Disease characteristics, treatment patterns, and outcomes of follicular lymphoma in patients 40 years of age and younger: an analysis from the National Lymphocare Study†.

BACKGROUND: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, with median age at diagnosis in the seventh decade. FL in young adults (YAs), defined as diagnosis at ≤40 years, is uncommon. No standard approaches exist guiding the treatment of YA FL, and little is known about their disease characteristics and outcomes. To gain further insights into YA FL, we analyzed the National LymphoCare Study (NLCS) to describe characteristics, initial treatments, and outcomes in this population versus patients aged >40 years. PATIENTS AND METHODS: Using the NLCS database, we stratified FL patients by age: 18-40 (YA), 41-60, 61-70, 71-80, and >80 years. Survival probability was estimated using Kaplan-Meier methodology. We examined associations between age and survival using hazard ratios and 95% confidence intervals (CIs) from multivariable Cox models. RESULTS: Of 2652 eligible FL patients in the NLCS, 164 (6%) were YAs. Of YA patients, 69% had advanced disease, 80% had low-grade histology, and 50% had good-risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI). Nineteen percent underwent observation, 12% received rituximab monotherapy, and 46% received chemoimmunotherapy [in 59% of these: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone)]. With a median follow-up of 8 years, overall survival (OS) at 2, 5, and 8 years was 98% (95% CI 93-99), 94% (95% CI 89-97), and 90% (95% CI 83-94), respectively. Median progression-free survival (PFS) was 7.3 years (95% CI 5.6-not reached). CONCLUSIONS: In one of the largest cohorts of YA FL patients treated in the rituximab era, disease characteristics and outcomes were similar to patients aged 41-60 years, with favorable OS and PFS in YAs. Longer-term outcomes and YA-specific survivorship concerns should be considered when defining management. These data may not support the need for more aggressive therapies in YA FL. CLINICAL TRIAL NUMBER: Roche/Genentech ML01377 (U2963n).

T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons.

Human immunodeficiency virus (HIV) infection leads to a progressive loss of CD4+ T helper (Th) type 1 cell-mediated immunity that is associated with defective in vitro CD4+ T cell proliferation and abnormal T cell death by apoptosis in response to T cell receptor (TCR) stimulation. Quantification of interleukin (IL)-2, interferon gamma, IL-4, IL-5, and IL-10 secretion by immunoassays, and of interferon gamma, IL-4 and IL-10 messenger RNA expression by competitive reverse transcriptase polymerase chain reaction after in vitro stimulation of the TCR revealed a similar Th1 cytokine profile in T cells from HIV-infected persons and from controls. These data indicated that the loss of CD4+ Th1 cell function in HIV-infected persons is not related to a Th1 to Th2 cytokine switch as previously proposed, but to a process of activation-induced death of CD4+ Th1 cells. Despite the absence of elevated levels of Th2 cytokines, apoptosis of CD4+ T cells, but not of CD8+ T cells, was prevented in vitro by antibodies to IL-10 or IL-4, two Th2 cytokines that downregulate Th1 cell responses, or by the addition of recombinant IL-12, a cytokine that upregulates Th1 functions. TCR-induced apoptosis of T cell hybridomas and preactivated T cells has been shown to involve the CD95 (Fas/Apo-1) molecule. CD4+ and CD8+ T cells from HIV-infected persons expressed high levels of the CD95 molecule, and, in contrast to T cells from controls, were highly sensitive to antibody-mediated CD95 ligation, which induced apoptosis in a percentage of T cells similar to that induced by TCR stimulation. As TCR-induced apoptosis, CD95-mediated apoptosis of CD4+ T cells, but not of CD8+ T cells, was prevented by the addition of recombinant IL-12. Together, these findings suggest that apoptosis of CD4+ T cells from HIV-infected persons involves an abnormal sensitivity to CD95 ligation, and to TCR stimulation in the presence of normal levels of Th2 cytokines. The preventive effect of IL-12 on both mechanisms has potential implications for the design of immunotherapy strategies aimed at the upregulation of CD4+ Th1 cell functions in AIDS.

Relationship of dehydroascorbic acid transport to cell lineage in lymphocytes from normal subjects and patients with chronic lymphocytic leukemia.

