Martin Bøgsted

Routine Bone Marrow Biopsy Has Little or No Therapeutic Consequence for Positron Emission Tomography/Computed Tomography–Staged Treatment-Naive Patients With Hodgkin Lymphoma

PURPOSE To investigate whether bone marrow biopsy (BMB) adds useful information to [(18)F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) staging in patients with Hodgkin lymphoma (HL). PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Routine Imaging for Diffuse Large B-Cell Lymphoma in First Complete Remission Does Not Improve Post-Treatment Survival: A Danish–Swedish Population-Based Study

PURPOSE Routine imaging for diffuse large B-cell lymphoma (DLBCL) in first complete remission (CR) is controversial and plays a limited role in detecting relapse. This population-based study compared the survival of Danish and Swedish patients with DLBCL for whom traditions for routine imaging have been different. PATIENTS AND METHODS Patients from the Danish and Swedish lymphoma registries were included according to the following criteria: newly diagnosed DLBCL from 2007 to 2012, age 18 to 65 years, and CR after R-CHOP/CHOEP. Follow-up for Swedish patients included symptom assessment, clinical examinations, and blood tests at 3- to 4-month intervals for 2 years, with longer intervals later in follow-up. Imaging was only recommended when relapse was clinically suspected. Follow-up for Danish patients was similar but included routine imaging (usually computed tomography every 6 months for 2 years). RESULTS Danish (n = 525) and Swedish (n = 696) patients with DLBCL had comparable baseline characteristics. Cumulative 2-year progression rate after CR was 6% (95% CI, 4 to 9) for International Prognostic Index (IPI) ≤ 2 versus 21% (95% CI, 13 to 28) for IPI > 2. Age > 60 years (hazard ratio [HR], 2.3; 95% CI, 1.6 to 3.4), elevated lactate dehydrogenase (HR, 2.3; 95% CI, 1.4 to 3.8), B symptoms (HR, 1.7; 95% CI, 1.1 to 2.5), and Eastern Cooperative Oncology Group performance status ≥ 2 (HR, 1.8; 95% CI, 1.0 to 3.0) were associated with worse post-CR survival. Imaging-based follow-up strategy had no impact on survival, neither for all patients nor for IPI-specific subgroups. CONCLUSION DLBCL relapse after first CR is infrequent, and the widespread use of routine imaging in Denmark did not translate into better survival. This favors follow-up without routine imaging and, more generally, a shift of focus from relapse detection to improved survivorship.

Role of routine imaging in detecting recurrent lymphoma; a review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma

After first‐line therapy, patients with Hodgkin lymphoma (HL) and aggressive non‐HL are followed up closely for early signs of relapse. The current follow‐up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore, a retrospective multicenter study of relapsed HL and aggressive non‐HL (nodal T‐cell and diffuse large B‐cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002–2011 and relapsed after achieving complete remission on first‐line therapy. Characteristics and outcome of imaging‐detected relapses were compared with other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient‐reported symptoms alone or in combination with abnormal blood tests or physical examination in 64% of the patients. Routine imaging prompted relapse investigations in 27% of the patients. The estimated number of routine scans per relapse was 91–255 depending on the lymphoma subtype. Patients with imaging‐detected relapse had lower disease burden (P = 0.045) and reduced risk of death following relapse (hazard ratio = 0.62, P = 0.02 in multivariate analysis). Patient‐reported symptoms are still the most common factor for detecting lymphoma relapse and the high number of scans per relapse calls for improved criteria for use of surveillance imaging. However, imaging‐detected relapse was associated with lower disease burden and a possible survival advantage. The future role of routine surveillance imaging should be defined in a randomized trial. Am. J. Hematol. 89:575–580, 2014.

Neutrophil Extracellular Traps in Ulcerative Colitis: A Proteome Analysis of Intestinal Biopsies

Background:The etiology of the inflammatory bowel diseases, including ulcerative colitis (UC), remains incompletely explained. We hypothesized that an analysis of the UC colon proteome could reveal novel insights into the disease etiology. Methods:Mucosal colon biopsies were taken by endoscopy from noninflamed tissue of 10 patients with UC and 10 controls. The biopsies were either snap-frozen for protein analysis or prepared for histology. The protein content of the biopsies was characterized by high-throughput gel-free quantitative proteomics, and biopsy histology was analyzed by light microscopy and confocal microscopy. Results:We identified and quantified 5711 different proteins with proteomics. The abundance of the proteins calprotectin and lactotransferrin in the tissue correlated with the degree of tissue inflammation as determined by histology. However, fecal calprotectin did not correlate. Forty-six proteins were measured with a statistically significant differences in abundances between the UC colon tissue and controls. Eleven of the proteins with increased abundances in the UC biopsies were associated with neutrophils and neutrophil extracellular traps. The findings were validated by microscopy, where an increased abundance of neutrophils and the presence of neutrophil extracellular traps by extracellular DNA present in the UC colon tissue were confirmed. Conclusions:Neutrophils, induced neutrophil extracellular traps, and several proteins that play a part in innate immunity are all increased in abundance in the morphologically normal colon mucosa from patients with UC. The increased abundance of these antimicrobial compounds points to the stimulation of the innate immune system in the etiology of UC.

Diffuse Large B-Cell Lymphoma Classification System That Associates Normal B-Cell Subset Phenotypes With Prognosis

PURPOSE Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell-associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. PATIENTS AND METHODS We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. RESULTS Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP-treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell-like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1-signature and major histocompatibility complex class II-signature genes, which are known to have a positive impact on prognosis. CONCLUSION Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.

