To investigate whether bone marrow biopsy (BMB) adds useful information to (18)Ffluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) staging in patients with Hodgkin ...lymphoma (HL).
Newly diagnosed patients with HL undergoing a pretherapeutic staging that encompasses both PET/CT and BMB were included in this retrospective study. The pattern of skeletal FDG uptake was categorized as uni-, bi-, or multifocal (≥ three lesions). Clinical stage, risk assessment, and treatment plan were determined with and without the contribution of BMB results according to the Ann Arbor classification and the guidelines from the German Hodgkin Study Group.
A total of 454 patients with HL were included of whom 82 (18%) had focal skeletal PET/CT lesions and 27 (6%) had positive BMB. No patients with positive BMB were assessed as having stage I to II disease by PET/CT staging. BMB upstaged five patients, assessed as being stage III before BMB; none of the 454 patients would have been allocated to another treatment on the basis of BMB results. Focal skeletal PET/CT lesions identified positive and negative BMBs with a sensitivity and specificity of 85% and 86%, respectively. The positive and negative predictive values of focal skeletal PET/CT lesions for BMB results were 28% and 99%, respectively.
A consistent finding of this study was the absence of positive BMBs in PET/CT-assessed stage I to II disease. The omission of staging BMB would not have changed the risk assessment or treatment strategy in this cohort of 454 newly diagnosed patients with HL.
Background. Persons infected with human immunodeficiency virus (HIV) are often hyporesponsive to immunization, including pneumococcal vaccines. We hypothesized that adding CPG 7909, a toll-like ...receptor 9 (TLR9) agonist and vaccine adjuvant, to 7-valent pneumococcal conjugate vaccine (7vPnC) would increase its immunogenicity in HIV-infected adults. Methods. We performed a double-blind, placebo-controlled, phase 1b/2a trial randomizing HIV-positive patients to receive double doses of 7vPnC (Prevnar) at 0 and 3 months and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPV-23; Pneumo Novum) at 9 months, with experimental patients receiving 1 mg of CPG 7909 added to each of their 3 vaccine doses; control patients had phosphate-buffered saline added instead. Immunogenicity and safety were evaluated for up to 10 months. The primary end point was the proportion of vaccine high responders at 9 months, defined as a 2-fold increase in IgG levels to ⩾1 µg/mL for at least 5 of 7 of the 7vPnC serotypes. Results. Ninety-seven participants were included in the study. The proportion of vaccine high responders was higher in the experimental group (n = 48) than among controls (n = 49; 48.8% vs 25.0%; P=.02) at 9 months. Greater proportions of high responders were also observed at 3 (51.1% vs 39.6%; P=.26), 4 (77.3% vs 56.3%; P=.03), and 10 months (87.8% vs 51.1%; P<.001). Mild systemic and injection site reactions to 7vPnC were more common in the experimental group than the control group (100% vs 81.3%; P=.002). CPG 7909 did not increase non-7vPnC IgG levels after PPV-23 immunization. No adverse effects on CD4+ cell count or organ functions occurred in either group. Conclusions. The addition of a TLR9 agonist to 7vPnC significantly enhanced the proportion of vaccine high responders. Trial registration. ClinicalTrials.gov identifier: NCT00562939.
The value of performing post-therapy routine surveillance imaging in patients with Hodgkin lymphoma is controversial. This study evaluates the utility of positron emission tomography/computed ...tomography using 2-18Ffluoro-2-deoxyglucose for this purpose and in situations with suspected lymphoma relapse.
We conducted a multicenter retrospective study. Patients with newly diagnosed Hodgkin lymphoma achieving at least a partial remission on first-line therapy were eligible if they received positron emission tomography/computed tomography surveillance during follow-up. Two types of imaging surveillance were analyzed: "routine" when patients showed no signs of relapse at referral to positron emission tomography/computed tomography, and "clinically indicated" when recurrence was suspected.