Dehydroascorbic acid is the principal form for the cellular uptake by blood cells of vitamin C. Since previous studies from this laboratory had shown a higher content of ascorbic acid and dehydroascorbic acid (DHA) in chronic lymphocytic leukemia (CLL) lymphocytes when compared to their normal counterparts, DHA uptake was characterized using these cells. The affinities of CLL and normal lymphocytes for DHA uptake were similar, as demonstrated by the Km values of 3.7 and 3.5 mM, respectively. Differences were found in other kinetic constants of DHA uptake. The Vmax for normal lymphocytes, 634 mumol/liter cell H2O/min, was approximately twice that of CLL cells, 392 mumol/liter cell H2O/min. In addition, the initial velocity and the maximal DHA uptake by normal lymphocytes were greater than that of CLL lymphocytes. These differences were not simply a reflection of lymphocyte subsets since CLL B-cells demonstrated lower uptake rates than did normal B-cells whereas CLL T-cells were similar to their normal counterparts. The alterations appear to be specific for the leukemic B-cell since they were not shared by neoplastic cells from two patients with T-cell CLL. When analyzed in light of the 3-fold greater cellular DHA and ascorbic acid content in B-cell CLL as compared to normal lymphocytes, these kinetic parameters support the occurrence of a concentration-dependent transport system for DHA. We conclude that the DHA uptake properties of CLL lymphocytes of B-cell origin serves to distinguish this lineage from T-cell CLL or normal lymphocytes.

Evaluation of two staging systems for HIV infection for use in developing countries.

OBJECTIVE: To evaluate the clinical axis of the World Health Organization (WHO) clinical staging system and the modified WHO staging system proposed by Montaner et al. using the lymphocyte strata > 1500, 1500-1000 and < 1000 cells x 10(6)/l. DESIGN: Cross-sectional study. PATIENTS: Four hundred and fifteen consecutive patients with HIV infection attending three HIV reference centres in Belgium. METHODS: Absolute CD4 lymphocyte counts were compared between stages within the two staging systems. RESULTS: Median CD4 lymphocyte counts decreased with increasing stage of disease in both staging systems. Differences in median CD4 lymphocyte counts between stages of each staging system were statistically significant (Kruskal-Wallis one-way analysis of variance, P < 0.001). The WHO clinical stage 1 and the modified WHO stage I had positive predictive values of 56 and 58%, respectively, for identifying patients with CD4 lymphocyte levels > 500 cells x 10(6)/l. The WHO clinical stage 4 and the modified WHO stage IV had positive predictive values of 79 and 80%, respectively, for identifying patients with CD4 lymphocyte levels < 200 cells x 10(6)/l. CONCLUSIONS: The WHO clinical staging system or a modified version of this system using lymphocytes stratification may be a good alternative in developing countries to the CD4 lymphocyte count-based HIV staging system used in the developed world. Cohort studies in developing countries are needed to assess their prognostic value.

PIP: In 1990, Belgium, physicians enrolled 415 consecutive patients attending HIV reference centers in Antwerp, Brussels, and Ghent in a cross-sectional study designed to evaluate the clinical axis of the WHO staging system with and without the lymphocyte stratification proposed by Montaner el al. (that is, modified WHO staging system) (1500, 1500- 1000, and 1000 cells x 1 million/l). They filled in a standardized questionnaire with all criteria of the WHO staging system. Laboratory personnel used standard hematology and flow cytometry techniques to determine absolute and CD4 lymphocyte counts. 80% of the patients were Caucasians. 46% of all patients were homosexual and 42% were heterosexual; 79.2% were men. Median CD4 lymphocyte counts fell in both staging systems as the stage of HIV infection increased. There were significant differences in median CD4 counts between stages of each staging system (p .001). The modified WHO staging system's stage I was more sensitive at identifying patients with CD4 lymphocyte counts of more than 500 cells x 1 million/l than the WHO clinical stage 1 (83% sensitivity vs. 48% sensitivity). The positive predictive value of WHO clinical stage 4 and of the modified WHO staging system's stage IV for identifying people with CD4 lymphocyte counts of less than 200 cells x 1 million/l was quite high (79% and 80%, respectively). The researchers suggested that clinicians use stages 4 and IV as end-points is clinical trials in developing countries. Clinicians completing the questionnaire knew the patients' earlier CD4 lymphocyte count, which may have introduced a bias in the study. For example, they may have more thoroughly examined patients with low CD4 lymphocyte counts than those with normal counts. Nevertheless, the study's results indicated that either one of these systems may be a good alternative in developing countries to the technical equipment-dependent CD4 lymphocyte count-based HIV staging system used in developed countries. Cohort studies in developing countries would evaluate their prognostic value.

