Dingli, David

The cellular age distribution of hierarchically organized tissues can reveal important insights into the dynamics of cell differentiation and self-renewal and associated cancer risks. Here, we examine the effect of progenitor compartments with varying differentiation and self-renewal capacities on the resulting observable distributions of replicative cellular ages. We find that strongly amplifying progenitor compartments, i.e. compartments with high self-renewal capacities, substantially broaden the age distributions which become skewed towards younger cells with a long tail of few old cells. For several of these strongly amplifying compartments, the age distribution becomes virtually independent of the influx from the stem cell compartment. By contrast, if tissues are organized into many downstream compartments with low self-renewal capacity, the shape of the replicative cell distribution in more differentiated compartments is dominated by stem cell dynamics with little added variation. In the limiting case of a strict binary differentiation tree without self-renewal, the shape of the output distribution becomes indistinguishable from that of the input distribution. Our results suggest that a comparison of cellular age distributions between healthy and cancerous tissues may inform about dynamical changes within the hierarchical tissue structure, i.e. an acquired increased self-renewal capacity in certain tumours. Furthermore, we compare our theoretical results to telomere length distributions in granulocyte populations of 10 healthy individuals across different ages, highlighting that our theoretical expectations agree with experimental observations.

AbstractSymptomatic hyperviscosity is a well‐established phenomenon in Waldenström macroglobulinemia (WM). Monoclonal IgM can variably impact intrinsic serum viscosity, leading to widely disparate symptomatic thresholds for development of hyperviscosity‐related symptoms. Data regarding the predictors of symptomatic hyperviscosity and outcomes related to this complication remain scarce and a recent study proposed that IgM >6000 mg/dL be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre‐empt hyperviscosity‐related injury. Herein, we attempt to identify predictors of the development of symptomatic hyperviscosity and its impact in patients with WM. Of 997 WM patients evaluated from January, 1996 through June, 2017, symptomatic hyperviscosity was observed in 130 (13%) patients. Overall survival (OS) of these 130 patients was similar to that of patients without symptomatic hyperviscosity (median: 11.5 vs 11.6 years; P = 0.63). On multivariate‐analysis, only viscosity >1.8 cp (risk ratio: 4.0, P = 0.02) assessed at the time of WM diagnosis was an independent predictor for the development of subsequent symptomatic hyperviscosity. Among patients with smoldering WM and IgM >6000 mg/dL at diagnosis (n = 13) who were managed expectantly, the median time‐to‐initial therapy was 6.9 years and only 15% developed hyperviscosity‐related symptoms subsequently. In summary, the occurrence of symptomatic hyperviscosity does not impact OS. Serum viscosity at diagnosis of WM, and not IgM concentration, represents the single most important independent predictor for development of subsequent hyperviscosity‐related symptoms. Patients with smoldering WM and high serum IgM can be safely observed in the absence of any indications per the Consensus recommendations to initiate WM‐directed therapy.

