An immunological signature to predict outcome in patients with triple-negative breast cancer with residual disease after neoadjuvant chemotherapy.

BACKGROUND: When triple-negative breast cancer (TNBC) patients have residual disease after neoadjuvant chemotherapy (NACT), they have a high risk of metastatic relapse. With immune infiltrate in TNBC being prognostic and predictive of response to treatment, our aim was to develop an immunologic transcriptomic signature using post-NACT samples to predict relapse. MATERIALS AND METHODS: We identified 115 samples of residual tumors from post-NACT TNBC patients. We profiled the expression of 770 genes related to cancer microenvironment using the NanoString PanCancer IO360 panel to develop a prognostic transcriptomic signature, and we describe the immune microenvironments of the residual tumors. RESULTS: Thirty-eight (33%) patients experienced metastatic relapse. Hierarchical clustering separated patients into five clusters with distinct prognosis based on pathways linked to immune activation, epithelial-to-mesenchymal transition and cell cycle. The immune microenvironment of the residual disease was significantly different between patients who experienced relapse compared to those who did not, the latter having significantly more effector antitumoral immune cells, with significant differences in lymphoid subpopulations. We selected eight genes linked to immunity (BLK, GZMM, CXCR6, LILRA1, SPIB, CCL4, CXCR4, SLAMF7) to develop a transcriptomic signature which could predict relapse in our cohort. This signature was validated in two external cohorts (KMplot and METABRIC). CONCLUSIONS: Lack of immune activation after NACT is associated with a high risk of distant relapse. We propose a prognostic signature based on immune infiltrate that could lead to targeted therapeutic strategies to improve patient prognosis.

[Serological diagnosis of celiac disease]. / Diagnostic sérologique de la maladie cœliaque.

Screening studies using high-sensitivity and specificity markers indicate a prevalence of celiac disease of up to 1% in European and North-American populations. Celiac disease is a frequent condition that has become an important public health issue. Yet the majority of cases remain undiagnosed due to the polymorphism of its clinical manifestations. The new insight in the pathogenesis of celiac disease has lead to the development of new diagnostic tools. Early screening of symptomatic patients and pre-identified at-risk groups significantly improves the quality of life while reducing morbidity and mortality. However, prophylactic benefits of early diagnosis by assessing the general population have not been shown in any study. French and Northern American scientific societies have introduced serological testing in their newly revised strategies to diagnose celiac disease. Older markers judged insufficiently accurate like anti-gliadin and anti-reticulin antibodies have recently been withdrawn from the list of reimbursed medical expenses in France. Anti-endomysium and tissue transglutaminase IgA antibodies have proven to be at this day the most sensitive and specific markers for the diagnosis and follow-up of patients on gluten-free diet, at the exception of IgA-deficient patients. Assays testing for IgG antibodies are recommended upon IgA-deficiency. Although very accurate, a better standardisation of current assays may enable serological testing to replace in a near future histological confirmation brought by small bowel biopsies which remains today the gold standard test to diagnose celiac disease. Indeed, serological testing represents and attractive alternative as it is less invasive, less expansive, laboursaving and more objective in interpretation.

Monitoring and biomonitoring of surface ozone in Florence, Italy.

An ambient air study was conducted in the city of Florence, Italy, in the summer 1996. Tropospheric ozone was continuously monitored with automatic analyzers in three stations, two located in the urban area and one in the hilly surroundings (Settignano). A biomonitoring campaign based on the tobacco cv. Bel-W3 plants was performed in the same area. The highest values were constantly recorded in the Settignano station. The highest 1-hour mean recorded was 197 nl/l; the accumulated exposure over a threshold of 40 nl/l (AOT40) was well above the critical levels standards for protection of the vegetation. A consistent temporal variation was observed and July proved to be the month with the highest ozone levels. Cumulative frequency distribution of ozone maximum daily concentrations exhibited a good fitting to log-normality. No 'week-end' effect was observed. Biomonitoring data were in good agreement with chemico-physical ones.

Prognostic value of plasma markers of immune activation in patients with advanced HIV disease treated by combination antiretroviral therapy.

We assessed the prognostic role of plasma levels of beta2-microglobulin, TNF-alpha, sTNFR-II, and IFN-gamma on the progression to AIDS in patients mostly treated with combination antiretroviral therapies. HIV-1-infected patients with advanced HIV disease (baseline CD4+ cell count between 50 and 250 x 10(6)/L) were included in a prospective cohort followed up for 36 months. In the 113 patients included, 22 first AIDS-defining events were reported. Cumulative probability of AIDS was 12% at M12, 18% at M24, and 20% at M36. Using a Cox model, the baseline level of sTNFR-II (hazard ratio of 3.75 for sTNFR-II > or =10 ng/ml vs < 10 ng/ml, P = 0.01) was associated with progression to AIDS. sTNFR-II remained a prognostic factor before and after the introduction of combinations of antiretrovirals. Whether or not this marker is of value in patients exclusively treated with highly active antiretroviral therapy needs to be assessed in specific studies.

Cell-associated HIV-1-DNA quantitation after highly active antiretroviral therapy-treated primary infection in patients with persistently undetectable plasma HIV-1 RNA.

OBJECTIVE: To determine the usefulness of cell-associated HIV-1-DNA quantification during the follow-up of highly active antiretroviral therapy (HAART)-treated primary-infected patients with persistently undetectable plasma RNA loads. PATIENTS AND METHODS: In 27 patients given HAART within a median of 24 days after symptomatic primary HIV infection, plasma and peripheral blood mononuclear cell (PBMC) HIV-1 RNA were less than 50 copies/ml and less than 50 copies/10(6) cells after 18 months of treatment. HIV-1 RNA and DNA were quantified every 6 months in PBMC in these 27 patients, 14 of whom accepted excision lymph node biopsy after month 18 for HIV-1-RNA and -DNA quantification in lymph node mononuclear cells (LNMC). RESULTS: The median decreases in plasma HIV-1 RNA, PBMC HIV-1 RNA and DNA over the 18 months of follow-up were 3.6 log (P< 0.005), 1.1 log (P< 0.05), and 1.0 log (P<0.001), respectively. HIV-1 DNA was detected in 92.3% of PBMC samples at baseline and at month 18. In LNMC, 100% of samples were detectable for HIV-1 DNA. CONCLUSION: In this highly selected population of patients with excellent plasma virological response under HAART, HIV-1 DNA showed a progressive decrease but was still detectable in 92.3% of samples at month 18, whereas all LNMC samples tested scored positive for HIV-1 DNA. The utility of proviral HIV-1-DNA monitoring was not clearly demonstrated in this 18-month follow-up of HAART-treated primary-infected patients. However, this finding could be reconsidered when using other therapeutic strategies such as structured treatment interruptions, reinforced treatment or additive immunotherapy.

JC virus remains latent in peripheral blood B lymphocytes but replicates actively in urine from AIDS patients.

JC virus (JCV) is thought to reach the central nervous system by a vascular route. To determine whether JCV is conveyed in peripheral blood as latent or reactivated virus, blood leukocytes, plasma, and urine from 50 AIDS patients and plasma and B lymphocytes from 60 AIDS patients were investigated. Peripheral blood from 88 human immunodeficiency virus-negative blood donors was studied. Nested polymerase chain reaction assays allowed the identification of JCV T DNA and VP1 mRNAs. The latter indicate viral replication. Blood harbored JCV DNA in 31.8% of AIDS patients (only 2.3% of blood donors; P > .001) and urine in 56%. VP1 mRNAs were detected in blood of 1 AIDS patient. Notably, 38% of DNA-positive urine samples and 10 cerebrospinal fluid samples (CSF) from AIDS patients with progressive multifocal leukoencephalopathy contained JCV mRNAs. Thus, JCV was significantly more frequent in blood from AIDS patients than from controls, but, in most instances, it was latent, whereas active replication was detected in urine and CSF.

Foscarnet decreases HIV-1 plasma load.

OBJECTIVE: To evaluate the effect of foscarnet on HIV-1 replication in vivo. PATIENTS AND METHODS: Seventeen AIDS patients with cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV) infection, Kaposi's sarcoma (KS), or a combination of these were treated with foscarnet. HIV RNA quantification (bDNA 2.0, Chiron, Emeryville, CA, U.S.A.), CMV pp65 antigenemia (Argene Biosoft, Varilhes, France), and CMV viremia were determined before and during therapy. RESULTS: Four patients had CMV retinitis (1 with KS), 2 patients had CMV pneumonia (1 with KS), 1 patient had CMV cholecystitis, 2 patients had VZV infection (1 with KS), 1 patient had HSV-2 infection, and 7 patients had KS alone. The decrease in HIV-1 load was -0.73 +/- 0.39 log copies/ml (p = 2.10(-6)) after 3 days of treatment and -1.15 +/- 0.49 log copies/ml (p < 10(-7)) after 10 days of treatment, compared with day 0. Furthermore, reduction of HIV-1 plasma load during foscarnet therapy did not depend on the presence or absence of CMV disease or on a positive pp65 antigenemia at day 0. CONCLUSION: We observed decreased HIV-1 plasma load in all patients treated with foscarnet, regardless of presence or absence of clinical or biologic CMV infection. This decrease supports the proposition that foscarnet anti-HIV-1 activity may be of clinical importance.

Course of specific T lymphocyte cytotoxicity, plasma and cellular viral loads, and neutralizing antibody titers in 17 recently seroconverted HIV type 1-infected patients.

