34 research outputs found
Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation
To investigate cytogenetic evolution after upfront autologous stem cell
transplantation for newly diagnosed myeloma we retrospectively analyzed
fluorescence in situ hybridization results of 128 patients with paired bone
marrow samples from the time of primary diagnosis and at relapse. High-risk
cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more
frequently after relapse (odds ratio: 6.33; 95% confidence interval:
1.86–33.42; P<0.001). No significant changes were observed for defined IGH
translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes
between primary diagnosis and relapse. IGH translocations with unknown
partners occurred more frequently at relapse. New deletion 17p and/or gain
1q21 were associated with cytogenetic heterogeneity, since some de novo
lesions with different copy numbers were present only in subclones. No
distinct baseline characteristics were associated with the occurrence of new
high-risk cytogenetic abnormalities after progression. Patients who relapsed
after novel agent-based induction therapy had an increased risk of developing
high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65–127.66;
P=0.03) compared to those who were treated with conventional chemotherapy.
Survival analysis revealed dismal outcomes regardless of whether high-risk
aberrations were present at baseline (hazard ratio, 3.53; 95% confidence
interval: 1.53–8.14; P=0.003) or developed at relapse only (hazard ratio,
3.06; 95% confidence interval: 1.09–8.59; P=0.03). Our results demonstrate
cytogenetic evolution towards high-risk disease after autologous
transplantation and underline the importance of repeated genetic testing in
relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26)
Liver resection or combined chemoembolization and radiofrequency ablation improve survival in patients with hepatocellular carcinoma
Background/ Aims: To evaluate the long-term outcome of surgical and non-surgical local treatments of patients with hepatocellular carcinoma (HCC). Methods: We stratified a cohort of 278 HCC patients using six independent predictors of survival according to the Vienna survival model for HCC (VISUM- HCC). Results: Prior to therapy, 224 HCC patients presented with VISUM stage 1 (median survival 18 months) while 29 patients were classified as VISUM stage 2 (median survival 4 months) and 25 patients as VISUM stage 3 (median survival 3 months). A highly significant (p < 0.001) improved survival time was observed in VISUM stage 1 patients treated with liver resection ( n = 52; median survival 37 months) or chemoembolization (TACE) and subsequent radiofrequency ablation ( RFA) ( n = 44; median survival 45 months) as compared to patients receiving chemoembolization alone (n = 107; median survival 13 months) or patients treated by tamoxifen only (n = 21; median survival 6 months). Chemoembolization alone significantly (p <= 0.004) improved survival time in VISUM stage 1 - 2 patients but not (p = 0.341) in VISUM stage 3 patients in comparison to those treated by tamoxifen. Conclusion: Both liver resection or combined chemoembolization and RFA improve markedly the survival of patients with HCC
an interim analysis from the prospective GMMG-MM5 trial
We investigated the impact of subcutaneous versus intravenous bortezomib in
the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared
bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide,
and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based
on data from relapsed myeloma, the route of administration for bortezomib was
changed from intravenous to subcutaneous after 314 of 604 patients had been
enrolled. We analyzed 598 patients who received at least one dose of trial
medication. Adverse events were reported more frequently in patients treated
with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates
of grade 2 or more peripheral neuropathy were higher in patients treated with
intravenous bortezomib during the third cycle (intravenous=8%;
subcutaneous=2%, P=0.001). Overall response rates were similar in patients
treated intravenously or subcutaneously. The presence of International Staging
System stage III disease, renal impairment or adverse cytogenetic
abnormalities did not have a negative impact on overall response rates in
either group. To our knowledge this is the largest study to present data
comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma.
We show better tolerance and similar overall response rates for subcutaneous
compared to intravenous bortezomib. The clinical trial is registered at
eudract.ema.europa.eu as n. 2010-019173-16
a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma
Background Despite novel therapeutic agents, most multiple myeloma (MM)
patients eventually relapse. Two large phase III trials have shown
significantly improved response rates (RR) of lenalidomide/dexamethasone
compared with placebo/dexamethasone in relapsed MM (RMM) patients. These
results have led to the approval of lenalidomide for RMM patients and
lenalidomide/dexamethasone has since become a widely accepted second-line
treatment. Furthermore, in RMM patients consolidation with high-dose
chemotherapy plus autologous stem cell transplantation has been shown to
significantly increase progression free survival (PFS) as compared to
cyclophosphamide in a phase III trial. The randomized prospective ReLApsE
trial is designed to evaluate PFS after lenalidomide/dexamethasone induction,
high-dose chemotherapy consolidation plus autologous stem cell transplantation
and lenalidomide maintenance compared with the well-established
lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is
a randomized, open, multicenter phase III trial in a planned study population
of 282 RMM patients. All patients receive three lenalidomide/dexamethasone
cycles and - in absence of available stem cells from earlier harvesting -
undergo peripheral blood stem cell mobilization and harvesting. Subsequently,
patients in arm A continue on consecutive lenalidomide/dexamethasone cycles,
patients in arm B undergo high dose chemotherapy plus autologous stem cell
transplantation followed by lenalidomide maintenance until discontinuation
criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B)
and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after
autologous stem cell transplantation (arm B) and every 3 months thereafter
(arm A + B). After finishing the study treatment, patients are followed up for
survival and subsequent myeloma therapies. The expected trial duration is 6.25
years from first patient in to last patient out. The primary endpoint is PFS,
secondary endpoints include overall survival (OS), RR, time to best response
and the influence of early versus late salvage high dose chemotherapy plus
autologous stem cell transplantation on OS. Discussion This phase III trial is
designed to evaluate whether high dose chemotherapy plus autologous stem cell
transplantation and lenalidomide maintenance after lenalidomide/dexamethasone
induction improves PFS compared with the well-established continued
lenalidomide/dexamethasone regimen in RMM patients. Trial registration:
ISRCTN16345835 (date of registration 2010-08-24)
Mouse models of diffuse large B cell lymphoma
Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies
Can 18F-NaF PET/CT before Autologous Stem Cell Transplantation Predict Survival in Multiple Myeloma?
There is an unmet need for positron emission tomography (PET) radiotracers that can image bone disease in multiple myeloma (MM) in a more sensitive and specific way than the widely used 18F-fluorodeoxyglucose (18F-FDG). Sodium fluoride (18F-NaF) is a highly sensitive tracer of bone reconstruction, evolving as an important imaging agent for the assessment of malignant bone diseases. We attempted to investigate for the first time the prognostic significance of 18F-NaF PET/CT in newly diagnosed, symptomatic MM patients planned for autologous stem cell transplantation (ASCT). Forty-seven patients underwent dynamic and static PET/CT with 18F-NaF before treatment. After correlation with the respective findings on CT and 18F-FDG PET/CT that served as reference, the 18F-NaF PET findings were compared with established factors of high-risk disease, like cytogenetic abnormalities as well as bone marrow plasma cell infiltration rate. Furthermore, the impact of 18F-NaF PET/CT on progression-free survival (PFS) was analyzed. Correlation analysis revealed a moderate, significant correlation of the 18F-NaF parameters SUVaverage and K1 in reference tissue with bone marrow plasma cell infiltration rate. However, no significant correlation was observed regarding all other 18F-NaF PET parameters. Survival analysis revealed that patients with a pathologic 18F-NaF PET/CT have a shorter PFS (median = 36.2 months) than those with a physiologic scan (median = 55.6 months) (p = 0.02). Nevertheless, no quantitative 18F-NaF parameter could be shown to adversely affect PFS. In contrast, the respective analysis for quantitative dynamic 18F-FDG PET/CT revealed that the parameters SUVmax, fractional blood volume (VB), k3 and influx from reference tissue as well as SUVaverage from MM lesions had a significant negative impact on patient survival. The herein presented findings highlight the rather limited role of 18F-NaF PET/CT as a single PET approach in MM
The prognostic significance of [18F]FDG PET/CT in multiple myeloma according to novel interpretation criteria (IMPeTUs)
Purpose!#![!##!Methods!#!Forty-seven patients with newly diagnosed MM underwent [!##!Results!#!Median follow-up from baseline and follow-up PET/CT were 85.1Â months and 76.7Â months, respectively. The number of focal, [!##!Conclusion!#!Several parameters utilized in IMPeTUs predict PFS in MM patients, suggesting the potentially significant role of the new criteria in patient stratification and response assessment. Additional studies are warranted for the further evaluation of IMPeTUs in the direction of establishment of robust cut-off values with a prognostic significance in the disease
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Impact of Hepatitis B Core Antibody Seropositivity on the Outcome of Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma
Hepatitis B core antibody (HBcAb) seropositivity has been associated with a higher rate of hepatitis B virus (HBV) reactivation after chemotherapy, even in patients who are hepatitis B surface antigen (HBsAg) negative. However, little is known about the risk of HBV reactivation after autologous hematopoietic stem cell transplantation (auto-HCT). We evaluated the incidence of HBV reactivation, liver toxicity, and survival in patients with multiple myeloma (MM) who received auto-HCT at our institution. We retrospectively identified 107 MM patients with resolved HBV infection (HBcAb positive, HBsAg negative) and 125 patients with negative HBV serology (control subjects) who were matched for age, timing of auto-HCT from diagnosis, cytogenetics, disease status at transplant, induction therapy, and preparative regimen. All patients underwent auto-HCT between 1991 and 2013. Primary endpoints were HBV reactivation, defined as HBsAg positivity or ≥10-fold increase in HBV DNA, and hepatotoxicity, as defined in the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. In the resolved HBV infection group, 52 patients (49%) were HBsAb positive and 24 (22%) had detectable HBV DNA before auto-HCT. Only 1 patient with resolved HBV infection received pre-emptive antiviral therapy with lamivudine, whereas 4 patients received lamivudine (n = 3) or tenofovir (n = 1) at reactivation after auto-HCT for a median duration of 12 months. HBV reactivation occurred in 7 of 107 patients (6.5%) in the resolved HBV group. Median time to HBV reactivation from auto-HCT was 16 months. The cumulative incidence of grade 2 or greater hepatotoxicity was 30% in the resolved HBV infection group and 22% in the control group (hazard ratio, 1.3; 95% confidence interval, .7 to 2.3; P = .4). Nonrelapse mortality for the 2 groups was not statistically different at 2 years (P = .06), although it trended higher in the control group than in the resolved HBV infection group (8% versus 1%). The median progression-free survival (PFS) and overall survival (OS) durations in the resolved HBV infection and control groups were 21 versus 18 months (P = .5) and 53 versus 67 months (P = .2), respectively. Our data suggest that resolved HBV infection in patients undergoing auto-HCT for MM is associated with a low risk of HBV reactivation and hepatotoxicity; these complications were reversible and did not adversely affect the PFS or OS