A total of 211 routine and 88 clinically indicated positron emission tomography/computed tomography studies were performed in 161 patients. In ten of 22 patients with recurrence of Hodgkin lymphoma, routine imaging surveillance was the primary tool for the diagnosis of the relapse. Extranodal disease, interim positron emission tomography-positive lesions and positron emission tomography activity at response evaluation were all associated with a positron emission tomography/computed tomography-diagnosed preclinical relapse. The true positive rates of routine and clinically indicated imaging were 5% and 13%, respectively (P = 0.02). The overall positive predictive value and negative predictive value of positron emission tomography/computed tomography were 28% and 100%, respectively. The estimated cost per routine imaging diagnosed relapse was US$ 50,778.
Negative positron emission tomography/computed tomography reliably rules out a relapse. The high false positive rate is, however, an important limitation and a confirmatory biopsy is mandatory for the diagnosis of a relapse. With no proven survival benefit for patients with a pre-clinically diagnosed relapse, the high costs and low positive predictive value make positron emission tomography/computed tomography unsuitable for routine surveillance of patients with Hodgkin lymphoma.
Vaccination responses may be affected by concomitant use of highly active antiretroviral therapy (HAART). We aimed to determine HAART's impact on seven-valent pneumococcal conjugate (7vPnC) vaccine ...immunization with or without a Toll-like receptor 9 (TLR9) agonist adjuvant.
Observational cohort study.
Adults with HIV were immunized with double doses of 7vPnC +/-1 mg CPG 7909, a TLR9 agonist and vaccine adjuvant, at 0 and 3 months, and 23-valent pneumococcal polysaccharide vaccine at 9 months. We measured IgG levels (ELISA) and opsonophagocytic activity (OPA) at months 0, 3, 4, 9, and 10. Persistent 7vPnC vaccine responders were defined as individuals with two-fold IgG increases to 1 microg/ml or more for at least five of the 7vPnC serotypes at 9 months.
We included 75 participants on HAART and 20 HAART-naive. Forty-one received CPG 7909 and 48 received placebo adjuvant. More persistent 7vPnC vaccine responders were found among HAART-treated than among HAART-naive (42.3 vs. 15.0%, P = 0.03). Mean loss of vaccine-specific IgG from month 4 to 9 was greater among HAART-naive than among HAART-treated (54.8 vs. 38.1%, P = 0.001). Functional activity (OPA) was higher among HAART-treated than among HAART-naive at 4, 9, and 10 months. In a logistic regression analysis (adjusted for baseline CD4 cell count, CPG 7909, smoking status, BMI, AIDS diagnosis, and age), HAART use was significantly associated with being persistent 7vPnC vaccine responder at month 9 odds ratio = 4.65, 95% confidence interval (CI) 1.07-20.2.
HIV-infected adults on HAART achieved a more durable antibody response of higher functional activity following pneumococcal conjugate vaccination than HAART-naive individuals, independently of baseline CD4 cell count.
Recent reports indicate that in vitro drug screens combined with gene expression profiles (GEP) of cancer cell lines may generate informative signatures predicting the clinical outcome of ...chemotherapy. In multiple myeloma (MM) a range of new drugs have been introduced and now challenge conventional therapy including high dose melphalan. Consequently, the generation of predictive signatures for response to melphalan may have a clinical impact. The hypothesis is that melphalan screens and GEPs of B-cell cancer cell lines combined with multivariate statistics may provide predictive clinical information.
Microarray based GEPs and a melphalan growth inhibition screen of 59 cancer cell lines were downloaded from the National Cancer Institute database. Equivalent data were generated for 18 B-cell cancer cell lines. Linear discriminant analyses (LDA), sparse partial least squares (SPLS) and pairwise comparisons of cell line data were used to build resistance signatures from both cell line panels. A melphalan resistance index was defined and estimated for each MM patient in a publicly available clinical data set and evaluated retrospectively by Cox proportional hazards and Kaplan-Meier survival analysis.
Both cell line panels performed well with respect to internal validation of the SPLS approach but only the B-cell panel was able to predict a significantly higher risk of relapse and death with increasing resistance index in the clinical data sets. The most sensitive and resistant cell lines, MOLP-2 and RPMI-8226 LR5, respectively, had high leverage, which suggests their differentially expressed genes to possess important predictive value.
The present study presents a melphalan resistance index generated by analysis of a B-cell panel of cancer cell lines. However, the resistance index needs to be functionally validated and correlated to known MM biomarkers in independent data sets in order to better understand the mechanism underlying the preparedness to melphalan resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Microbial translocation may contribute to the immunopathogenesis in HIV infection. We investigated if microbial translocation and inflammation were associated with innate and adaptive immune ...responses in adults with HIV.
This was an observational cohort study. Sera from HIV-infected and HIV-uninfected individuals were analyzed for microbial translocation (soluble CD14, lipopolysaccharides LPS, endotoxin core antibody, and anti-α-galactosyl antibodies) and inflammatory markers (high sensitivity C-reactive protein, IL-6, IL-1 receptor antagonist, soluble tumor necrosis factor receptor II, and IL-10) with enzyme-linked immunosorbent assays. Peripheral blood mononuclear cells (PBMC) from HIV-infected persons and healthy controls (primed with single-stranded HIV-1-derived RNA) were stimulated with LPS, and cytokine production was measured. Finally, HIV-infected patients were immunized with Prevnar 7vPnC±CpG 7909 followed by Pneumo Novum PPV-23. Effects of microbial translocation and inflammation on immunization were analyzed in a predictive regression model. We included 96 HIV-infected individuals, 76 on highly active antiretroviral therapy (HAART), 20 HAART-naive, and 50 healthy controls. Microbial translocation and inflammatory markers were higher among HIV-infected persons than controls. Cytokine levels following LPS stimulation were increased in PBMCs from HAART-naive compared to HAART-treated HIV-infected persons. Further, RNA-priming of PBMCs from controls acted synergistically with LPS to augment cytokine responses. Finally, high serum LPS levels predicted poor vaccine responses among HAART-naive, but not among HAART-treated HIV-infected individuals.
LPS acts synergistically with HIV RNA to stimulate innate immune responses in vitro and increasing serum LPS levels seem to predict poor antibody responses after vaccination among HAART-naive HIV-infected persons. Thus, our results suggest that microbial translocation may be associated with innate and adaptive immune dysfunction in untreated HIV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Post-therapy surveillance imaging in patients with lymphoma remains controversial. We report our experience with positron emission tomography/computed tomography (PET/CT) surveillance in patients ...with aggressive non-Hodgkin lymphoma in first complete remission (CR). The 138 PET/CTs performed in 52 patients revealed four unsuspected relapses. In one patient, relapse was visualized by fluorodeoxyglucose (FDG) accumulation without any significant CT pathology. The specificity and sensitivity of surveillance PET/CT were 89% and 100%, respectively. The predictive values of positive and negative PET/CTs were 21% and 100%, respectively. The cost of half-yearly routine PET/CT surveillance during the first 2 years in CR was $US8552 per patient and accounted for 81% of the total follow-up costs. PET/CT was effective in detecting unexpected relapse and normal PET/CT supported continuous CR. However, the impact of PET/CT was limited by the high number of false-positive results and PET/CT surveillance was costly compared to CT surveillance.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The purpose of this study was to establish a procedure capable of isolating distinct B-cell subpopulations from human tonsils as a basis for subsequent molecular analyses. Overall, 5 distinct B-cell ...subpopulations were purified from fresh tonsils based on their fluorescence surface marker expression: naive B cells, centroblasts, centrocytes, memory B cells, and plasmablasts. The immunophenotypic identity of the subpopulations was verified by quantitative real-time reverse transcriptase-polymerase chain reaction using the proliferation marker MKI-67 and 6 B-cell-associated differentiation markers (BACH2, BCL6, PAX5, IRF4, PRDM1, and XBP1). Furthermore, within the centroblast compartment, large and small centroblasts could be distinguished and large centroblasts were shown to proliferate with a morphologic appearance of a "centroblast"-like cell but with lower gene expression of the germinal center markers BCL6 and BACH2 vs small centroblasts. This study has established a detailed and fast procedure for simultaneous sorting of up to 5 distinct maturation-associated B-cell subpopulations from human tonsils.
Abstract 2637
Hodgkin lymphoma (HL) has traditionally been regarded as a disease primarily affecting the lymphatic organs. The introduction of dual modality 18F-fluorodeoxyglucose positron emission ...tomography/computed tomography (PET/CT) may challenge this statement as PET/CT reveals more sites of extranodal disease than CT alone. The aim of this study was to characterize the clinico-pathological and prognostic features of newly diagnosed HL patients with PET/CT-ascertained skeletal involvement.
We performed a retrospective analysis of the pre-therapeutic PET/CT results from newly diagnosed HL patients at four Danish university hospitals. Criteria for inclusion in the study were (a) histologically verified HL, (b) age ≥15 years, and (c) PET/CT-based staging. Clinical information was obtained from the Danish Lymphoma Registry (LYFO) supplemented by review of medical records. Imaging reports were reviewed for extent of disease. Patients were divided into three groups according to their pattern of PET/CT-positivity: HL confined to lymphatic organs (lymph nodes, spleen, thymus, Waldeyer’s ring) (group 1); HL with focal skeletal PET/CT lesions as the only extranodal involvement (group 2); HL with any extranodal involvement, including skeletal lesions if other extranodal sites were concurrently involved (group 3).
A total of 454 patients with newly diagnosed HL were included and the median follow-up time was 34 months (range 1–113). Focal skeletal PET/CT lesions were identified in 82 patients (18%). HL was confined to nodal areas in 336 (74%) patients (group 1). Among the 118 (26%) patients with extranodal disease, 39 had focal skeletal PET/CT lesions as their only extranodal manifestation (group 2), while 79 had involvement of other extranodal sites with or without co-existing skeletal lesions (groups 3). Group 1 patients exhibited the most favorable combination of clinico-pathological features, group 3 patients displayed most adverse combination of clinico-pathological features, whereas group 2 was intermediate (Table). In a 1:1 comparison between group 1 and 2 patients, the latter had significantly lower hemoglobin (Hgb) levels, higher erythrocyte sedimentation rates (ESR) and higher occurrence of B-symptoms.
The PFS for group 2 patients was similar to that of group 3 patients (p=0.85), but significantly shorter than that of group 1 patients (p<0.001) (Figure). After adjusting for other risk factors in a multivariate Cox model, the presence of focal skeletal PET/CT lesions remained independently associated with shorter PFS (p=0.009).
PET/CT-based identification of focal skeletal lesions as the only extranodal involvement in patients with newly diagnosed HL is not uncommon. This group of patients frequently presents with systemic symptoms and elevated ESR. In addition, their PFS is inferior to that of patients with nodal HL, but similar to that of HL patients with other types of extranodal disease. Although rarely histologically verified, these focal skeletal lesions are thus likely to represent extranodal manifestations of HL.Group 1 (n=336)Group 2 (n=39)Group 3 (n=79)p-valueμMedian age, years3746500.002ECOG Performance, %...0776940 <0.001.1202346.2336.3055.4003Male:female ratio1.211.791.550.4Histological subtype, %... Nodular sclerosis5659600.09. Mixed cellularity212115. Lymphocyte rich533. Lymphocyte depleted103. Classical Hodgkin, unspecified101519. Nodular lymphocytic predominant720Hemoglobin, g/dL13.212.411.60.0001*Total leukocytes, 109/L8.79.39.60.06Thrombocytes, 109/L3083633540.02Lymphocytes, 109/L1.601.701.340.01Erythrocyte sedimentation rate, mm/h2646630.0001*Serum albumin, g/l4240350.0001Serum LDH, IU/L1862092240.005B-symptoms, %385678<0.001*μFisher's exact test for categorical variables; Kruskal-Wallis test for continuous values.*Group 2 differs significantly from group 1 (Wilcoxon rank-sum test). Display omitted
Hutchings:Takeda/Millennium: Consultancy.
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