Cecilia Simonelli

Clinical Features and Outcome of Primary Effusion Lymphoma in HIV-Infected Patients: A Single-Institution Study

PURPOSE To describe the clinical features and outcome of HIV-associated primary effusion lymphoma (PEL) and to compare them with those of the other HIV-associated non-Hodgkins lymphomas (NHLs). PATIENTS AND METHODS From April 1987 to June 2002, 277 patients with HIV infection and systemic NHL were diagnosed and treated in our institution. Clinical features and outcome of PEL patients were compared with the features and outcomes of 162 patients belonging to the following histologic subtypes: plasmoblastic lymphoma of oral cavity (PBLOC, n = 11), immunoblastic lymphoma (IBL, n = 76), and centroblastic B-cell lymphoma (CBCL, n = 75). RESULTS Among the 277 NHL patients, PEL was diagnosed in 11 patients (4%). Eight of 11 patients were treated with a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like regimen. Complete remission was reached in 42% of patients, with a median survival time of 6 months. When the clinical features and outcome of 11 PEL patients were compared with the other three groups of patients affected by NHL, at the onset of the disease, no statistically significant differences were observed in demographic data, CD4 absolute number, HIV viremia plasma levels, and clinical characteristics. When we compared the outcome of PEL patients with the CBCL group, a statistically significant worse outcome was observed; however, the clinical outcome of PEL patients was not significantly different from the outcome observed in the other two groups (PBLOC and IBL groups). CONCLUSION PEL is a rare HIV-associated NHL type occurring as a late manifestation of HIV infection with a poor clinical outcome and a shorter overall survival compared with CBCL patients.

Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data

Chronic fatigue syndrome (CFS) has been widely studied by neuroimaging techniques in recent years with conflicting results. In particular, using single-photon emission computed tomography (SPECT) and perfusion tracers, hypoperfusion has been found in several brain regions, although the findings vary across research centers. The objective of this study was to investigate brain metabolism of patients affected by CFS, using [18F]fluorine-deoxyglucose (18FDG) positron emission tomography (PET). We performed 18FDG PET in 18 patients who fulfilled the criteria of the working case definition of CFS. Twelve of the 18 patients were females; the mean age was 34 +/- 15 years (range, 15-68) and the median time from CFS diagnosis was 16 months (range, 9-138). Psychiatric diseases and anxiety/neurosis were excluded in all CFS patients. CFS patients were compared with a group of 6 patients affected by depression (according to DSM IV-R) and 6 age-matched healthy controls. The CFS patients were not taking any medication at the time of PET, and depressed patients were drug-free for at least 1 week before the PET examination. The PET images examined 22 cortical and subcortical areas. CFS patients showed a significant hypometabolism in right mediofrontal cortex (P = 0.010) and brainstem (P = 0.013) in comparison with the healthy controls. Moreover, comparing patients affected by CFS and depression, the latter group showed a significant and severe hypometabolism of the medial and upper frontal regions bilaterally (P = 0.037-0.001), whereas the metabolism of brain stem was normal. Brain 18FDG PET showed specific metabolism abnormalities in patients with CFS in comparison with both healthy controls and depressed patients. The most relevant result of our study is the brain stem hypometabolism which, as reported in a perfusion SPECT study, seems to be a marker for the in vivo diagnosis of CFS.

Effects of subcutaneous interleukin-2 therapy on CD4 subsets and in vitro cytokine production in HIV+ subjects.

