THE DYNAMICAL U(n) QUANTUM GROUP Koelink, Erik; Van Norden, Yvette
International Journal of Mathematics and Mathematical Sciences,
2006, Letnik:
2006, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We study the dynamical analogue of the matrix algebra M ( n ), constructed from a dynamical R ‐matrix given by Etingof and Varchenko. A left and a right corepresentation of this algebra, which can be ...seen as analogues of the exterior algebra representation, are defined and this defines dynamical quantum minor determinants as the matrix elements of these corepresentations. These elements are studied in more detail, especially the action of the comultiplication and Laplace expansions. Using the Laplace expansions we can prove that the dynamical quantum determinant is almost central, and adjoining an inverse the antipode can be defined. This results in the dynamical GL( n ) quantum group associated to the dynamical R ‐matrix. We study a ∗‐structure leading to the dynamical U ( n ) quantum group, and we obtain results for the canonical pairing arising from the R ‐matrix.
•Previous research often conclude that car drivers fail to yield to motorcycles (MCs).•However, these studies do not take differences in exposure into account.•We circumvented this by analysing ...relative crash causes on intersections.•In many scenarios car drivers do not fail to yield to MCs more often than to cars.•Only when the car makes a left turn, drivers fail to yield to MCs relatively often.
The most common type of conflict in which a motorcyclist is injured or killed is a collision between a motorcycle and a car, often in priority situations. Many studies on motorcycle safety focus on the question why car drivers fail to give priority and on the poor conspicuity of motorcycles. The concept of ‘looked-but-failed-to-see’ crashes is a recurring item. On the other hand, it is not entirely unexpected that motorcycles have many conflicts with cars; there simply are so many cars on the road. This paper tries to unravel whether – acknowledging the differences in exposure – car drivers indeed fail to yield for motorcycles more often than for other cars. For this purpose we compared the causes of crashes on intersections (e.g. failing to give priority, speeding, etc.) between different crash types (car–motorcycle or car–car). In addition, we compared the crash causes of dual drivers (i.e. car drivers who also have their motorcycle licence) with regular car drivers. Our crash analysis suggests that car drivers do not fail to give priority to motorcycles relatively more often than to another car when this car/motorcycle approaches from a perpendicular angle. There is only one priority situation where motorcycles seem to be at a disadvantage compared to cars. This is when a car makes a left turn, and fails to give priority to an oncoming motorcycle. This specific crash scenario occurs more often when the oncoming vehicle is a motorcycle than when it is a car. We did not find a significant difference between dual drivers and regular car drivers in how often they give priority to motorcycles compared to cars.
Introduction:
About one third of all patients with Chronic Lymphocytic Leukemia (CLL) have quasi-identical, so-called stereotyped B-cell receptors (BCR) that can be divided into subsets ...(Agathangelidis et al. Blood 2012). At present, 19 major subsets have been described that account for approximately 12% of all patients with CLL. Of these, subsets #1 and #2 are associated with a poor prognosis (Baliakas et al. Lancet Hematology 2014). The HOVON68 trial compared fludarabine and cyclophosphamide (FC) chemotherapy to chemo-immunotherapy with low-dose alemtuzumab (FCA) as a first line treatment in selected high risk patients defined as either harboring 17p deletion, 11q deletion, trisomy 12, having unmutated mmunoglobulin heavy variable genes (IGHV) and/or VH3-21. The study showed a benefit of adding low-dose alemtuzumab to FC (Geisler et al. Blood 2014). Here, we studied the impact of BCR stereotypy subsets on the primary outcome progression free survival (PFS) and overall survival (OS).
Methods:
Sequences from IGHV mutational analyses were collected from participating centers in Sweden, Norway, Finland, Denmark, and the Netherlands. Subsets were assigned based on the ARResT/AssignSubsets software (Bystry et al. Bioinformatics 2015). Analysis for recurrent mutations were performed by next generation sequencing by a 454 based platform (Roche Diagnostics Corporation, Indianapolis, USA). All other clinical data were extracted from the HOVON database as of November 2016. Kaplan-Meier curves, log-rank tests, and Cox regression models were used for survival analysis. Fisher's exact test was used for contingency table analysis. P-values < 0.05 were considered statistically significant.
Results:
A total of 187 sequences were available. Of these, 176 were suitable for analysis. We found a total of 37 patients (21%) that could be assigned to one of the 19 major subsets: Subset #2 was the most frequent (n=12, 6.8%), thereafter subset #8 (n=7, 4.0%), subset #6 (n=6, 3.4%), and subset #1 (n=5, 2.8%). The median follow-up time for patients still alive was 78.6 months. By November 2016, 148 patients (84%) had had an event (no response to treatment, progression, or death) and 77 patients (44%) had died.
