Myeloma Patients with Deletion of 17p: Impact of Tandem Transplant and Clone Size

Introduction The presence of deletion 17p or monosomy 17 (del(17p)/-17) detected by fluorescence in situ hybridization (FISH) is well-established as a high-risk (HR) factor in multiple myeloma (MM). The del(17p)/-17 clone size and the clinical impact in patients that have ≥60% involved nuclei is controversial. Optimal treatment is also controversial, with tandem autologous stem cell transplantation (ASCT) explored but not uniformly adopted in the real world (ENM02, StaMMina). At our center, we have routinely offer tandem transplantation for del(17p)/-17 and now review our experience over a 10-year period, including the significance of del(17p)/-17 genetic variations on outcomes. Methods We performed a retrospective chart review of all patients identified with del(17p)/-17 patients who were offered tandem transplant and underwent at least one ASCT at Princess Margaret Cancer Centre from 2009-2019. Patient and disease characteristics, responses, and survival outcomes were collected from the Myeloma and Transplant databases and electronic patient records under REB approval. Results Patient, disease, and treatment characteristics. We identified 100 patients with del(17p)/-17 who underwent ASCT at our center. These patients were separated into three groups: those with a deletion of the TP53 locus (57%), those that had monosomy 14 (17%), and those with a relative loss the TP53 locus (eg. aneusomy or polyploidy,13%). The median % of nuclei with del(17p) was 39% (range 5-93%), with 27 (25%) over 60%. 28% of patients carried at least one other cytogenetic abnormality besides del(17p), most commonly t(4;14). All patients were intended for tandem transplant, but only 69 (69%) completed both transplants. Reasons for not proceeding to a second transplant were: patient declined (29%), toxicity (26%), clinical trial (19%), progression prior to the second transplant (13%), with one early death (3%). Median age at transplant was 61 years (range 40-72); most were male (61%) with advanced R-ISS II and III (97%). The most common induction regimen used was cyclophosphamide, bortezomib and dexamethasone (CYBORD)(87%), with 10% requiring a 2 nd induction regimen for inadequate response/progression. Standard conditioning was melphalan 200mg/m 2 for both first and second transplants. Median time from diagnosis to first ASCT was 5.9 months (range 3-24) and time from first to second transplant was 3.3 months (range 1-7). Most patients (90; 84%) received maintenance therapy post-transplant: 47% lenalidomide, 29% multiple agents (commonly lenalidomide and a proteasome inhibitor) Response and survival outcomes After induction, the rate of VGPR (very good partial response) or greater was 53%, increasing to 73% after 1 st ASCT, 85% after 2 nd ASCT. At a median follow-up of 32 months (range 3-130), the median PFS for all patients was 39.2 months 95% CI (24.1-46) and median OS was not yet reached (NYR) (95% CI 57.9-NYR). When analyzed by whether single or tandem transplant was performed, median PFS was 21.8 months (95% CI 10.3-43.3) for single ASCT, and 42.1 months (95% CI 32.8-NYR) for tandem ASCT (P=0.0096). The median OS was 57.6 months for single ASCT (95% CI 22.2-86.5), but NYR for tandem ASCT (95% CI 105.6-NYR) (p=0.0022). On subgroup analysis, patients with ≥60% del(17p) achieved a median PFS 45 months (95% CI 14.4-NYR) and median OS 68.5 months (95% CI 20.9-68.5), median was only PFS 24.9 months (95% CI0.4-NYR) and median OS 29.3 months (95% CI 0.4-68.5) for those who received single ASCT. (table1) TP53 signal pattern analysis (table 2) showed the median OS for patients with monosomy 17 was NYR, while it was 105.7 months for patients with deletion, and 86.5 months for those with relative loss. Median PFS was 43.3 months for the monosomy group, 32.8 months for deletion group, and NYR for relative loss. Conclusions Our experience shows that MM patients with del(17p)/-17 appear to have deeper responses and improved outcomes with more aggressive tandem transplantation. However, approximately 1/3 of our patients intended for tandem transplant did not undergo a second transplant, identifying a focus of future investigation and optimization. Our analysis also suggests that clone size of del(17p) >60% does impact OS negatively, but improved with tandem transplantation. The type of deletion also appears to affect outcomes with deletion having worse PFS but not worse OS. Figure 1 Figure 1. Disclosures Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Reece: Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; Sanofi: Honoraria; BMS: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria. Trudel: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Roche: Consultancy; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding. Chen: Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.

Preliminary Study on the Loss Laws of Bearing Capacity of Tunnel Structure

The bearing capacity of the tunnel structure is the essential basis for the structural safety of tunnel engineering. Due to the unpredictability and uncertainty in the tunnel’s surrounding environment, a systematic and unambiguous study on the bearing capacity of the tunnel structure is still lacking. The analysis framework of the bearing capacity of the tunnel structure is discussed and a method describing the bearing capacity loss of the tunnel structure is proposed in this paper. Furthermore, the loss laws of the tunnel structure bearing capacity under various characteristic factors are preliminarily investigated, and suggestions on the research of bearing capacity are put forward. First, the current research contents and methods of the tunnel structure technical status, mechanical characteristics, and bearing performance (directly mentioned) are summarized, the relevant concepts related to tunnel structure bearing capacity are analyzed, and it is clarified that the bearing capacity loss of the tunnel structure can be considered according to the technical status of lining damage preliminary. Then, based on analysis of main causes and influence path of the bearing capacity loss, the influencing factors of the bearing capacity of the tunnel structure are attributed to external load action (i.e., all external causes acting on the tunnel structure in the form of external loads) and material deterioration (i.e., all internal causes leading to the decrease in mechanical properties such as structure strength/stiffness). Several typical factors are listed with specific examples, respectively. Considering the uncertainty of the absolute value of the bearing capacity caused by the surrounding environment of the tunnel, a method describing the bearing capacity of the tunnel structure using relative loss rate and relative value of index is proposed based on the current relevant analysis data of mechanical characteristics of the tunnel structure. Based on the given definitions and rules, the related data on the quantitative analysis of mechanical characteristics of lining structure reported in the literature are statistically analyzed again from the view of loss laws of the bearing capacity. Taking three factors including crack, insufficient lining thickness, and cavity as examples, the corresponding model of the bearing capacity loss is preliminarily analyzed and interpreted. The simplest linear model can be employed to preliminarily describe the relationship between defect indexes and relative loss rate of the bearing capacity, especially pertinent mechanical data collected from numerical analysis. Moreover, the loss laws of the bearing capacity in practical analysis and model tests (especially when the variation range of factors is wide) can be simulated by a logistic growth model. Through the analysis of the typical factor model, the key points of the research on the bearing capacity of the tunnel structure are discussed, and some suggestions are put forward for the follow-up related research.

A New Class of Estimators Based on a General Relative Loss Function

Motivated by the relative loss estimator of the median, we propose a new class of estimators for linear quantile models using a general relative loss function defined by the Box–Cox transformation function. The proposed method is very flexible. It includes a traditional quantile regression and median regression under the relative loss as special cases. Compared to the traditional linear quantile estimator, the proposed estimator has smaller variance and hence is more efficient in making statistical inferences. We show that, in theory, the proposed estimator is consistent and asymptotically normal under appropriate conditions. Extensive simulation studies were conducted, demonstrating good performance of the proposed method. An application of the proposed method in a prostate cancer study is provided.

Migration and changing law of PHC content under the action of ocean current

According to the survey dataset of the waters of Jiaozhou Bay in May 1993, this paper studies the migration and changing process of PHC content caused by marine oil spill in the waters of Jiaozhou Bay. In May, take the center of eastern waters, H3107, as the source of marine oil spill, where PHC content is 51.00μg/L. Then a series of concentric circles with different gradients are formed with H3107 station as the center. The PHC content decreases from the high content of 51.00μg/L in the center to the surroundings along the gradient, to 4.16μg/L in the waters of bay mouth, 31.60μg/L in the central waters of the bay, 27.00μg/L in the northern waters, and 48.40μg/L in the northeast waters. According to the horizontal absolute loss rate model of material content, it can be calculated that the value of horizontal absolute loss rate of PHC content in the surface layer of the water body from the eastern center to the bay mouth in May is calculated to be 0.44 Yang Dongfang absolute number; to the central waters of the bay, 0.13 Yang Dongfang absolute number; to the northern waters of the bay, 0.33 Yang Dongfang absolute number; to the northeastern waters of the bay, 0.06 Yang Dongfang absolute number. According to the horizontal relative loss rate model of material content, it is calculated that in May, from the eastern central waters to the waters of bay mouth, the horizontal relative loss rate of PHC content in the surface layer of water body is 8.67 Yang Dongfang relative number; to the central waters of the bay, 2.72 Yang Dongfang relative number; to the northern waters of the bay, 6.47 Yang Dongfang relative number; to the northeastern waters of the bay, 1.33 Yang Dongfang relative number. Therefore, taking H3107, the central point in the eastern part of Jiaozhou Bay, as the source of marine oil spills, its PHC content decreases to the surroundings, whose horizontal absolute loss rate is within 0.06–0.44 Yang Dongfang absolute number and the horizontal relative loss rate is within 1.33–8.67 Yang Dongfang relative number. The order of the horizontal absolute (relative) loss rate of PHC content from low to high is: waters in the northeast of the bay < waters in the bay center < waters in the north of the bay < waters in the bay mouth. The Yang Dongfang horizontal loss rate model of material content reveals the migration and changing law of PHC content during the process of ocean current carrying PHC content: 1) In the downstream direction of the ocean current, the PHC content decreases at the slowest rate, and its loss is the smallest during the migration process. In the countercurrent direction of the ocean current, the PHC content declines the fastest, and the loss is greatest during the migration process. 2) In the downstream direction of the ocean current, as the migration distance continues to increase, the PHC content continues to decline and its loss is gradually increasing during the migration process. 3) In waters where the ocean current does not pass, the PHC content decreases slowly, and the PHC content reaches a relatively high value. During the migration process, its loss is relatively small. The PHC content reaches the waters where the ocean current does not pass, and the loss content is between the loss of the PHC content carried by the ocean current in the downstream direction and the upstream direction.

Chemical Weathering, First Cycle Quartz Sand, and its bearing on Quartz Arenite

A self-consistent set of experimentally determined rates of mineral dissolution (Francke, 2009) has been used to estimate the relative loss of common constituents of plutonic igneous rocks that supply quartz to sands to be lithified as first-cycle quartz arenite. A first-order decay equation is used setting the decay constant of calcite to one, which renders the time-steps of loss dimensionless but keeps the relative loss of each mineral constant. Calculations show that 99.33% of pure calcite would dissolve only after 5 time-steps. On a relative scale, it would take about 1250, 900, and 1040 time-steps respectively to reduce the original compositions of quartz-bearing mafic plutonic, granodioritic, and granitic rocks to leave >95% undissolved quartz as residue that will qualify as quartz-sand, the precursor to first-cycle quartz arenite. These are very large numbers indicating that chemical dissolution alone, as in chemical weathering by itself, is not sufficient to generate first-cycle quartz sand; accompanied mechanical weathering is necessary. Therefore, it is necessary to re-evaluate many explicitly stated inferences of warm, humid climate in provenance studies of first-cycle quartz arenites.

The statistical importance of a study for a network meta-analysis estimate

Background: In pairwise meta-analysis, the contribution of each study to the pooled estimate is given by its weight, which is defined based on the inverse variance of the estimate from that study. For network meta-analysis (NMA), the contribution of direct (and indirect) evidence is easily obtained from the diagonal elements of the hat matrix. It is, however, not fully clear how to generalize this to the percentage contribution of each study to a NMA estimate. Methods: After briefly discussing available approaches, we want to question whether it is possible to obtain unique percentage contributions and discuss another approach. We define the importance of each study for a NMA estimate by the reduction of the estimate's variance when adding the given study to the others. An equivalent interpretation is the relative loss in precision when the study is left out. Results: Importances are values between 0 and 1. An importance of 1 means that the study is an essential link of the pathway in the network connecting one of the treatments with the other. These numbers in general do not add to one and thus cannot be interpreted as `percentage contributions'. Conclusions: Importances generalize the concept of weights in pairwise meta-analysis in a natural way. Moreover, they are uniquely defined, easily calculated, and have an intuitive interpretation. We give some real examples for illustration.

Estimating the longevity of glaciers in the Xinjiang region of the Tian Shan through observations of glacier area change since the Little Ice Age using high-resolution imagery

Glacial retreat in response to warming climates in the arid Xinjiang region of northwestern China directly impacts downstream water resources available for local communities. We used high-resolution satellite imagery from 1969 to 2014 to delineate spatial changes in 54 active glaciers in the upper Kaidu River Basin in the Tian Shan as well as their past expanses during the Little Ice Age (LIA). We manually delineated their boundaries based on the interpretation of glacial, geomorphic and topographic features. From the total glacier surface area, we estimated glacier volume and mass. From 1969 to 2014, glacier area decreased by 10.1 ± 1.0 km2 (relative loss of 34.2 ± 3.5%) and mass by 1.025 ± 0.108 Gt (relative loss of 43 ± 4.6%). From the LIA maximum (est. 1586 CE) to 1969, relative losses were less (25.7 ± 4.3% area loss and 33.1 ± 5.7% mass loss). Our results indicate that glacier recession is accelerating over time and that the glaciers are currently losing over 1.5 times more relative area than elsewhere in the Tian Shan. Using linear and non-linear projections, we estimate that these glaciers may disappear between 2050 and 2150 CE if climatic warming continues at the same pace.