Relationships were sought between specific anti-HIV cytotoxic T lymphocyte (CTL) responses (against structural and regulatory proteins of the HIV-1 LAI isolate) and plasma and cellular viral loads (VLs) in 17 recently HIV-1-infected patients including 3 displaying asymptomatic primary infection (PI) followed up for 12 months. Plasma VL was correlated directly with CD8 counts and inversely with CD4 counts. Cytotoxic reactions were observed in all patients and directed mainly against structural proteins. The earliest CTL responses were against Gag and Env proteins detected in 87 and 75% of the subjects, respectively, within the first month following PI. Anti-Env and Gag cytotoxic responses were inversely correlated with the plasma VL. Reactions against the pol gene products were thought to be either less involved in or less efficient for the initial decrease of viremia. Responses against regulatory gene products were weak and variable, apart from Nef, which was recognized by half of the subjects. Neutralizing antibodies were not detected before month 3, and were found only in six patients at subsequent times. Two of three patients with asymptomatic PI had a low viral burden and either a delayed response or one limited to a few protein CTL responses, suggesting that the magnitude of the CTL response depends on the initial plasma VL. The third patient displayed viral and CTL parameters identical to those of the patients with symptomatic PI. However, two subjects with symptomatic PI exhibited similarly low plasma VL and moderate CTL responses. Overall, the results suggest that the CTL response may not be the sole factor controlling viremia.

Activity of rifabutin, clarithromycin, ethambutol, sparfloxacin and amikacin, alone and in combination, against Mycobacterium avium complex in human macrophages.

Disseminated infection with Microbacterium avium complex (MAC) in patients with AIDS is currently treated with a combination of antimycobacterial agents in order to prevent the selection of resistant mutant strains. Although clinical and microbiological responses can generally be achieved within a few weeks, relapses are common and require modification of the combination regimen or identification of effective alternate therapies. In this study we investigated the activities of rifabutin 0.5 mg/L, sparfloxacin 1 mg/L, clarithromycin 4 mg/L, amikacin 16 mg/L and ethambutol 2 mg/L, alone and in combination, against nine strains of M. avium isolated from the blood of patients with AIDS in order to identify regimens with the greatest therapeutic potential. Macrophages derived from human monocytes were infected with M. avium and inoculated with a single drug or a combination of drugs; cfu counts were performed at 0, 4 and 7 days after infection. At day 4 and at day 7, the combination of rifabutin, clarithromycin, amikacin and sparfloxacin displayed the highest degree of activity. However, the activity did not differ significantly from that of the combination of rifabutin, clarithromycin and ethambutol. The results of this study confirm the activity of combinations including rifabutin and clarithromycin (+/- ethambutol) in human monocyte-derived macrophages and suggest potentially useful associations in incorporating sparfloxacin and amikacin.

Fatty acids and plasma antioxidants in HIV-positive patients: correlation with nutritional and immunological status.

OBJECTIVE: To investigate red blood cell (RBC) and plasma fatty acids (FA) in HIV-positive patients in relation to oxidative stress and nutritional or immunological status. DESIGN AND METHODS: FA, plasma selenium, vitamins A and E were measured in 95 patients divided into four groups according to CD4 cells. RESULTS: Poly- and di-unsaturated FA (PUFA, DUFA) decreased and saturated FA (SFA) increased in RBC in the patients below 400/mm3 and in plasma in the patients below 50/mm3. RBC SFA correlated to CD4 cells, PUFA to MDA. Unlike vitamin E, plasma vitamin A and selenium decreased in most groups. Plasma SFA and MUFA correlated negatively to selenium and PUFA and DUFA to vitamin E. No correlation was found between PUFA and nutritional markers. CONCLUSION: FA seem to be modified during HIV infection by oxidative stress and disease evolution, but not by denutrition.

Plasma lipids in HIV-infected patients: a prospective study in 95 patients.

The present study aimed to determine plasma lipid levels in 95 HIV-infected patients divided into four groups according to the CD4 lymphocyte counts comparatively to a control group of 20 HIV-negative normolipidaemic subjects. A relationship between lipidic abnormalities and immune or nutritional status was also investigated. The patients below 200 CD4 lymphocyte mm-3 (groups 1 and 2) had significantly lower total cholesterol than the controls. The patients below 400 CD4 lymphocytes mm-3 (groups 1, 2, 3) had significantly higher triglycerides and Lp(a) but lower LDL-cholesterol than the controls. In all HIV-positive patients, whatever their CD4 lymphocyte count, HDL-C and apoA1 were lower than in the controls. By multivariate analysis triglycerides were positively correlated to acute opportunistic infections and to interferon-alpha levels, while cholesterol was negatively correlated to TNF-alpha, and LDL-C was positively correlated to albuminaemia. The latter parameter was the only lipidic value to correlate with nutritional markers. The contamination route, or the presence of wasting, was not correlated to any lipidic disorder.

[Interferon and blood tumor necrosis factor in 95 patients with HIV infection]. / Interféron et facteur de nécrose tumorale sériques chez 95 patients infectés par le VIH.

We have measured TNF-alpha and interferon alpha in 95 HIV positive patients and 20 healthy subjects. TNF-alpha was higher in the HIV+ patients (P = 0.0001) and was correlated to the CD4 cell count (P = 0.02) and cholesterol (negatively) (P = 0.04). Interferon-alpha was correlated to the wasting syndrome (P = 0.002), hypertriglyceridemia (P = 0.004) and haematocrit (P = 0.04).