HIV infection is characterized by the reduction of the CD4+, CD45RA+, CD26+, and CD28+ lymphocyte subsets and of the in vitro production of IL-2, IL-4, and interferon-gamma; on the contrary, chemokine production is usually increased. These abnormalities are only partially restored by antiretroviral chemotherapy. Therapy with interleukin-2 has been proposed to restore the functions of the immune system, but the mechanisms by which IL-2 exerts its activities are unknown. The aim of this study was to define the effects of rIL-2 administration on CD4+, CD45RA+, CD45R0+, and CD26+ lymphocytes and on the in vitro production of IL-2, IL-4, IL-10, IFN-gamma, RANTES, and sCD30 in HIV+ patients. 10 HIV+ patients with CD4 cell counts between 200 and 500 cells/mm3 were treated with six cycles of subcutaneous recombinant IL-2 administration, in combination with zidovudine and didanosine. This therapeutic regimen resulted in a remarkable increase in the number of CD4+ cells and in the prolonged reduction of the levels of viremia. CD45R01 cells were expanded during the first cycle of therapy, while CD45RA+/CD26+ cells predominated after the third cycle. At this time, the in vitro production of IL-2, IL-4, IFN-gamma, and sCD30 were significantly upregulated. These results demonstrate that rIL-2 in HIV+ patients induces the reconstitution of the CD4/CD45RA lymphocytes subtype. This expanded cell population recovered the ability to produce in vitro IL-2, IL-4, and IFN-gamma. These effects may be beneficial to HIV+ patients by improving their immune response to microorganisms or vaccines.

CD8 lymphocyte phenotype and cytokine production in long-term non-progressor and in progressor patients with HIV-1 infection

In most HIV‐1‐infected patients, clinical and immunological progression develops within a few years. Few infected people, termed long‐term non‐progressors (LTNP), remain healthy and immunologically stable for a long time. The factors governing the maintenance of this condition are not well known, but it is conceivable that CD8+ lymphocytes, cells that play a central role in controlling in vitro HIV replication, may have a part in vivo in this process. The aim of this study was to characterize the phenotypic profile and the cytokine production of CD8+ cells in a group of LTNP patients who had stable CD4+ cell counts (>500/mm3) for at least 7 years. Their CD8+ absolute numbers were similar to a control group composed of HIV‐1+ patients who have a progressive decline of their CD4+ cell counts. However, our multiparameter immunofluorescence studies show that a clinical and immunologically stable condition is associated with the presence of a CD28+, CD95 strongly positive CD8+ population, while disease progression is marked by the CD28−CD95+CD8+ subset. Purified CD8+ cells from LTNP retain their ability to produce IL‐2, interferon‐gamma (IFN‐γ) and, to a lesser degree, to produce IL‐10 and IL‐4. In contrast, CD8+ cells from progressors are unable to secrete IL‐2 and IL‐10. Although CD8+ cytokine profile does not fit with the proposed T helper (Th)1/Th2 switch in progressive HIV infection, LTNP CD8+ T cells maintain their capacity to produce IL‐2 and IL‐10 (Th0‐like), a pattern very similar to that observed in normal HIV healthy controls. We suggest that CD8+ cells expressing CD28, CD95 and having a Th0‐like profile may be considered to be associated with long‐term survival.

Improvement of Systemic Human Immunodeficiency Virus-Related Non-Hodgkin Lymphoma Outcome in the Era of Highly Active Antiretroviral Therapy

To assess the impact of highly active antiretroviral therapy (HAART) on the outcome of systemic human immunodeficiency virus-related non-Hodgkin lymphoma (HIV-NHL), we retrospectively analyzed 235 patients in whom HIV-NHL was diagnosed from April 1988 through December 1999. A multivariate Cox proportional hazards model was used to estimate prognostic factors for overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS). Complete remission occurred in 49% of patients, and the 3-year rates of OS, PFS, and DFS were 19%, 49%, and 73%, respectively. The greatest risk for shortened OS, PFS, and DFS was associated with no HAART use (compared with long-term HAART use); hazard ratios were 17.42 (95% confidence interval [CI], 17.42-40.25), 9.11 (95% CI, 3.71-22.32), and 8.54 (95% CI, 1.19-61.11), respectively. Our study suggests that the long-term use of HAART may favorably change the outcome for patients with systemic HIV-NHL.

Age and serum lactate dehydrogenase level are independent prognostic factors in human immunodeficiency virus-related non-Hodgkin's lymphomas: a single-institute study of 96 patients.

PURPOSE The role of classical pragnostic factors (ie, age, performance status [PS], stage, extranodal involvement, and serum lactate dehydrogenase [LDH] level) included in the International Index for diffuse large-cell non-Hodgkins lymphoma (NHL) of the general population is presently unknown in the setting of human immunodeficiency virus (HIV). To assess the prognostic value of these factors in HIV-related NHL, we reviewed the cohort of patients with HIV-related NHL diagnosed and treated with combination chemotherapy (CT) at our institution. PATIENTS AND METHODS Ninety-six patients with systemic HIV-related NHL diagnosed and treated with combination CT regimens between September 1987 and December 1993 at the Centro di Riferimento Oncologico, Aviano, Italy, were studied. All clinical and laboratory data were evaluated by univariate and multivariate analyses, using overall survival as the end point. RESULTS Complete remission (CR) occurred in 48% of patients; the overall median survival and disease-free survival times were 7 and 13 months, respectively. Among the classical and HIV-related prognostic factors, the following had a statistically significant influence on survival: PS > or = 2, elevated LDH level, age greater than 40 years, a CD4 cell count less than 100/microL, active opportunistic infections at diagnosis of NHL, and B symptoms. Multivariate analyses showed that only age, serum LDH level, and CD4 cell count were independent predictors of shortened survival. The increased hazard for patients greater than 40 years of age was 1.6 (95% confidence interval [CI], 1.2 to 2.3), for patients with increased LDH it was 1.8 (95% CI, 1.01 to 3.1), and for patients with a CD4 cell count less than 100/microL it was 1.7 (95% CI, 1.01 to 2.9). CONCLUSIONS Our study shows that in addition to HIV-related prognostic factors, ie, CD4 cell count less than 100/microL, classical prognostic factors such as age and serum LDH level are independent prognostic factors and should be included in the design of future clinical trials of HIV-related NHL.

Immunological changes in peripheral blood and in lymphoid tissue after treatment of HIV-infected subjects with highly active anti-retroviral therapy (HAART) or HAART + IL-2.

This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained from peripheral blood and lymphoid tissue from HIV+ individuals treated with highly active anti‐retroviral therapy (HAART) alone or in combination with 6 million units international (MUI) s.c. IL‐2. Before treatment, the HIV+ patients had reduced CD4 and increased CD8 values in the peripheral blood and lymphoid tissue and impaired cytokine production by peripheral blood mononuclear cells (PBMC). After 24 weeks of treatment, all the HIV+ patients demonstrated increased CD4 values in peripheral blood and lymphoid tissue. The use of IL‐2 did not promote an additional CD4 expansion compared with HAART alone; increased ‘naive’ and CD26+ CD4 cells and reduced CD8 cells were found in the peripheral blood and lymphoid tissue of the IL‐2‐treated, but not of the HAART‐treated patients. Both types of treatment induced a significant reduction of the CD8/CD38+ cells. While HAART alone had negligible effects on cytokine production by PBMC, the combined use of HAART + IL‐2 was unable to increase the endogenous production of IL‐2, but caused an increase of IL‐4, IL‐13 and interferon‐gamma (IFN‐γ) and a reduction of monocyte chemoattractant protein‐1 (MCP‐1) production. These data suggest that, although in this schedule IL‐2 has minimal efficacy on CD4 recovery when compared with HAART alone, it produces an increase of ‘naive’ and CD26+ CD4 cells and a partial restoration of cytokine production. These data may be used to better define clinical trials aiming to improve the IL‐2‐dependent immunological reconstitution of HIV‐infected subjects.

Plasma HHV-8 viral load in HHV-8-related lymphoproliferative disorders associated with HIV infection

This is a mono‐institutional analysis of the clinical features, immunological and virological findings, and prognostic factors of patients with HIV infection and HHV‐8‐lymphoproliferative disorders. Patients with Multicentric Castleman Disease and HHV‐8‐related lymphoma diagnosed and treated from April 1987 to June 2004 were included in the study. HHV‐8 and HIV plasma viral load, CD4+ count, hematologic parameters, and general wellbeing (performance status) were assessed at the onset of the diseases and analyzed in order to identify possible prognostic factors. Nine patients with Multicentric Castleman disease, and 16 with HHV‐8‐related lymphomas (13 primary effusion lymphomas and 3 solid lymphomas), were diagnosed and treated out of 327 HIV‐related non‐Hodgkins lymphomas. Four patients with Multicentric Castleman disease received only antiretroviral drugs; 5 HAART plus oral etoposide. Nine patients with primary effusion lymphoma were treated with a CHOP‐like regimen (Cyclophosphamide, Prednisone anthracyclines, Vinca alkaloids, Bleomycin, Etoposide) and HAART; 1 with etoposide and HAART, 1 with HAART alone. The patients with solid lymphoma underwent CHOP‐like chemotherapy. Patients with Multicentric Castleman disease showed lower median values of HHV‐8 viral load and longer overall survival compared with HHV‐8‐related lymphomas. Patients with viral load of HHV‐8, >40,000 cp/ml had a significant shorter overall survival. In the univariate analysis, HHV‐8‐related lymphoma, HHV‐8 viral load >40,000 cp/ml and performance status >2 were associated with an increased risk of death. Multivariate analysis confirmed the diagnosis of lymphoma as an independent predictor of shorter survival. J. Med. Virol. 81:888–896, 2009.

Immune Recovery after Autologous Stem Cell Transplantation Is Not Different for HIV-Infected versus HIV-Uninfected Patients with Relapsed or Refractory Lymphoma

BACKGROUND High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are feasible and effective salvage treatments for human immunodeficiency virus (HIV)-related relapse or refractory lymphoma. Among the main concerns with ASCT in HIV-infected persons is the additional immune depletion caused by treatment, which could amplify the preexisting immune deficit. The aims of our study were to assess the impact of conventional chemotherapy before salvage treatment was administered, in this population, and to evaluate immune reconstitution dynamics during ASCT. METHODS All 33 HIV-infected and HIV-uninfected patients who underwent comparable ASCT protocols at the National Cancer Institute (Aviano, Italy) who underwent 1 month of follow-up after transplantation were included in a prospective immunological study. Demographic, clinical, and immunovirological data were obtained before administration of induction therapy, during transplantation, and at 24 months of follow-up. RESULTS Before HDC, no significant differences were observed in CD4(+) cell subsets and signal joint T cell receptor excision circles (sjTRECs), although HIV-infected persons had inverted ratios of CD4(+) cells to CD8(+) cells because they had higher CD8(+) T cell counts, compared with HIV-uninfected persons. After ASCT, this inversion was also observed in HIV-uninfected patients up to 24 months. CD4(+) cell subsets had similar recoveries, with a temporary setback in HIV-infected persons 3 months after reinfusion, together with an increase in infections. sjTRECs demonstrated similar dynamics in both populations and serve as a useful predictive marker of recovery of CD4(+) cell subsets. No significant changes emerged in HIV DNA levels during the follow-up period, with values at 24 months significantly lower than those at baseline. CONCLUSIONS Our study demonstrated that ASCT in HIV-infected persons with lymphoma does not worsen the initial immune impairment and does not enhance viral replication or the peripheral HIV reservoir in the long term.

Human Chorionic Gonadotropin in the Treatment of HIV-related Kaposi's Sarcoma

To evaluate the antineoplastic activity of human chorionic gonadotropin (hCG) in the treatment of HIV-related Kaposis sarcoma (KS), two clinical trials focusing on two different schedules of administration and types of hCG preparation were conducted. In the low-dose group, hCG (Profasi-HP) was administered three times a week intramuscularly at a dose ranging from 4000 to 32,000 IU for 4 months and no objective response was observed among 5 evaluable patients. In the high-dose group, hCG (Gonadotrafon) was given intramuscularly three times a week at a dose ranging from 100,000 to 300,000 IU for 3 months with 1 partial response among 8 evaluable patients. In 6 patients evaluated for HIV viral load, no significant reduction in HIV viraemia was observed. In conclusion, hCG showed very limited activity against KS and no influence on HIV viral load, along with emerging dose-limiting toxicity and high cost of the therapy.