Streaming Aggregation using Reconfigurable Hardware

High throughput and low latency streaming aggregation is essential for many applications that analyze massive volumes of data in real-time. In many cases, high speed stream aggregation can be achieved incrementally by computing partial results for multiple windows. However, for particular problems, temporarily storing all incoming raw data to a single window before processing is more efficient or even the only option. This thesis presents the first FPGA-based single window stream aggregation designs for tuple-based and time-based windowing policies. The proposed approach is able to support challenging queries required in realistic stream processing problems. More precisely, holistic, distributive, and algebraic aggregation functions, as well as custom ones can be supported. Our designs offer aggregation for large number of concurrently active keys and handles large window sizes and frequent aggregations. Maxeler\u27s dataflow engines (DFEs), which suit well the stream processing characteristics, are used to implement the designs. DFEs have a direct feed of incoming data from the network as well as direct access to off-chip DRAM. The tuple-based single window DFE processes up to 8 million tuples-per-second (1.1 Gbps) offering 1-2 orders of magnitude higher throughput than a state-of-the-art stream processing software system. The processing latency is less than 4 usec, 4 orders of magnitude lower latency than software. The time-based single-window stream aggregation DFE offers high processing throughput, up to 150 Mtuples/sec, similar to related GPU systems, which however do not support both time-based and single windows. It also offers an ultra-low processing latency of 1-10 usec, at least 4 orders of magnitude lower than software-based solutions

Reconfigurable-Hardware Accelerated Stream Aggregation

High throughput and low latency stream aggregation is essential for many applications that analyze massive volumes of data in real-time. Incoming data need to be stored in a single sliding-window before processing, in cases where incremental aggregations are wasteful or not possible at all. However, storing all incoming values in a single-window puts tremendous pressure on the memory bandwidth and capacity. GPU and CPU memory management is inefficient for this task as it introduces unnecessary data movement that wastes bandwidth. FPGAs can make more efficient use of their memory but existing approaches employ only on-chip memory and therefore, can only support small problem sizes (i.e. small sliding windows and number of keys) due to the limited capacity. This thesis addresses the above limitations of stream processing systems by proposing techniques for accelerating single sliding-window stream aggregation using FPGAs to achieve line-rate processing throughput and ultra low latency. It does so first by building accelerators using FPGAs and second, by alleviating the memory pressure posed by single-window stream aggregation. The initial part of this thesis presents the accelerators for both windowing policies, namely, tuple- and time-\ua0based, using Maxeler\u27s DataFlow Engines\ua0(DFEs) which have a direct feed of incoming data from the network as well as direct access to off-chip DRAM. Compared to state-of-the-art stream processing software system, the DFEs offer 1-2 orders of magnitude higher processing throughput and 4 orders of magnitude lower latency. The later part of this thesis focuses on alleviating the memory pressure due to the various steps in single-window stream aggregation. Updating the window with new incoming values and reading it to feed the aggregation functions are the two primary steps in stream aggregation. The high on-chip SRAM bandwidth enables line-rate processing, but only for small problem sizes due to the limited capacity. The larger off-chip DRAM size supports larger problems, but falls short on performance due to lower bandwidth. In order to bridge this gap, this thesis introduces a specialized memory hierarchy for stream aggregation. It employs Multi-Level Queues (MLQs) spanning across multiple memory levels with different characteristics to offer both high bandwidth and capacity. In doing so, larger stream aggregation problems can be supported at line-rate performance, outperforming existing competing solutions. Compared to designs with only on-chip memory, our approach supports 4 orders of magnitude larger problems. Compared to designs that use only DRAM, our design achieves up to 8x higher throughput. Finally, this thesis aims to alleviate the memory pressure due to the window-aggregation step. Although window-updates can be supported efficiently using MLQs, frequent window-aggregations remain a performance bottleneck. This thesis addresses this problem by introducing StreamZip, a dataflow stream aggregation engine that is able to compress the sliding-windows. StreamZip deals with a number of data and control dependency challenges to integrate a compressor in the stream aggregation pipeline and alleviate the memory pressure posed by frequent aggregations. In doing so, StreamZip offers higher throughput as well as larger effective window capacity to support larger problems. StreamZip supports diverse compression algorithms offering both lossless and lossy compression to fixed- as well as floating- point numbers. Compared to designs using MLQs, StreamZip lossless and lossy designs achieve up to 7.5x and 22x higher throughput, while improving the effective memory capacity by up to 5x and 23x, respectively

Current and potential roles of immuno-PET/-SPECT in CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapies have evolved as breakthrough treatment options for the management of hematological malignancies and are also being developed as therapeutics for solid tumors. However, despite the impressive patient responses from CD19-directed CAR T-cell therapies, ~ 40%−60% of these patients' cancers eventually relapse, with variable prognosis. Such relapses may occur due to a combination of molecular resistance mechanisms, including antigen loss or mutations, T-cell exhaustion, and progression of the immunosuppressive tumor microenvironment. This class of therapeutics is also associated with certain unique toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and other “on-target, off-tumor” toxicities, as well as anaphylactic effects. Furthermore, manufacturing limitations and challenges associated with solid tumor infiltration have delayed extensive applications. The molecular imaging modalities of immunological positron emission tomography and single-photon emission computed tomography (immuno-PET/-SPECT) offer a target-specific and highly sensitive, quantitative, non-invasive platform for longitudinal detection of dynamic variations in target antigen expression in the body. Leveraging these imaging strategies as guidance tools for use with CAR T-cell therapies may enable the timely identification of resistance mechanisms and/or toxic events when they occur, permitting effective therapeutic interventions. In addition, the utilization of these approaches in tracking the CAR T-cell pharmacokinetics during product development and optimization may help to assess their efficacy and accordingly to predict treatment outcomes. In this review, we focus on current challenges and potential opportunities in the application of immuno-PET/-SPECT imaging strategies to address the challenges encountered with CAR T-cell therapies

