviral therapy.
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http://dx.doi.org/10.1007/s00251-005-0031-zDOI Listing
October 2005

Cross-reactivity to highly pathogenic avian influenza H5N1 viruses after vaccination with nonadjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a potential priming strategy.

J Infect Dis 2005 Apr 14;191(8):1210-5. Epub 2005 Mar 14.

Influenza Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Antigenically well-matched vaccines against highly pathogenic avian influenza H5N1 viruses are urgently required. Human serum samples after immunization with MF59 or nonadjuvanted A/duck/Singapore/97 (H5N3) vaccine were tested for antibody to 1997-2004 human H5N1 viruses. Antibody responses to 3 doses of nonadjuvanted vaccine were poor and were higher after MF59-adjuvanted vaccine, with seroconversion rates to A/HongKong/156/97, A/HongKong/213/03, A/Thailand/16/04, and A/Vietnam/1203/04 of 100% (P < .0001), 100% (P < .0001), 71% (P = .0004), and 43% (P = .0128) in 14 subjects, respectively, compared with 27%, 27%, 0%, and 0% in 11 who received nonadjuvanted vaccine. These findings have implications for the rational design of pandemic vaccines against influenza H5.
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http://dx.doi.org/10.1086/428948DOI Listing
April 2005

Highly active antiretroviral therapy restores CD4+ Vbeta T-cell repertoire in patients with primary acute HIV infection but not in treatment-naive HIV+ patients with severe chronic infection.

J Acquir Immune Defic Syndr 2004 Mar;35(3):213-22

Department of Biomedical Sciences, Section of General Pathology, University of Modena and Reggio Emilia School of Medicine, Modena, Italy.

In drug-naive HIV+ patients, we analyzed the effects of highly active antiretroviral therapy (HAART) on the reconstitution of the T-cell receptor (TCR) repertoire. We followed 2 groups of patients for 1 year: 18 individuals who experienced acute HIV infection and 24 patients who had HIV infection for many years but never took HAART. They were compared with 10 healthy controls who were longitudinally analyzed for the same period. We performed cytofluorometric analysis of the Vbeta TCR repertoire and detected the clonality of different Vbeta families by the spectratyping method. A new statistical approach based on the use of mixed models was then employed to analyze the data. Before the beginning of therapy, the repertoire of patients with acute or chronic infection was significantly different from that of healthy controls. After therapy, patients with acute HIV infection showed an improvement of the repertoire among either CD4+ or CD8+ T lymphocytes. Conversely, patients with chronic infection were capable of changing their repertoire among CD8+ but not CD4+ T lymphocytes. Our results indicate that HAART can restore the T-cell repertoire in individuals whose immune system is not severely compromised by the infection.
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http://dx.doi.org/10.1097/00126334-200403010-00001DOI Listing
March 2004

Persistently biased T-cell receptor repertoires in HIV-1-infected combination antiretroviral therapy-treated patients despite sustained suppression of viral replication.

J Acquir Immune Defic Syndr 2003 Oct;34(2):140-54

Department of Clinical Medicine, University La Sapienza, Rome, Italy.

In most HIV-1-infected patients, highly active antiretroviral therapy (HAART) reduces plasma viral load to <50 copies/mL and increases CD4+ T-cell number and function. However, it is still unclear whether alterations of T-cell receptor (TCR) beta-chain variable region (BV) repertoire, tightly related to disease progression, can be fully recovered by long-term treatment with HAART. This study analyzed the evolution of both T-cell subset composition and TCRBV perturbations in chronically HIV-1-infected patients with moderate immunodeficiency during 36 months of HAART. Despite persistently suppressed HIV replication, the rate of CD4+ T-cell repopulation, after an initial burst, progressively declined throughout the study period, resulting in a mean CD4+ T-cell count at the end of follow-up that was still significantly lower in HIV patients than in HIV-seronegative controls. This was seen in association with an incomplete restitution of both CD4 and CD8 TCRBV repertoire disruptions and was also demonstrated by the appearance of new TCRBV oligoclonal expansions occurring during HAART. In conclusion, these data indicate that 3 years of fully suppressive HAART may be not adequate to normalize CD4 counts and TCRBV repertoires in patients starting HAART with moderately advanced disease.
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http://dx.doi.org/10.1097/00126334-200310010-00004DOI Listing
October 2003

Correlates of HIV-1 shedding in cervicovaginal secretions and effects of antiretroviral therapies.

AIDS 2003 Oct;17(15):2169-76

Clinic of Infectious Diseases, University of Bari, Italy.

Objectives: To evaluate the determinants of HIV-1 RNA shedding in cervicovaginal secretions and the effects of antiretroviral therapy in a group of infected women.