Immunological detection of mycobacterial antigens in infected fluids, cells and tissues by latex agglutination. Animal model and clinical application.

We devised an immunoassay for the detection of mycobacterial antigens in cell lysates and in tissue extracts which is based on the agglutination of latex particles coated with anti-Mycobacterium bovis F(ab')2, followed by counting of non-agglutinated particles. Mycobacterium bovis cell lysates were tested and a reference curve was established, having a lower limit of detection of 15-20 Mycobacteria. We were able to detect mycobacterial antigens in cell lysates from bronchoalveolar washings and in spleen and liver lysates obtained from experimentally infected rabbits. Antigens were also detected in ten out of 11 samples obtained from patients with proven tuberculous infection. These samples were readily distinguished from 32 negative control samples after pepsin treatment. In contrast, periodate treatment of samples to destroy carbohydrate, abolished all reactivity. Following gel filtration chromatography we identified three peaks with antigenic properties in samples of all types. The detection of mycobacterial carbohydrate antigens by latex agglutination and particle counting should be a useful adjunct in the diagnosis of tuberculosis.

A multidot immunobinding assay for the serodiagnosis of tuberculosis. Comparison with an enzyme-linked immunosorbent assay.

A simple dot immunobinding (dot blot) assay procedure has been developed for the detection of antibodies directed against a soluble mycobacterial antigen preparation. This technique was compared with the widely used ELISA, in a study of samples from tuberculous patients. Dot blots were read on a densitometer. The correlation between both assays was excellent (r = 0.91; P less than 0.001); 90% of sera from tuberculous patients were detected using both techniques and a serial two-fold dilution method. Assessments of the end-points of titration curves by reflectometry and simple visual interpretation gave similar results. The dot blot assay is easier to perform and appears to be a practical alternative to ELISA for the detection of anti-mycobacterial antibodies in tuberculous patients.

Antimycobacterial antibodies in pleural effusions.

We devised a dot blot assay to evaluate the IgG and IgA response to P32, a recently isolated antigen specific to mycobacteria. Pleural fluids and the corresponding sera were tested, obtained from five patients with pleural tuberculosis proven by direct examination and/or culture and from 14 patients with pleural effusions of other origins. We measured the total IgG and IgA levels in all samples and determined the anti-P32 titer after adjusting IgG and IgA respectively to the same levels in all samples. Those pleural fluids and sera from tuberculous patients contained a higher proportion of anti-P32 antibodies than samples obtained from nontuberculous control subjects; in those patients, the proportion of anti-P32 antibodies was generally higher in pleural effusion fluid than in serum.

Antibody levels to whole culture filtrate antigens and to purified P32 during treatment of smear-positive tuberculosis.

Antimycobacterial IgG levels were measured repeatedly during treatment in 12 patients with moderate or severe pulmonary tuberculous disease using a dot immunobinding assay. We used reflectance densitometry equipment to quantify the immunoperoxidase staining and a Mycobacterium bovis BCG culture filtrate and the purified P32 protein as antigens. Antibody response against whole culture filtrate and P32 antigen increased after a three-month period of treatment. After this antibiotherapy was completed, the estimated amount of antibodies directed against the P32 decreased while those against the whole culture filtrate remained at the same level. A serologic test using P32 as the antigen seems to allow a better discrimination between active and healed tuberculosis.

High-dose chemotherapy and autologous CD34-positive blood stem cell transplantation for multiple myeloma in an HIV carrier.

The epidemiology and clinical outcome of multiple myeloma in human immunodeficiency virus (HIV)-positive patients is poorly documented. There are uncertainties concerning the optimal management of this rare disorder. We report on the use of myeloablative chemotherapy with autologous stem cell transplantation in an HIV-positive patient with multiple myeloma.

Autologous stem cell infusion for acute myeloblastic leukemia in an HIV-1 carrier.

