Publications by authors named "Richard Rosenquist"

287 Publications

RPS15 mutations rewire RNA translation in chronic lymphocytic leukemia.

Blood Adv 2021 07;5(13):2788-2792

Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.

Recent studies of chronic lymphocytic leukemia (CLL) have reported recurrent mutations in the RPS15 gene, which encodes the ribosomal protein S15 (RPS15), a component of the 40S ribosomal subunit. Despite some evidence about the role of mutant RPS15 (mostly obtained from the analysis of cell lines), the precise impact of RPS15 mutations on the translational program in primary CLL cells remains largely unexplored. Here, using RNA sequencing and ribosome profiling, a technique that involves measuring translational efficiency, we sought to obtain global insight into changes in translation induced by RPS15 mutations in CLL cells. To this end, we evaluated primary CLL cells from patients with wild-type or mutant RPS15 as well as MEC1 CLL cells transfected with mutant or wild-type RPS15. Our data indicate that RPS15 mutations rewire the translation program of primary CLL cells by reducing their translational efficiency, an effect not seen in MEC1 cells. In detail, RPS15 mutant primary CLL cells displayed altered translation efficiency of other ribosomal proteins and regulatory elements that affect key cell processes, such as the translational machinery and immune signaling, as well as genes known to be implicated in CLL, hence highlighting a relevant role for RPS15 in the natural history of CLL.
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http://dx.doi.org/10.1182/bloodadvances.2020001717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288675PMC
July 2021

Clinical utility of whole-genome sequencing in precision oncology.

Semin Cancer Biol 2021 Jun 25. Epub 2021 Jun 25.

NIHR Oxford Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, United Kingdom. Electronic address:

Precision diagnostics is one of the two pillars of precision medicine. Sequencing efforts in the past decade have firmly established cancer as a primarily genetically driven disease. This concept is supported by therapeutic successes aimed at particular pathways that are perturbed by specific driver mutations in protein-coding domains and reflected in three recent FDA tissue agnostic cancer drug approvals. In addition, there is increasing evidence from studies that interrogate the entire genome by whole-genome sequencing that acquired global and complex genomic aberrations including those in non-coding regions of the genome might also reflect clinical outcome. After addressing technical, logistical, financial and ethical challenges, national initiatives now aim to introduce clinical whole-genome sequencing into real-world diagnostics as a rational and potentially cost-effective tool for response prediction in cancer and to identify patients who would benefit most from 'expensive' targeted therapies and recruitment into clinical trials. However, so far, this has not been accompanied by a systematic and prospective evaluation of the clinical utility of whole-genome sequencing within clinical trials of uniformly treated patients of defined clinical outcome. This approach would also greatly facilitate novel predictive biomarker discovery and validation, ultimately reducing size and duration of clinical trials and cost of drug development. This manuscript is the third in a series of three to review and critically appraise the potential and challenges of clinical whole-genome sequencing in solid tumors and hematological malignancies.
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http://dx.doi.org/10.1016/j.semcancer.2021.06.018DOI Listing
June 2021

Analytical demands to use whole-genome sequencing in precision oncology.

Semin Cancer Biol 2021 Jun 10. Epub 2021 Jun 10.

MLL Munich Leukemia Laboratory, Munich, Germany. Electronic address:

Interrogating the tumor genome in its entirety by whole-genome sequencing (WGS) offers an unprecedented insight into the biology and pathogenesis of cancer, with potential impact on diagnostics, prognostication and therapy selection. WGS is able to detect sequence as well as structural variants and thereby combines central domains of cytogenetics and molecular genetics. Given the potential of WGS in directing targeted therapeutics and clinical decision-making, we envision a gradual transition of the method from research to clinical routine. This review is one out of three within this issue aimed at facilitating this effort, by discussing in-depth analytical validation, clinical interpretation and clinical utility of WGS. The review highlights the requirements for implementing, validating and maintaining a clinical WGS pipeline to obtain high-quality patient-specific data in accordance with the local regulatory landscape. Every step of the WGS pipeline, which includes DNA extraction, library preparation, sequencing, bioinformatics analysis, and data storage, is considered with respect to its logistics, necessities, potential pitfalls, and the required quality management. WGS is likely to drive clinical diagnostics and patient care forward, if requirements and challenges of the technique are recognized and met.
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http://dx.doi.org/10.1016/j.semcancer.2021.06.009DOI Listing
June 2021