Methods: A total of 122 women from whom paired peripheral blood and cervicovaginal lavage samples were available were enrolled in the study. HIV-1 RNA was quantified in the plasma and cell-free fraction of cervicovaginal lavages by the nucleic acid sequence-based amplification assay (lower limit of detection 80 copies/ml).

Results: Seventy-one per cent of the women had detectable viral load in the cervicovaginal lavage and this appeared to be correlated to plasma viral load and to the degree of immunodeficiency as expressed by the absolute number of CD4 cells. Antiretroviral-treated patients had a lower risk of shedding the virus in the genital tract, but this association was limited to patients treated with highly active antiretroviral therapy (HAART). However, in 25% of women with undetectable plasma viral load, a genital shedding of the virus was demonstrated.

Conclusion: Plasma viral load may fail as a marker of infectivity of genital secretions. HAART treatment seems to be more efficacious in suppressing viral shedding at the genital level. The female genital tract represents a distinct compartment for HIV-1 replication/evolution.
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http://dx.doi.org/10.1097/00002030-200310170-00004DOI Listing
October 2003

Antibody responses and HIV-1 viral load in HIV-1-seropositive subjects immunised with either the MF59-adjuvanted influenza vaccine or a conventional non-adjuvanted subunit vaccine during highly active antiretroviral therapy.

Vaccine 2003 Sep;21(25-26):3629-37

Department of Hygiene, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.

Objective: To study immunological and virological parameters in HIV-1-seropositive adults treated with highly active antiretroviral therapy (HAART) for at least 7 months after immunisation with MF59-adjuvanted (FLUAD, Chiron, Siena, Italy) or with non-adjuvanted (AGRIPPAL, Chiron) trivalent influenza vaccine.

Design: Blood samples, collected before and after vaccination, were analysed for the presence of antibodies against the vaccine antigens, for number of CD4+ T lymphocytes and HIV-1 RNA levels.

Results: Forty-four volunteers received FLUAD and 40 AGRIPPAL influenza vaccine. Thirty days after vaccination both adjuvanted and non-adjuvanted vaccines induced significant increases of anti-influenza virus antibodies. However, antibody titres found in volunteers receiving adjuvanted vaccine were in general significantly higher when compared with those found in the non-adjuvanted vaccine group. The requirements of the European Commission of influenza vaccine for a non-elderly adult population were always met by recipients of the adjuvanted vaccine, even in those with the lowest CD4+ cell counts (<200 cells/mmc). The subjects receiving the non-adjuvanted vaccine failed to met these requirements. The CD4+ T lymphocytes and plasma HIV-1 RNA levels remained stable in the long term, both in people receiving adjuvanted or non-adjuvanted vaccine.

Conclusion: MF59-adjuvanted influenza induced a significant higher immune responses as compared with conventional vaccine in HIV-seropositive HAART-treated patients. Both vaccines were safe regarding HIV RNA viral replication and loss of CD4+ T lymphocytes.
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http://dx.doi.org/10.1016/s0264-410x(03)00408-0DOI Listing
September 2003

Infection with human herpesvirus-8 and its correlation with hepatitis B virus and hepatitis C virus markers among rural populations in Cambodia.

Am J Trop Med Hyg 2003 Apr;68(4):501-2

Department of Public Health, Tor Vergata University, Rome, Italy.

Among 164 individuals in a rural population of Cambodia, antibodies to human herpesvirus-8 (HHV-8) were found among 56.6% of the women and 50.6% of the men. Seropositivity for HHV-8 tended to decrease with age (P < 0.001) and was not associated with exposure to hepatitis B virus (HBV) or HCV. Human herpesvirus-8, which shows a high rate of infection during childhood, does not seem to have the same pattern of transmission as HBV. This suggests very early acquisition of infection with HHV-8 in Cambodia.
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April 2003

Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects.

Arch Intern Med 2002 Oct;162(18):2125-32

Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy.

Background: The effect of chronic coinfection with hepatitis viruses on the response to therapy against human immunodeficiency virus 1 (HIV-1) remains debated.

Methods: In a prospective cohort study, the effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) serostatus on the outcome of potent HIV-1 therapy was analyzed in HIV-1-infected patients previously naive to antiretroviral therapy. Changes from baseline CD4+ cell counts and HIV RNA levels over time were analyzed by linear regression models. Time to clinical progression and time to reach virologic and immunologic response were analyzed by multivariate Cox proportional hazards regression models.

Results: We studied 1320 patients, among whom 600 were HCV antibody-positive and 90 were HBV surface antigen-positive. During a median follow-up of 37 months (range, 1-48 months), clinical progression was observed in 99 patients (56 new acquired immunodeficiency syndrome-defining events and 43 deaths). In multivariate models, HCV-positive HBV-negative patients showed a shorter time to clinical progression (hazard ratio, 1.55; 95% confidence interval, 1.00-2.41). Patients who were HCV-positive also showed mean CD4+ recoveries over time that were at least 30 cells/ micro L fewer than those of seronegative patients. Hepatitis virus serostatus did not affect the virologic response to HIV-1 therapy.