An International Real-World Analysis of Relapsed/Refractory Lymphoma Occurring During Pregnancy

Cancer complicates ~1 in 1000 pregnancies, which translates into ~4000 cases annually in the United States. Lymphoma is the fourth most common malignancy and the most common hematological malignancy present during pregnancy. Although there are published reports of lymphoma occurring during pregnancy, most are among patients with newly diagnosed disease, and there is a near absence of data regarding the presentation, management, and maternal and neonatal outcomes of patients with relapsed/refractory lymphoma that occurs during pregnancy. [...

Evaluation of Ki-67 expression and large cell content as prognostic markers in MZL: a multicenter cohort study

Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression ( > 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 >20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03–2.05). Ki-67 > 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having >10% LC. The presence of LC was associated with high Ki-67 (p < 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining >20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT

Evaluation of Ki-67 Expression and Large Cell Content as Prognostic Markers in MZL: a Multicenter Cohort Study

Marginal zone lymphoma (MZL) can have varied presentations and pathologic features, including high Ki-67 expression ( \u3e 20%) as well as increased numbers of large B cells (LC). However, there are limited data available demonstrating the prognostic significance of these variables in patients with MZL. In this multi-institutional retrospective cohort study of patients with MZL treated at 10 centers, we evaluated the association between the presence of Ki-67 expression and increased LCs on survival and risk of histologic transformation (HT). A total of 785 patients were included (60% with extranodal MZL, 20% with nodal MZL, and 20% with splenic MZL). Among the 440 patients with Ki-67 staining, 22% had high Ki-67 (Ki-67 \u3e20%). The median progression-free survival (PFS) for patients with high Ki-67 was 5.4 years compared to 7.0 years for patients with low Ki-67 (HR = 1.45, 95%CI = 1.03-2.05). Ki-67 \u3e 20% strongly correlated with high LDH level. The risk of HT was higher in patients with increased Ki-67 than those without (5-year risk, 9.8% vs 3.87%, p = 0.01). Twelve percent of patients had LC reported on biopsy with 6% having \u3e10% LC. The presence of LC was associated with high Ki-67 (p \u3c 0.001), but not associated with shorter PFS or overall survival (OS). The cumulative risk for HT was higher in patients with LC compared to those without LC (5-year risk, 9.4% vs 2.9%, p = 0.04). Receipt of anthracycline-based therapy did not impact PFS or OS in either group. Ki-67 staining \u3e20% was a prognostic factor for worse survival and strongly correlated with elevated LDH. Novel therapies should be investigated for their potential ability to overcome the high-risk features in MZL. Our data reinforce the importance of obtaining biopsies at relapse or progression, particularly in patients with baseline high Ki-67 and increased LCs, given their increased risk for HT

Impact of Age on Biology, Presentation and Outcomes in Marginal Zone Lymphoma: Results From a Multicenter Cohort Study

Given the paucity of age-specific data about biology, presentation, and treatment outcomes in adults with MZL, we sought to evaluate differences between younger (≤ 70 years) and older (\u3e 70 years) patients with MZL in a large retrospective cohort treated in the contemporary era (2010 onwards). The primary objective was progression-free survival (PFS), while secondary objectives included the evaluation of overall survival (OS) and the cumulative incidence of transformation between the 2 groups. A total of 598 patients were included in the analysis and among these 32% were \u3e 70 years of age. There were no age-based differences in the prevalence of NMZL, SMZL, and EMZL. Older patients had a higher incidence of adverse prognostic features at diagnosis such as worse performance status, advanced stage disease, and bone marrow involvement, yet were more likely to be treated with single-agent rituximab than chemoimmunotherapy. Age \u3e 70 years was associated with inferior PFS and OS after controlling for clinically relevant risk factors and accounting for differences in first-line treatment. Receipt of rituximab monotherapy was associated with significantly inferior PFS overall, however, the type of first-line therapy did not impact OS in any group. Our data suggests that despite the development of new drugs for MZL, age remains an independent predictor of inferior outcomes. Investigation of targeted therapy combinations in the first-line setting may yield the required balance of efficacy and toxicity in older adults with MZL

Impact of Detectable Monoclonal Protein at Diagnosis on Outcomes in Marginal Zone Lymphoma: A Multicenter Cohort Study

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein at diagnosis. After adjusting for factors associated with inferior PFS in univariate models, presence of M-protein remained significantly associated with inferior PFS (hazard ratio, 1.74; 95% confidence interval, 1.20-2.54; P = .004). We observed no significant difference in the PFS based on the type or quantity of M-protein at diagnosis. There were differential outcomes in PFS based on the first-line therapy in patients with M-protein at diagnosis, in that, those receiving immunochemotherapy had better outcomes compared with those receiving rituximab monotherapy. The cumulative incidence of relapse in stage 1 disease among the recipients of local therapy was higher in the presence of M-protein; however, this did not reach statistical significance. We found that M-protein at diagnosis was associated with a higher risk of histologic transformation. Because the PFS difference related to presence of M-protein was not observed in patients receiving bendamustine and rituximab, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further

Impact of Early Relapse within 24 Months after First-Line Systemic Therapy (POD24) on Outcomes in Patients with Marginal Zone Lymphoma: A US Multisite Study

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis