Max Richter Score Pdf 16
Garcia Miller
Reich/Richter was premiered with the film Moving Picture (946-3) by Gerhard Richter and Corinna Belz. The work may be performed on its own or with film in concert; the film must be licensed separately for use in performance.
Richter said he was making a film of the book together with Corinna Belz and would I consider writing the music? I said it was a very interesting project and that I would like to see some of the film. They sent some and I agreed to compose the score.
It was one factor but what really got me involved was the very beginning of the film with the pulsating, color shifting, glowing stripes. Instead of dividing, mirroring, and repeating, the film was multiplying and repeating. In computer terms, the initial stripes were made with 2 pixels. Then they gradually grew to 4, 8, 16, 32, and so on.
Now, just before I started work on this project, I completed two pieces: Runner and Music for Ensemble and Orchestra. Both pieces end with an oscillation between two gradually changing notes played by almost all the instruments. I felt that I wanted to begin a piece with that oscillation, and here the film began with 2 pixels. It was a perfect way to move from the end of my just-completed pieces to the beginning of this project. The structure of the music would be tied to the structure of the film. That was the basic idea.
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Patients and methods: An electronic database search of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who presented at The University of Texas M.D. Anderson Cancer Center (Houston, TX) between January 1975 and June 2005 was performed, and patient medical records were reviewed.
Conclusion: A score to predict an individual patient's risk of death is proposed. Chemotherapy and rituximab combinations are effective in RS. Patients with available donors may be considered for allogeneic SCT as postremission therapy.
Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma in the context of chronic lymphocytic leukemia. The scarcity of biologic information about RS has hampered the identification of molecular predictors of RS outcome. We addressed this issue by performing a comprehensive molecular characterization of 86 pathologically proven RS. TP53 disruption (47.1%) and c-MYC abnormalities (26.2%) were the most frequent alterations, whereas common genetic lesions of de novo diffuse large B-cell lymphoma were rare or absent. By multivariate analysis, lack of TP53 disruption (hazard ratio, 0.43; P = .003) translated into significant survival advantage with 57% reduction in risk of death. An algorithm based on TP53 disruption, response to RS treatment, and Eastern Cooperative Oncology Group performance status had 80.9% probability of correctly discriminating RS survival (c-index = .809). RS that were clonally unrelated to the paired chronic lymphocytic leukemia phase were clinically and biologically different from clonally related RS because of significantly longer survival (median, 62.5 months vs 14.2 months; P = .017) and lower prevalence of TP53 disruption (23.1% vs 60.0%; P = .018) and B-cell receptor stereotypy (7.6% vs 50.0%; P = .009). The molecular dissection of RS into biologically distinct categories highlights the genetic heterogeneity of this disorder and provides clinically relevant information for refining the prognostic stratification of patients.
Recent studies have indicated that, at the time of CLL diagnosis, the molecular features of the leukemic clone are important for the subsequent risk of RS development.6-9 Conversely, the pattern of genetic lesions acquired by RS on transformation is scarcely known, and available evidence is limited to small case series.10-18 Cytogenetic and molecular studies have shown that RS is associated with a higher degree of genomic complexity than is CLL, suggesting that transformation to RS might result from accumulation of novel genetic lesions that drive clinicopathologic shift and change the course of the disease.10-18
The conventional definition of RS is currently based on clinicopathologic grounds and does not take into account the immunogenetic heterogeneity of the disease. In fact, the clonal relationship between CLL and the developing DLBCL suggests that 2 types of RS may exist: (1) transformation of CLL to a clonally related DLBCL that accounts for the majority of cases and (2) development of a DLBCL unrelated to the CLL clone.9,19-22
The clinical outcome of patients with RS is generally considered poor.3,4 However, a large study of histologically proven RS has reported that survival of patients with RS can vary from a few weeks to 15 years.23 The recognition that RS outcome is not uniformly poor has prompted the development of the RS score that is currently the only available tool to predict RS prognosis.23 Given the limited understanding of the disease at the molecular level, the RS score was conceived on clinical grounds and does not take into account the biology of the disease.23 Despite the availability of the RS score, the identification of patients with RS projected to experience a long survival remains an unresolved issue that may benefit from the development of novel RS prognosticators.
This study aimed at a comprehensive molecular characterization of RS. By investigating the biology and the immunogenetic heterogeneity of the disease, we identified novel biologic predictors of RS survival with potentially important implications for the clinical management of patients with RS. First, this study shows that TP53 disruption critically affects RS survival, thus providing the rationale for exploring therapeutic agents that overcome TP53 disruption in this disease. Second, we report that clonally unrelated RS is clinically and biologically distinct from clonally related cases and is characterized by an outcome similar to that of de novo DLBCL. Accordingly, we propose that the diagnosis of RS should be restricted to clonally related cases.
Rearrangements of IGHV-D-J genes were amplified with subgroup-specific primers as previously reported.9 Sequences were aligned to ImMunoGeneTics sequence directory.26 The following information was extracted: IGHV-D-J gene usage, percentage of identity to germline, and VH CDR3 length. The occurrence of stereotyped VH CDR3 was analyzed as reported.9 The clonal relationship between the CLL phase and the RS phase was established in 63 cases (73.2%) by comparing IGHV-D-J and VH CDR3 sequences.
The final model for RS survival was internally validated with a bootstrapping resampling technique. The first step of validation showed that TP53 disruption, achievement of CR after RS induction treatment, and poor ECOG PS > 1 were the sole covariates selected at high frequency (> 90%) as independent predictors of RS survival in each one of the 1000 bootstrap samples that were generated (Table 4). This step of the analysis validated that TP53 disruption, achievement of CR after RS induction treatment, and poor ECOG PS > 1 are the most important variables affecting RS survival in this series. The second step of the validation analysis showed that the HRs produced from the original series were very close to those produced from the 1000 bootstrap samples (Table 4). This step validated the stability of the final model for RS survival prediction on the basis of TP53 disruption, achievement of CR after RS induction treatment, and poor ECOG PS > 1.
By recursive-partitioning analysis, TP53 status, response to RS induction treatment, and ECOG PS were used to build an algorithm for classifying patients with RS according to risk of death (Figure 2).
In this cohort, the prognostic model that included TP53 status, response to RS induction treatment, and ECOG PS allowed to better discriminate RS survival compared with the RS score that is based solely on clinical parameters,23 namely ECOG PS, LDH, platelet count, tumor size, and number of prior therapies (Figure 3). In fact, more than one-half (58.5%) RS that are assigned by our model to the intermediate risk group would otherwise be classified as favorable risk according to the RS score (Table 5).23 In addition, the model based on TP53 status, response to RS induction treatment, and ECOG PS had a significantly higher probability of correctly predicting RS survival (c-index = .809) compared with the clinical RS score (c-index = .750; P < .001).
The results of this study indicate that RS is characterized by molecular and immunogenetic heterogeneity that might be important for clinical outcome. The original contributions of this study in the field of RS include the demonstration that (1) TP53 disruption is one of the major factors affecting RS survival and (2) clonally unrelated RS is clinically and biologically distinct from clonally related RS and is characterized by an outcome similar to that of de novo DLBCL.
In this cohort, TP53 disruption and c-MYC abnormalities emerged as the 2 most frequent recurrent genetic lesions in RS. Analysis of sequential samples documented that TP53 disruption and c-MYC abnormalities are frequently acquired at transformation, thus pointing to the pathogenetic relevance of these genetic lesions for the acquisition of an aggressive large cell phenotype. Acquisition of TP53 mutations and c-MYC aberrations represent a dual-hit genetic mechanism shared by other models of transformation from indolent to aggressive lymphomas,45,47,48 suggesting that, to a certain extent, the clinicopathologic transformation of B-cell malignancies follows similar pathways in different disease contexts. The high prevalence of TP53 disruption in RS probably reflects the selection of a chemorefractory clone under the pressure of previous CLL treatments49 and might explain the poor outcome of this disease and the limited sensitivity to conventional drugs.
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