Conclusions: Clinical progression of HIV-1 disease after starting potent antiretroviral therapy is accelerated by concomitant infection with HCV. Compared with patients without coinfection, coinfected patients showed impaired CD4+ cell recovery, despite similar virologic response to HIV-1 therapy. These findings may have important implications for the treatment of HCV and for the timing of initiation of HIV-1 therapy in coinfected individuals.
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http://dx.doi.org/10.1001/archinte.162.18.2125DOI Listing
October 2002

Kinetics of CD4 cells after discontinuation of antiretroviral therapy in patients with virological failure and a CD4 cell count greater than 500 cells/microl.

AIDS 2002 Jul;16(11):1551-4

Clinic of Infectious and Tropical Diseases, University of Modena and Reggio Emilia, Modena, Italy.

After a median of 37 months on antiretroviral therapy, 16 patients were asked to discontinue treatment instead of changing it. After a median observation time of 10.5 months, most patients experienced a rapid and progressive decrease in their CD4 cell count, even without a high viral load rebound. This decline was unrelated to the CD4 cell count and HIV-RNA values at interruption, but was more profound in patients in whom the M184V mutation had disappeared after lamivudine discontinuation.
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http://dx.doi.org/10.1097/00002030-200207260-00013DOI Listing
July 2002

Age-related disability in multiple sclerosis.

Ann Neurol 2002 Apr;51(4):475-80

Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy.

There is evidence that the clinical course of multiple sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital-based cohort of definite cases of multiple sclerosis (n= 1,463). Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person-years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007). Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan-Meier method with age as a categorical time-varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001). Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001). Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset. Furthermore, a multiplicative effect on Expanded Disability Status Scale score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients. In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in multiple sclerosis and suggest that an age-adjusted progression index may be a more relevant criterion for defining differences between multiple sclerosis groups.
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http://dx.doi.org/10.1002/ana.10147DOI Listing
April 2002

Primary human herpesvirus 8 infection in immunocompetent children.

JAMA 2002 Mar;287(10):1295-300

Department of Public Health and Cellular Biology, University Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.

Context: Human herpesvirus 8 (HHV-8) infection causes Kaposi sarcoma and lymphoproliferative disorders in immunosuppressed adults. Its manifestations in immunocompetent hosts are unknown.

Objectives: To determine whether HHV-8 primary infection is symptomatic in immunocompetent children and to identify the epidemiological and virological correlates of HHV-8 infection.

Design And Setting: Prospective cohort study conducted in the pediatric emergency department of a hospital in Alexandria, Egypt, between December 1, 1999, and April 30, 2000.

Patients: Eighty-six children aged 1 to 4 years who were evaluated for a febrile syndrome of undetermined origin.

Main Outcome Measures: Serological assay and polymerase chain reaction of blood and saliva samples for HHV-8. Information on potential risk factors for HHV-8 infection was also collected.

Results: Thirty-six children (41.9%) were seropositive; HHV-8 DNA sequences were detected in 14 (38.9%) of these 36 children (detected in saliva in 11 of 14). Significant associations were found between HHV-8 infection and close contact with at least 2 other children in the community (36 of 63 vs 6 of 23 for <2 children; adjusted odds ratio [OR], 3.50; 95% confidence interval [CI], 1.11-12.22) and admission to the emergency department in December or January (28 of 47 vs 14 of 39 for February-April; adjusted OR, 3.15; 95% CI, 1.23-8.58). Six children had suspected primary HHV-8 infection; all but 1 had a febrile cutaneous craniocaudal maculopapular rash, which was more common among these children (5 of 6 vs 10 of 75; P<.001). For 3 of these 6 children, a second blood sample was obtained after the convalescence phase, and all 3 seroconverted for HHV-8.

Conclusions: Primary infection with HHV-8 may be associated with a febrile maculopapular skin rash among immunocompetent children. The finding of HHV-8 DNA sequences in saliva supports the hypothesis that transmission through saliva is the main mode of transmission in the pediatric age group.
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http://dx.doi.org/10.1001/jama.287.10.1295DOI Listing
March 2002

HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma.

Nat Med 2002 Mar;8(3):225-32

Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.

Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These PIs also block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol). These effects are mediated by the inhibition of endothelial- and KS-cell invasion and of matrix metalloproteinase-2 proteolytic activation by PIs at concentrations present in plasma of treated individuals. As PIs also inhibit the in vivo growth and invasion of an angiogenic tumor-cell line, these data indicate that PIs are potent anti-angiogenic and anti-tumor molecules that might be used in treating non-HIV KS and in other HIV-associated tumors.
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http://dx.doi.org/10.1038/nm0302-225DOI Listing
March 2002