Compared to patients belonging to other major subsets, patients with subset #2 did not differ significantly as to: age group above 65 years, gender, treatment arm, cytogenetic aberrations by FISH, WHO performance status, beta2microglobulin level>3.5 mg/L, or in complete response rates, However, patients with subset #2 had more advanced disease (Binet stage C 83% vs. 52%, p=0.04) and as expected less often unmutated IGHV genes (67% vs. 100%, p=0.01). Nineteen of 37 patients (51%) was analyzed for recurrent mutations: Only SF3B1 mutations was found in patients with subset #2, and the frequency was slightly higher compared to other major subsets (57% vs. 17%, p=0.13), in whom also KRAS2 (17%) and BRAF15 (8%) mutations was found.
Unexpectedly, patients with subset #2 had a longer PFS compared to patients with other major subsets (median PFS #2: 51.2 months vs. other major #: 31.1 months, p=0.002, Figure), or compared to patients with usage of the same IGHV gene (e.g. median PFS for 7 patients with VH3-21/non #2: 15.4 months, p<0.05, data not shown). Furthermore, by Cox regression analysis, belonging to subset #2 was favorable for PFS compared to other major subsets, also when adjusting for treatment arm in the analysis (subset #2 HR: 0.22 0.08-0.57, p=0.002; FCA HR=0.37 0.17-0.78, p=0.01). Generally, patients belonging to a major subset did not differ as to PFS compared to other patients (median PFS major subset: 37.1 months vs. non major subset: 37.2 months, p=0.46). As to OS, no significant differences between groups were found.
Discussion and conclusions:
As expected, stereotypy was found more frequently in the HOVON68 trial that selected for high risk patients as compared to patients from large multi-institutional studies (Stamatopoulos at al. Leukemia 2017). Surprisingly, patients belonging to subset #2 had a better PFS after chemo-(immuno) therapy compared to other major subsets, albeit the numbers are small. Our data suggest that, chemo-(immuno) therapy may still have a place for patients otherwise assessed as ‘high risk’ such as patients with B-cell receptor stereotypy subset #2. Thus, selection of patients for trials as well as the exact treatment regimen may have major impact on the significance of biomarkers.
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Vojdeman:Roche: Other: Travel support in 2015; Gilead: Other: Travel support. Kimby:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Research Funding; Pfizer: Research Funding. Van Oers:Roche: Consultancy; ISA therapeutics: Consultancy; Novartis: Consultancy; Immunicum: Consultancy. Kater:Celgene: Consultancy, Research Funding; Johnson & Johnson: Research Funding; Abbvie: Research Funding. Niemann:Roche: Consultancy, Other: Travel grant; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Novo Nordisk Foundation: Research Funding; The Danish Cancer Society: Research Funding; Novartis: Other: Travel grant; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding.
Introduction:
Although the majority of Acute Myeloid Leukemia (AML) patients achieve a complete morphological remission (CR) after induction therapy, relapse rates remain high. Molecular Minimal ...Residual Disease (MRD) detection by PCR-based technologies has been shown to improve relapse prediction but has been restricted to specific genetically-defined subsets of AML only. Next-Generation Sequencing (NGS) has the advantage that it allows for the assessment of a broad range of disease-related gene mutations in a single assay. Residual leukemia-specific mutations in bone marrow in morphological CR after induction therapy are supposed to represent the source of relapse. However, persistent mutations may also represent clonal hematopoiesis, analogous to age-related clonal hematopoiesis of indeterminate potential (CHIP) present in healthy individuals. It is currently unknown which and to what extent the persisting somatic mutations after induction therapy contribute to AML relapse. Here, we present a comprehensive study, detailing the value of molecular MRD detection by NGS, in a large prospective cohort of newly diagnosed AML.
Methods:
482 AML patients (<65 years) were treated with 2 cycles of standard induction chemotherapy followed by consolidation in HOVON-SAKK clinical trials (www.hovon.nl). NGS was performed to detect mutations in a panel of 54 genes frequently mutated in myeloid malignancies (Illumina) at diagnosis and in bone marrow in morphological CR after completion of induction therapy. Thompson-Tau outlier testing was performed to reliably detect persisting mutations above background error rates. The primary and secondary endpoints of the study were relapse and overall survival, respectively. To establish and subsequently test our definition of NGS MRD, the cohort was split into a representative training (n=283) and validation cohort (n=147). The Cumulative Incidence of Relapse (CIR) was estimated with competing-risks regression analyses according to the method of Fine & Gray. The Cox proportional hazard model was used to calculate overall survival estimates. P-values <0.05 were considered significant.