Probabilistic models for access strategies to dynamic information elements

In various network services remote access to dynamically changing information elements is a required functionality. Three fundamentally different strategies for such access are investigated in this paper: (1) a reactive approach initiated by the requesting entity, and two versions of proactive approaches in which the entity that contains the information element actively propagates its changes to potential requesters, either (2) periodically or (3) triggered by changes of the information element. This paper develops probabilistic models for these scenarios, which allow to compute a number of performance metrics, with a special focus on the mismatch probability. In particular, we use matrix-analytic methods to obtain explicit expressions for the mismatch probability that avoid numerical integration. Furthermore, limit results for information elements spread over a large number of network nodes are provided, which allow one to draw conclusions on scalability properties. The impact on mismatch probability of different distribution types for the network delays as well as for the time between changes of the information element are obtained and discussed through the application of the model in a set of example scenarios. The results of the model application allow for design decisions on which strategy to implement for specific input parameters and specific requirements on the performance metrics.

Multiparametric Flow Cytometry Profiling of Neoplastic Plasma Cells in Multiple Myeloma

The clinical impact of multiparametric flow cytometry (MFC) in multiple myeloma (MM) is still unclear and under evaluation. Further progress relies on multiparametric profiling of the neoplastic plasma cell (PC) compartment to provide an accurate image of the stage of differentiation. The primary aim of this study was to perform global analysis of CD expression on the PC compartment and subsequently to evaluate the prognostic impact. Secondary aims were to study the diagnostic and predictive impact.

Impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography staging in newly diagnosed classical Hodgkin lymphoma: fewer cases with stage I disease and more with skeletal involvement

Abstract 18F-Fluorodeoxyglucose positron emission tomography/ computed tomography (PET/CT) is a highly accurate staging method in classical Hodgkin lymphoma (cHL). We retrospectively compared the staging results obtained in two large cohorts of patients with cHL diagnosed before (n = 324) and after (n = 406) the introduction of PET/CT staging in a retrospective study. In PET/CT staged patients, stage I disease was less frequent (16% vs. 27%, p < 0.001) while stage IV disease was more frequent (17% vs. 10%, p = 0.02). Imaging-detected skeletal involvement was recognized more often in PET/CT staged patients (17% vs. 2%, p < 0.001), and the presence of focal skeletal PET/CT lesions was associated with higher risk of progression (hazard ratio [HR] 1.96, 95% confidence interval [CI]: 1.14–3.36). The German Hodgkin Study Group (GHSG) risk classification (early, intermediate, advanced disease) predicted outcome in PET/CT staged patients. In conclusion, PET/CT led to higher disease stages, and the more frequently diagnosed skeletal lesions may be an adverse prognostic factor.

High miR-34a expression improves response to doxorubicin in diffuse large B-cell lymphoma

The standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) is the immunochemotherapy-based R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Resistance to treatment, intrinsic or acquired, is observed in approximately 40% of patients with DLBCL, who thus require novel interventions to survive. To identify biomarkers for cytotoxic response assessment, microRNAs (miRNAs) associated with doxorubicin sensitivity were determined by combining global miRNA expression profiling with systematic dose-response screens in 15 human DLBCL cell lines. One candidate, miR-34a, was tested in functional in vitro studies and in vivo in a retrospective clinical cohort. High expression of miR-34a was observed in cell lines sensitive to doxorubicin, and upregulation of miR-34a is documented here to increase doxorubicin sensitivity in in vitro lentiviral transduction assays. High expression of miR-34a had a prognostic impact using overall survival as outcome. With risk stratification of DLBCL samples based on resistance gene signatures (REGS), doxorubicin-responsive samples had statistically significant upregulated miR-34a expression. Classification of the DLBCL samples into subset-specific B cell-associated gene signatures (BAGS) revealed differentiation-specific expression of miR-34a. Our data further support FOXP1 as a target of miR-34a, suggesting that downregulation of FOXP1 may sensitize DLBCL cells to doxorubicin. We conclude that miRNAs, in particular miR-34a, may have clinical utility in DLBCL patients as both predictive and prognostic biomarkers.

Predicting response to multidrug regimens in cancer patients using cell line experiments and regularised regression models

BackgroundPatients suffering from cancer are often treated with a range of chemotherapeutic agents, but the treatment efficacy varies greatly between patients. Based on recent popularisation of regularised regression models the goal of this study was to establish workflows for pharmacogenomic predictors of response to standard multidrug regimens using baseline gene expression data and origin specific cell lines. The proposed workflows are tested on diffuse large B-cell lymphoma treated with R-CHOP first-line therapy.MethodsFirst, B-cell cancer cell lines were tested successively for resistance towards the chemotherapeutic components of R-CHOP: cyclophosphamide (C), doxorubicin (H), and vincristine (O). Second, baseline gene expression data were obtained for each cell line before treatment. Third, regularised multivariate regression models with cross-validated tuning parameters were used to generate classifier and predictor based resistance gene signatures (REGS) for the combination and individual chemotherapeutic drugs C, H, and O. Fourth, each developed REGS was used to assign resistance levels to individual patients in three clinical cohorts.ResultsBoth classifier and predictor based REGS, for the combination CHO, were of prognostic value. For patients classified as resistant towards CHO the risk of progression was 2.33 (95% CI: 1.6, 3.3) times greater than for those classified as sensitive. Similarly, an increase in the predicted CHO resistance index of 10 was related to a 22% (9%, 36%) increased risk of progression. Furthermore, the REGS classifier performed significantly better than the REGS predictor.ConclusionsThe regularised multivariate regression models provide a flexible workflow for drug resistance studies with promising potential. However, the gene expressions defining the REGSs should be functionally validated and correlated to known biomarkers to improve understanding of molecular mechanisms of drug resistance.