Single-cell profiling has become a common practice to investigate the complexity of tissues, organs, and organisms. Recent technological advances are expanding our capabilities to profile various ...molecular layers beyond the transcriptome such as, but not limited to, the genome, the epigenome, and the proteome. Depending on the experimental procedure, these data can be obtained from separate assays or the very same cells. Yet, integration of more than two assays is currently not supported by the majority of the computational frameworks avaiable.
We here propose a Multi-Omic data integration framework based on Wasserstein Generative Adversarial Networks suitable for the analysis of paired or unpaired data with a high number of modalities (>2). At the core of our strategy is a single network trained on all modalities together, limiting the computational burden when many molecular layers are evaluated.
Source code of our framework is available at https://github.com/vgiansanti/MOWGAN.
Introduction. A multidimensional geriatric assessment has been shown to predict therapy-related toxicities in elderly hematology patients. No data are yet available on the use of combined functional ...and comorbidity scores in the allogeneic stem cell transplant (alloSCT) setting. The Lymphoma Italian Foundation (FIL) score, a multidimensional approach, combines the geriatric comorbidity score using the cumulative illness rating scale-geriatric (CIRS-G) with the activities of daily living (ADL) score, instrumental activity of daily living (IADL) score, and older age.
Aims. The aim of the present study was to evaluate the role of the multidimensional FIL score in predicting alloSCT outcome, in terms of transplant-related mortality (TRM), relapse incidence (RI) and overall survival (OS).
Patients and methods. Overall, 228 patients older than 60 years were submitted for alloSCT in Italy and France, during the last 10 years (2009-2018). Patients' characteristics are detailed in Table 1. The median age of the study population was 64 years (range, 60-76), and 155 (68%) were male. Acute myeloid leukemia was the most common indication for transplant (53%) and complete remission status was recorded in 54% of cases at transplantation. A matched unrelated donor, sibling donor or alternative donor was utilized in 41%, 31%, and 28% of cases, respectively. Stem cell source was derived from peripheral blood in 82%, bone marrow in 8%, and cord blood in 10% of cases. Utilization of a myeloablative conditioning regimen was reserved for only 20% of patients. Median number of CD34+ x10^6/Kg infused cells was 5 (range, 0,01-12,9), and of CD3+ x10^7/Kg cells 18 (range, 0,2-47,8). The median follow-up period of the cohort was 36 months (range, 12-138).
Overall survival was estimated by the Kaplan-Meier method from the date of transplant to the date of last follow-up or death; the log-rank test was used to detect differences between subgroups. The Fine and Gray competing risk regression model was used for calculation of TRM and RI. Univariate and multivariate analyses were carried out using the Cox proportional-hazards regression model.
Results. A total of 121 (53%) patients died at last follow-up. The cause of death was related to TRM in 60 (49%) cases comprising infection (31), toxicity (13), acute GVHD (9), and chronic GVHD (7); disease relapse was the ultimate cause of death in 61 (51%) cases . The 2-year expected TRM, RI and OS were 25%, 36% and 49%, respectively.
The FIL score was measured in 215 patients and classified patients as ‘fit’ in 125 (58%) casesa nd ‘unfit/frail’ in 90 (42%). According to the FIL score, fit patients were more frequently in complete remission (CR) at alloSCT compared with unfit/frail patients (78% vs 21%, p<0.01) and had a higher median Karnofsky performance status (KPS) (100 versus 90, p<0.01). A Sorror score (HCI-CI) was available in 222 patients (97%), 71 patients had an HCI-CI of 0 (32%), 35 patients scored 1 (16%), 40 patients scored 2 (18%), and 76 patients scored >2 (34%).
Interestingly, the HCI-CI (HR 1.06, 95%CI 0.96-1.16, p=0.27) failed to predict alloSCT outcome. In contrast , FIL score, predicted fit patients to have a better 2- and 5-year OS of 66% and 59% compared to 32% and 30% in unfit/frail patients (p<0.0001). Notably, RI at 2-years did not significantly differ according to FIL score (33% and 37% in fit and unfit/frail patients respectively, p=0.39); but a significantly higher TRM was observed in the unfit/frail cohort, with a predicted 2-year TRM of 13% in fit versus 28% in unfit/frail patients (p<0.0001) (Figure 1). On univariate analysis, CR status at alloSCT (HR 0.52, 95%CI 0.36-0.74, p=0.0003), KPS > 80 (0.53, 95%CI 0.36-0.78, p=0.0013) and FIL frail/unfit status (2.83, 95%CI 1.93-4.17, p<0.0001) were associated with survival; according to multivariable analysis, only KPS >80 (HR 0,56, 95%CI 0,37-0,85, p=0.0066) and FIL score (HR 2,20, 95%CI 1,27-3,78, p=0.0046) maintained significant associations with OS (Figure 2).
Conclusions. In a fairly large cohort of elderly patients (≥60 years) undergoing alloSCT at two European transplant centers, a multidimensional geriatric approach appears to be more accurate compared to a sole comorbidity assessment, in predicting alloSCT outcome and identifying patients at high risk of TRM. This simple tool could easily be applied before transplant for better patient selection and tailoring of treatment.
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Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.
Evaluation of elderly patients' eligibility for allogeneic stem cell transplantation (allo-SCT) is crucial. A comprehensive geriatric assessment (CGA) has demonstrated important prognostic value in ...hematology. However, its role in allo-SCT transplant setting has still to be defined.