We present the case of an asymptomatic HIV carrier, who presented with acute myeloblastic leukemia in third relapse and successfully underwent autologous stem cell transplantation as a rescue treatment. This observation supports the conclusion that tolerance of autologous bone marrow or stem cell transplant in patients with HIV may correlate with a low viral burden and relatively good immune function.

Fifty cases of human immunodeficiency virus (HIV) infection: immunoultrastructural study of circulating lymphocytes.

The peripheral lymphocytes of 50 cases of human immunodeficiency virus (HIV) infection (13 of acquired immune deficiency syndrome (AIDS), 17 of AIDS related complex (ARC), and 20 healthy carriers) were studied immunoultrastructurally. The prevalence of "tubuloreticular structures" and "tubular confronting cisternae" increased with the progression of the disease. Numerous tubular confronting cisternae were noted in patients presenting with a high serum acid labile alpha-interferon values. The patients with depressed natural killer cell activity were characterised by circulating immature natural killer cells with abundant multivesicular bodies that were devoid of "parallel tubular arrays". With an immunogold staining technique the location of HIV antigen was detected ultrastructurally, both at the surface of "hand-mirror" natural killer cell lymphocytes and inside vacuolised cells, probably corresponding to infected T4 lymphocytes. These findings indicate the usefulness of electron microscopic techniques in evaluating the pathology and the pathogenetic outcome of AIDS.

Importance of method in the determination of syncytium-inducing phenotype of human immunodeficiency virus type 1 clinical isolates.

The in vitro syncytium induction capacity of human immunodeficiency virus type 1 (HIV1) isolates is an important marker in the progression of the disease. Two methods have been widely used to determine the biological phenotype of HIV1. These two methods, the direct MT-2 assay and the supernatant assay, were compared for the detection of syncytium-inducing (SI) variants on 275 blood samples obtained from 87 HIV infected patients during a 13 month follow-up period. A SI virus was detected in 152 blood samples. In 44 blood samples, the HIV isolate was found to be SI by only one method, but was SI by both methods in another blood sample of the follow up. Among SI carriers discordant results between the methods were more frequent when the patient was on antiretroviral therapy, and a transient reversion to a non syncytium-inducing (NSI) strain confirmed by both assays was sometimes observed. The supernatant assay has a 93% sensitivity and the direct MT-2 assay has a 78% sensitivity for detection of the SI phenotype. The supernatant assay is as rapid as and less tedious than the MT-2 assay. Antiretroviral therapy could have some effects in decreasing or even suppressing the SI part of the virus population of patients with SI phenotype.

Spontaneous apoptosis and highly active antiretroviral therapy (HAART).

Increased programmed cell death (PCD) or apoptosis has been detected in the T cells of HIV-infected subjects; it is held partially responsible for the continuous loss of CD4+ T cells during the natural course of HIV infection. Highly active antiretroviral therapy (HAART) decreases the viral load and leads to an increase of CD4+ count in vivo. In this study we evaluated PCD in total peripheral blood mononuclear cells, CD8+ and CD4+ lymphocytes before and four weeks after initiation of HAART. Seven HIV-1-infected patients were investigated. Viral load was assessed by RT-polymerase chain reaction and PCD by flow cytometry using apoptosis by 7 amino actinomycin D (7AAD) and propidium iodide (PI). After four weeks of HAART, CD4+ T and CD8+ T cell levels were stable, and plasma HIV-RNA copies were significantly decreased. In four of the patients (4/7), HIV-RNA levels were reduced to undetectable levels (fewer than 400 copies per milliliter). A statistically significant reduction of apoptosis among CD4+ cells was observed (P < 0.03), though neither in the CD8+ T cell population nor in peripheral blood mononuclear cells (PBMCS). These results demonstrate the beneficial effect of HAART on apoptosis of CD4+ cells in the early treatment stage.

Pyogenic arthritis caused by streptococcus equisimilis (group-C streptococcus) in a patient with AIDS.

A patient with the Acquired ImmunoDeficiency Syndrome (AIDS) treated with a daily low dose of corticosteroids for chronic atopic dermatitis experienced a sudden episode of unilateral knee arthritis. Culture of the purulent synovial liquid yielded a pure culture of Streptococcus Equisimilis. A four week period of intravenous antibiotherapy combined with repeated drainages allowed a complete recovery of articular function.

Acute Sjögren-like syndrome as the first manifestation of a generalized CMV infection in a patient with AIDS.

We report the first case of generalized cytomegalovirus (CMV) disease in an AIDS patient who presented with an acute Sjögren-like syndrome and was diagnosed by parotid gland biopsy. All symptoms disappeared after a few days of intravenous ganciclovir therapy.

Macular CMV retinitis: a case report.

PURPOSE: Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection associated with AIDS. It usually affects the peripheral retina, sparing the macula. We describe an atypical CMV retinitis exclusively confined to the macula. METHODS: A 43-year-old man with the diagnosis of AIDS developed a white retinal lesion confined to the macula of the right eye. Two weeks later, a more typical granular appearance was observed leading to presumption of CMV retinitis. RESULTS: The patient was treated with ganciclovir without success. With foscarnet, a good response was obtained, leading to total healing of the lesion. CONCLUSIONS: CMV retinitis has to be taken into consideration in all lesions confined to the macula in immunodepressed patients. An early diagnosis is crucial to avoid blindness.

[The immunodeficiency treatment unit]. / L'Unité de Traitement des Immunodéficiences.

Physicians of the unit have first taken care of patients with acquired Immunodeficiency in 1981. We have become an independent "Reference Centre" in 1998. The multidisciplinary team follows more than 300 patients on a regular basis. AIDS has been amply publicized, but other immuno-deficiencies have not. Primary immunodeficiencies are "orphan" diseases; they can be as serious, or more severe even, than AIDS. About 60 patients with "PID" are followed by the team. We are involved in research, and have participated in the identification of a mutation of an HIV co receptor that protects against HIV infection. We also studied the pathogenesis of Kaposi's sarcoma, and the immunological basis of adverse reactions to intravenous gammaglobulins.

[Immune deficiencies: diagnosis, management, some perspectives]. / Déficits immunitaires primaires: diagnostic, prise en charge, quelques perspectives.

Severe primary immunodeficiencies (PID) are rare; their global incidence is comparable to that of childhood leukemia; they include more than 100 different entities. Clinical manifestations are: unusually severe or frequent infections or infections that do not respond to adequate treatment; an increased risk of certain malignancies; sometimes auto-immune manifestations. Delayed diagnosis and management of PID can lead to severe and irreversible complications or to death. PID can become manifest only in the adult; in common variable immune deficiency, the median age at diagnosis is between the 2nd and the 3rd decade of life. PID are often transmitted genetically; recent progresses in molecular biology have allowed more precise and earlier, including antenatal, diagnosis. Molecular treatment of 3 infants with a severe immunodeficiency has recently been achieved in April 2000. Those progresses were mostly based on the study of immunodeficiency databases. We present here the work of a Belgian group specialized in PID; meetings have started in June 1997. This group establishes guidelines for the diagnosis and treatment of PID, adapted to the local situation. The elaboration of a national register of PID is also underway; this has to provide all guaranties of anonymity to patients and families. Such a register already exists at the European level; it has provided the basis for new diagnostic and therapeutic possibilities. The inclusion of Belgian data in this register should allow essential progresses essential for our patients.

Use of immunoglobulins in adults in a university hospital: a retrospective study.

New applications are always being developed for immunoglobulins; new recommendations are regularly published. We wished to know the indications used in a large hospital. A hundred and thirty-six adult patients were prescribed immunoglobulins from January to December 2008. Three preparations in intravenous immunoglobulins were available (one liquid, 2 freeze-dried). Fourteen charts were rejected for clerical errors. A hundred and twenty two charts were available for statistical study. Thirty-six patients were on immunoglobulins for antibody deficiency, 19 were followed in haematology for chronic lymphoid leukaemia or multiple myeloma, 19 were treated after lung transplantation, 17 had received a kidney transplant, 1 after heart transplantation: these indications were substitution. Twenty for Guillain Barré and chronic demyelinating polyneuropathy, 10 in immune thrombocytopenic purpura: this was for immunomodulation. Recommendations were followed by the prescribers; charts were reviewed in March and November 2009. Side-effects were rare. (0.6%) (1).