Results:
In 430 out of 482 (89.2%) AML patients somatic driver mutations were present at diagnosis. In 51.4% of subjects persisting mutations were detected in bone marrow in morphological CR at highly variable variant allele frequencies (VAF 0.0002-0.47), predominantly persisting in DNMT3A (78.7%), TET2 (54.2%) and ASXL1 (51.6%). These persistent mutations in DNMT3A, TET2 and ASXL1 (DTA) in the training cohort did not associate with the incidence of relapse at any VAF cut-off, indicating a stage of clonal hematopoiesis rather than a condition of impending relapse. In contrast, in the subset of AML patients with persisting DTA mutations, a significant correlation with relapse was observed when any other persistent non-DTA mutation was considered (training cohort: 5-years CIR 76.4% vs. 39.4%; p=0.002). In the training cohort NGS MRD, as defined by persistent non-DTA mutations, was found to be highly associated with the risk of relapse (SHR:1.85 95%CI 1.27-2.70; p=0.001), which was confirmed in the validation set (SHR:2.81 95%CI 1.64-4.79; p<0.001) (Fig. 1). In fact, NGS MRD was significantly associated with CIR when the training and validation series were combined (5-years CIR 58.3% versus 33.9% (p<0.001)) (Fig. 2). In addition, NGS MRD predicted for reduced survival in both cohorts (training: HR:1.64 95%CI 1.12-2.42; p=0.012 and validation: HR:3.08 95%CI 1.87-5.08; p<0.001). Finally, multivariable analysis including the data of all 430 AML patients, with adjustment for age, WBC, ELN2017 risk and number of induction cycles needed to achieve CR, revealed that NGS MRD expresses profound independent prognostic significance for relapse (SHR:1.89 95%CI:1.34-2.65; p<0.001) and overall survival (HR:1.64 95%CI:1.18-2.27; p=0.003). In sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation NGS MRD remained highly prognostic for relapse and survival.
Conclusions:
In an unprecedentedly large prospective study including training and validation cohorts, targeted NGS MRD detection is established as a powerful and independent predictor for relapse and survival. NGS MRD is applicable in virtually all newly diagnosed adults with AML while persistent CHIP-related mutations lack prognostic value.
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Ossenkoppele:J&J: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; Roche: Honoraria; Novartis: Research Funding.
Introduction. Since publication of the pivotal CLL011 phase 3 trial, combination of chlorambucil and anti-CD20 MAb has become the standard first-line CLL treatment for patients unfit for FCR. ...Lenalidomide (Len) has been proven effective both as monotherapy and in combination with rituximab. Although recent studies in CLL suggest that Len is mostly beneficial as consolidation treatment, the exact place and duration of this drug is still not optimized. Moreover, Len has shown a distinct and more difficult to manage toxicity profile in the context of CLL, potentially hampering combination treatment with this drug. We therefore conducted a phase 2 study to evaluate efficacy and safety of a combination of chlorambucil, rituximab and individual dosed Len (induction-I) followed by 6 months of Len monotherapy (induction-II).
Methods. Treatment-naïve patients were eligible for this study if they had treatment indications per IWCLL 2008 criteria, WHO PS ≤2 and adequate hepatic and renal function. Initially, a phase 1 study was performed to determine the maximum tolerated dose of chlorambucil in combination with rituximab and Len. Although no major toxicities were observed with chlorambucil at a dose of 10mg/m2 on days 1-7 in 6 patients, a trend was observed of decreased tolerability of Len. Therefore, the phase 2 part of the study was conducted with chlorambucil at a dose of 7mg/m2 on days 1-7, cycle 1-6. Rituximab was given IV at day 1 at a dose of 375mg/m2 cycle 1 and 500mg/m2 cycle 2-6. Len was started on day 9 of cycle 1 at 2.5 mg orally and from then on administered daily and continuously. At cycle 2, Len was increased to 5 mg and at cycle 3 to a maximum of 10 mg or continued at the maximum tolerated dose. Following 6 cycles of combination treatment, patients continued Len monotherapy for 6 cycles of 28 days. A CT-scan was performed after 6 and 12 cycles, MRD was measured on peripheral blood after cycle 12. Antithrombotic prophylaxis (acetyl salicylic acid) was mandatory and support with g-CSF was to be given in case of grade ≥3 neutropenia. The primary endpoint was ORR.