To evaluate the feasibility and efficacy of the Fondazione Italiana Linfomi (FIL)-score, a combined comorbidity (CIRS-G) and functionality (ADL/IADL) score, on allo-SCT outcome.
This is a retrospective study involving 228 elderly (>60y) patients consecutively submitted to allo-SCT at our centers from 2008 to 2018. Median follow-up 36 months (range, 1-118).
The median age was 64 years (range, 60-76), and 155 (68%) were male. AML was the most common indication for transplant (53%), DRI was high/very-high in 42% of cases. A matched unrelated, sibling or alternative donor was utilized in 41%, 30%, and 29% of cases, respectively. Stem cell source was derived from peripheral blood in 82% of patients. Myeloablative conditioning regimen was reserved for only 20% of patients. Based on FIL score, available in 215 patients, 125 (58%) patients were classified as “fit” and 90 as “unfit/frail.” According to FIL score, fit patients were more frequently diagnosed with AML (p<0.001), belonged to lower DRI classes (p=0.002), had lower HCT-CI (p=0.02) and higher KPS (p<0.001). A total of 121 (53%) patients died after a median follow-up of 36 months (NRM 49%, relapse-related 51%). FIL score was found to highly predict survival, due to an excess of NRM in unfit/frail group, and confirmed its independent prognostic role on OS (HR 0.37; 95% CI 0.25-0.55; p<0.0001) and NRM (HR 0.34, 95% CI 0.19-0.58, p=0.0001). Interestingly, the HCI-CI failed in allo-SCT OS and NRM prediction (HR 1.06, 95% CI 0.96-1.16, p=0.27 and HR 1.02, 95% CI 0.87-1.21, p=0.78). As evaluated by the likelihood ratio test and C-statistics, FIL score showed a strong predictive value for OS and NRM (28.45 and 19.37; 0.637 SE 0.023 and 0.668 SE 0.032, respectively).
A comprehensive geriatric assessment with FIL score seems to add significant prognostic information in elderly patients submitted to allo-SCT. The pre-transplant adoption of this easy-to-use tool could help the patients' selection and management.
Radioimmunotherapy (RIT) after an induction phase with conventional chemoimmunotherapy became an attractive strategy of consolidation for patients with advanced follicular lymphoma: in particular, in ...many studies RIT was represented by yttrium‐90‐ibritumomab tiuxetan (90Y‐IT). Independently by the different front‐line treatment, updates on the long‐term follow‐up of these studies are needed because the disease course of follicular lymphoma is characterised by multiple relapses and progressively shorter durations of response. We report updated long‐term efficacy and toxicity results of a multicenter phase II study on sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by 90Y‐IT as front‐line therapy for untreated patients with intermediate/high‐risk follicular lymphoma. With a median follow‐up of 84 months, only 19/49 (38.8%) complete response patients relapsed, yielding an estimated long‐term disease‐free survival of 62.6%. The 7‐year overall survival was 72.7%. Four (7.3%) second acute myeloid leukemia occurred, with a median time following RIT of 42 months. A relevant patients' responsiveness to subsequent therapies occurred: approximately 65% of relapsed patients obtained a good clinical response after the second‐line treatment. These data represented the first evidence of a real role even in the long period of 90Y‐IT after a fludarabine‐containing regimen plus rituximab in the treatment of high‐risk follicular lymphoma.
Consolidation with radioimmunotherapy (RIT) after the induction phase including conventional chemoimmunotherapy became an attractive strategy for patients with advanced follicular lymphoma but updates of the long‐term outcomes of this approach are lacking. For this reason, we report updated long‐term efficacy and toxicity results of a sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by 90Y‐IT as a front‐line therapy for untreated patients with intermediate/high‐risk follicular lymphoma. These data represented the first evidence of a real role even in the long period of RIT after a fludarabine‐containing regimen plus rituximab in the treatment of high‐risk follicular lymphoma: a long‐term of disease‐free survival (63%) and a relevant patients' responsiveness to subsequent therapies.
The purpose of this study was to quantify perfusion in the area of choroidal neovascularization (CNV) using laser speckle flowgraphy (LSFG) before and after intravitreal anti-vascular endothelial ...growth factor (VEGF) injection.
Retrospective case series. Fifteen eyes of 15 patients with treatment-naïve CNV due to age-related macular degeneration (AMD) and with available LSFG images were included. The main outcome was the mean blur rate (MBR) quantified as a measure of perfusion within the CNV area observed on indocyanine green angiography. Twelve patients had available longitudinal data until one month after the injection, used to evaluate changes in perfusion, central macular thickness (CMT), visual acuity, and ocular perfusion pressure. Reproducibility of LSFG measurements was investigated at each time point from two images taken within five minutes.
Intraclass correlation coefficients for LSFG measurements were higher than 0.8 indicating excellent reproducibility. There was a significant decrease in perfusion after one week (-26.4 ± 14.4%;
= 0.027), whereas, after one month, perfusion was no longer significantly different from baseline (
= 0.121). CMT showed a progressive decrease over the follow-up period. Changes in perfusion were strongly correlated with changes in CMT after one week, but not thereafter.
This pilot study suggests a method to select a region in the CNV area to quantify perfusion using LSFG. MBR could represent a parameter possibly related to regrowth of the CNV after anti-VEGF treatment. Large-scale studies are needed to assess the usefulness of LSFG in defining re-treatment criteria for neovascular AMD.
LSFG technology to quantify perfusion could provide useful biomarkers for therapeutic management of CNV.
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