Abstract Introduction: Hyperdiploidy on FISH portends a good prognosis in myeloma. We compared hyperdiploidy determined by MFC to that by conventional FISH. Methods: We studied 1711 patients with plasma cell disorders who had simultaneous FISH and DNA index testing. Monotypic plasma cells in bone marrow are identified by MFC with antibodies to CD19, CD38, CD45, CD138, kappa and lambda; followed by staining by DAPI. DNA index is determined by dividing the measured DNA content of the G0/G1 abnormal plasma cells by the DNA content of the normal G0/G1 plasma cells present. Plasma cells with DNA content index of <0.95 are hypodiploid and G0/G1 DNA content index of >1.05 are considered hyperdiploid. Results: Distribution DNA index and FISH results are described in Table 1. Sensitivity and specificity of DNA index by hyperdiploidy was 86% and 83%. Cohen's Kappa coefficient for concordance was 0.69. Sensitivity increased to 94% for those with 2 or more trisomies and 97% for 3 or more trisomies. Of the 104 patients with trisomy and non-hyperdiploid DNA index, 62% patients had monosomy (mono) or deletion (del) 13q. Overall, DNA index was lower in patients with mono 13/del 13q (1.01; 0.97-1.11) compared to those without (1.07; 1.0-1.19), p<0.001. After excluding patients with mono 13/del 13q, sensitivity and specificity of hyperdiploidy by DNA index were 92% and 82%, kappa = 0.73. Hyperdiploidy was seen in 55% of 272 patients with newly diagnosed myeloma. Sensitivity and specificity were 88% and 93%, kappa = 0.78. After median follow-up of 2.3 yrs, those with hyperdiploid DNA index had better progression free survival at 2,3 and 5 years, 62%, 45% and 21% compared to 50%, 33% and 13% in non-hyperdiploid group, p=0.05. Median overall survival (OS) was not reached; estimated 2, 3 and 5 year OS was 83%, 76% and 63% vs. 76%, 64% and 44%, respectively; p=0.08. Conclusions: DNA index by MFC is a rapid method to determine hyperdiploidy, with potential for replacing trisomy testing by FISH, especially when coupled with monosomy FISH probes. Hyperdiploid N=768 n/N (%)Diploid N=762 n/N (%)Hypodiploid N=78 n/N (%)P1P2Any trisomy 619/765 (81)96/758(13)8/76 (11)<0.001<0.001One chromosome42587733191429-111362Others12204Two chromosomes8525-Three or more chromosomes492131Any translocation124/744 (17)566/748 (76)53/74 (72)<0.001<0.001t(4;14)106313t(11;14)2240127t(14;16)5325t(14;20)38-t(6;14)8104Unknown partner76524Trisomy + Translocation95/743 (13)60/744 (8)6/74 (8)0.0090.002Monosomy 13/17 or deletion 13q/17p252/759 (33)295/744 (40)54/74 (73)<0.0010.0001Monosomy 13/Deletion 13q208/717 (29)282/718 (39)20/70 (29)Monosomy 17/Deletion 17p70/749 (9)50/735 (7)20/72 (28)P1= three groups; P2= hyperdiploid vs. non-hyperdiploid Citation Format: Surbhi Sidana, Nidhi Tandon, Dragan Jevremovic, Rhett P. Ketterling, Angela Dispenzieri, Morie A. Gertz, Francis K. Buadi, Martha Q. Lacy, William Morice, Curtis A. Hanson, Michael Timm, Patricia Greipp, Linda B. Baughn, David Dingli, Suzanne R. Hayman, Wilson I. Gonsalves, Prashant Kapoor, Robert A. Kyle, Nelson Leung, Ronald S. Go, John A. Lust, S.Vincent Rajkumar, Shaji K. Kumar. Hyperdiploidy in plasma cell disorders using multi-parametric flow cytometry (MFC) vs. FISH [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 655.

Abstract The use of replication-competent viruses as oncolytic agents is rapidly expanding, with several oncolytic viruses approved for cancer therapy. As responses to therapy are highly variable, understanding the dynamics of therapy is critical for optimal application of virotherapy in practice. Although mathematical models have been developed to understand the dynamics of tumor virotherapy, a scarcity of in vivo data has made difficult parametrization of these models. To tackle this problem, we studied the in vitro and in vivo spread of two oncolytic measles viruses that induce expression of the sodium iodide symporter (NIS) in cells. NIS expression enabled infected cells to concentrate radioactive isotopes that could be reproducibly and quantitatively imaged using SPECT/CT. We observed a strong linear relationship in vitro between infectious virus particles, viral N and NIS gene expression, and radioactive isotope uptake. In vivo radioisotope uptake was highly correlated with viral N and NIS gene expression. Similar expression patterns between viral N and NIS gene expression in vitro and in vivo implied that the oncolytic virus behaved similarly in both scenarios. Significant titers of viable virus were consistently isolated from tumors explanted from mice that had been injected with oncolytic measle viruses. We observed a weaker but positive in vivo relationship between radioisotope uptake and the viable virus titer recovered from tumors; this was likely due to anisotropies in the viral distribution in vivo. These data suggest that methods that enable quantitation of in vivo anisotropies are required for continuing development of oncolytic virotherapy. Significance: These findings address a fundamental gap in our knowledge of oncolytic virotherapy by presenting technology that gives insight into the behavior of oncolytic viruses in vivo. Cancer Res; 78(20); 5992–6000. ©2018 AACR.