Results. 63 patients were enrolled of whom 57 in the phase 2 part of the study. As 4 patients were not eligible (SLL, not CLL), all further analyses were performed on 53 patients. Baseline patients characteristics are shown in the Table.
47 patients (89%) completed induction-I and 36 patients (68%) completed induction-II. Reasons for dropout were progression (n=1), excessive toxicity (n=8) and refusal (n=2) during or after induction-I and excessive toxicity (n=5) and refusal (n=1) during induction-II. During Induction-I, full dose of Len dosed to 10mg could be given to 56% of patients in cycle 3, ,64% in cycle 4, and 57% in cycle 6. At cycle 12 of Induction-II 75% of remaining 36 patients received Len at the full dose.
ORR after induction-I was 83% (all PR) and for the 42 patients who started induction II, the ORR after induction-II was 93% (14% CR). Depth of response improved after induction-II in 8 patients (2 from SD to PR and 6 from PR to CR). Flow-based MRD could be performed in 41 patients, 4 achieved MRD negativity.
The 3-year PFS was 54% and the 3-year OS was 95% with a median follow-up of 27 months (see figure).
Tumor lysis syndrome (TLS) and tumor flare reaction (TFR) have been of specific concern in earlier CLL trials incorporating Len. Using the individualized dose schedule, no TLS was observed, while TFR occurred in 5 patients (9%, one grade 3). As for hematologic toxicities, grade 3-4 neutropenia, thrombocytopenia and anemia occurred in 36%, 6% and 0% of treatment cycles respectively at induction-I and 33%, 6% and 0% at induction-II. Other grade 3-4 toxicities occurred in 44% of patients during induction-I (top 3: general, skin, and gastrointestinal (GI)). At induction-II 19% of patients experienced grade 3-4 toxicities, of which 10% infections and 7% GI.
Another Len-specific concern has been second primary malignancies (SPM). In our study cohort 6 patients with SPM were observed (all but one a localized skin cancer).
Conclusions. Addition of Len to a backbone of chlorambucil and rituximab followed by a fixed duration of Len monotherapy in 1st line FCR-unfit patients results in high remission rates with PFS rates that seem comparable to those observed with novel combinations including novel CD20 MAb or kinase inhibitors. Although Len-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile.
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Kater:Celgene: Consultancy, Research Funding; Johnson & Johnson: Research Funding; Abbvie: Research Funding. Van Oers:Roche: Consultancy; ISA therapeutics: Consultancy; Novartis: Consultancy; Immunicum: Consultancy. Schipperus:Amgen: Research Funding. Chamuleau:Genmab: Research Funding; Gilead: Research Funding. Nijland:Novartis Pharmaeuticals Corporation: Honoraria; Kite Pharma: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; MIllennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Doorduijn:Roche: Honoraria; Celgene: Honoraria. van Gelder:Roche: Honoraria. Raymakers:Roche: Honoraria.
Radiotherapy (RT) is an essential component of cancer treatment. There is a lack of RT services in sub-Saharan Africa as well as limited knowledge regarding clinical practices. The purpose of this ...study was to identify and describe the patterns for RT treatment in Ethiopia.
We performed a retrospective analysis of 1,823 patients treated with cobalt RT at a large referral hospital in Addis Ababa, Ethiopia, from May 2015 through January 2018. Paper charts were reviewed for patient and treatment characteristics. Descriptive statistics were computed using SPSS (IBM, Armonk, NY).
Among patients treated for cancer, 98% (n = 1,784) were adults, 78% (n = 1,426) were female, 5% (n = 85) were HIV positive, 30% (n = 555) were from Addis Ababa, and the median age was 48 years (interquartile range IQR, 38-58 years). Cervical cancer was the most frequent cancer treated (47%, n = 851), followed by breast cancer (15%, n = 274) and head and neck cancer (10%, n = 184). Seventy-three percent of patients (n = 1,339) presented at a late stage, and 62% (n = 1,138) received palliative RT. The wait times were the shortest for patients receiving palliative treatment (median, 0 days; IQR, 0-15 days; n = 1,138), whereas wait times were longer for patients receiving curative treatment (median, 150 days; IQR, 60-210 days; n = 685). Three percent of patients (n = 56) had documented grade 3 or 4 acute toxicity; of these, 59% (n = 33) were patients with head and neck cancer.
Cervical cancer accounted for half of patients treated; thus, a majority of patients were adult females. Most patients had advanced-stage cancer, and goals of care were palliative. Wait times were long for patients with curative-intent cancer as a result of low capacity for RT services.
Dynamical quantum groups constructed from a FRST-construction using a solution of the quantum dynamical Yang–Baxter equation are equipped with a natural pairing. The interplay of the pairing with ...*-structures, corepresentations and dynamical representations is studied, and natural left and right actions are introduced. Explicit details for the elliptic
U
(
2
)
dynamical quantum group are given, and the pairing is calculated explicitly in terms of elliptic hypergeometric functions. Dynamical analogues of spherical and singular vectors for corepresentations are introduced.
Background
Large representative population-based studies in acute myeloid leukemia (AML) are scarce and restricted to reports from Sweden including cohorts until the year 2006 (Derolf, Blood 2009 & ...Juliusson, Blood 2009). So far, long-term data on primary treatment and trial participation in an unselected AML population are lacking. We conducted a nationwide population-based study to assess patterns of primary treatment, trial participation and survival among adult patients diagnosed with AML in the Netherlands from 1989 to 2012.
Methods
We selected all adult patients (≥18 years) diagnosed between 1989 and 2012 with acute promyelocytic leukemia (APL; N = 585; median age, 52 years; 47% males) and non-APL AML (N = 12,032; median age, 66 years; 54% males) from the nationwide population-based Netherlands Cancer Registry (NCR). Data on primary treatment for individual patients, that is, supportive care only, chemotherapy (CT) and stem cell transplantation (SCT), were retrieved from the NCR. We obtained data on the type of SCT, that is, autologous (autoSCT) or allogeneic SCT (alloSCT), from the HOVON SCT working group registry, and data on trial participation from the HOVON and EORTC cooperative trial groups. Trial participation of APL patients was outside the scope of this study. Patients were categorized into four calendar periods (1989-1994, 1995-2000, 2001-2006 and 2007-2012) and five age groups (18-40, 41-60, 61-70, 71-80 and >80 years), unless otherwise stated. We calculated relative survival rates (RSRs) as a measure of disease-specific survival.
Results
The overall age-standardized incidence of non-APL AML (3.0 per 100,000) and APL (0.15 per 100,000) remained stable over time. The proportion of patients with non-APL AML and APL diagnosed in individuals >60 years of age were 65% and 36%, respectively.
In the overall series, 40%, 52% and 64% of the patients with non-APL AML in the first three age groups received CT, 15%, 10% and <1% received autoSCT and 38%, 27% and 7% received alloSCT, respectively. The use of alloSCT for non-APL AML increased over time among patients up to 70 years of age and were gradually applied in patients 61-70 years of age since the early 2000s (Fig 1A). Among patients with non-APL AML over 70 years of age, treatment remained conservative over time (Fig 1A). Overall, 77%, 78%, 75% and 52% of patients with APL aged 18-40, 41-60, 61-70 and >70 years received CT. The use of CT for APL increased over time in all age groups (Fig 1B).
When a clinical trial was open for accrual, the inclusion rate was 68%, 57%, 30%, and 11% among patients with non-APL AML in the first four age groups, respectively. Of the patients that were not entered into a clinical trial and survived at least 30 days after diagnosis, 90%, 85%, 73% and 41% in the first four age groups received intensive therapy (CT, auto- and alloSCT) off-study, respectively.
There was an overall improvement in RSRs over the study period among patients with non-APL AML and APL. The 5-year RSRs (with 95% confidence interval) increased from 12% (11%-14%), to 20% (18%-21%) for non-APL AML and from 45% (35%-54%) to 66% (58%-74%) for APL in the first and last calendar period, respectively. This improvement was mainly confined to patients with non-APL AML (Fig 2A) and APL (Fig 2B) up to 70 years of age. In addition, the RSRs also increased over time in elderly patients with APL above 70 years of age (Fig 2B).
Conclusions
In this comprehensive population-based study, we found that survival over the past two decades increased among patients with non-APL AML up to 70 years of age and among patients with APL in all age groups. This may be explained by the increased use of intensive and potentially curative treatment over time. The inclusion rate in clinical trials that employ intensive treatment approaches decreased with age, with a particular low accrual in patients above the age of 60. Survival remained poor and unchanged among patients with non-APL AML over 70 years of age, possibly due to the lack of age-adapted treatment approaches and the lack of clinical trials addressing the issue of age and frailty. Therefore, there is a need to design specific trials with innovative treatment strategies in elderly, frail patients who are not eligible for current clinical trials.
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No relevant conflicts of interest to declare.
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