Molecular diagnostics and reporting in lymphoid malignancies: Current status and beyond.

Hematol Oncol 2021 Jun;39 Suppl 1:73-77

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1002/hon.2849DOI Listing
June 2021

Trailblazing precision medicine in Europe: A joint view by Genomic Medicine Sweden and the Centers for Personalized Medicine, ZPM, in Germany.

Semin Cancer Biol 2021 May 24. Epub 2021 May 24.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Genomic Medicine Sweden (GMS), Sweden.

Over the last decades, rapid technological and scientific advances have led to a merge of molecular sciences and clinical medicine, resulting in a better understanding of disease mechanisms and the development of novel therapies that exploit specific molecular lesions or profiles driving disease. Precision oncology is here used as an example, illustrating the potential of precision/personalized medicine that also holds great promise in other medical fields. Real-world implementation can only be achieved by dedicated healthcare connected centers which amass and build up interdisciplinary expertise reflecting the complexity of precision medicine. Networks of such centers are ideally suited for a nation-wide outreach offering access to precision medicine to patients independent of their place of residence. Two of these multicentric initiatives, Genomic Medicine Sweden (GMS) and the Centers for Personalized Medicine (ZPM) initiative in Germany have teamed up to present and share their views on core concepts, potentials, challenges, and future developments in precision medicine. Together with other initiatives worldwide, GMS and ZPM aim at providing a robust and sustainable framework, covering all components from technology development to clinical trials, ethical and legal aspects as well as involvement of all relevant stakeholders, including patients and policymakers in the field.
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http://dx.doi.org/10.1016/j.semcancer.2021.05.026DOI Listing
May 2021

[Genomic Medicine Sweden - a national initiative for the broad introduction of precision medicine in Swedish healthcare].

Lakartidningen 2021 05 11;118. Epub 2021 May 11.

professor, överläkare, Karolinska institutet och Karolinska universitetssjukhuset.

The Genomic Medicine Sweden (GMS) initiative aims to strengthen precision medicine across the country. This will be accomplished through the implementation of large-scale sequencing techniques in Swedish healthcare. With a patient-centered view, initial efforts will focus on rare diseases, cancer, pharmacogenomics, and infectious diseases, and subsequently extend to complex diseases. GMS is being implemented as a broad collaborative project involving healthcare, universities with medical faculty, SciLifeLab, industry and patient organizations. To deliver top tier diagnostics, regional genomic medicine centers (GMC) are currently under establishment together with a national informatics infrastructure for data sharing. GMS will also offer a unique resource for research that could pave the way for the development of novel drugs, and enhance collaboration with industry. In summary, GMS provides Sweden with an opportunity to take an international forefront position in the field of precision medicine.
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May 2021

[Precision diagnostics and therapy in hematological malignancies].

Lakartidningen 2021 05 10;118. Epub 2021 May 10.

professor, överläkare, Karolinska institutet och Karolinska universitetssjukhuset.

Precision diagnostics and therapy have been implemented rather early in clinical hematology due to the easy accessibility of blood and bone marrow, allowing not only for consecutive genetic analysis at diagnosis, remission and relapse, but also for culturing these cells and testing new drugs in vitro. One contributing factor has also been the relatively low number of »driver« mutations in hematologic malignancies and that some of them are gain of function mutations that are relatively easy to target by drugs. Examples of this development are ABL1-, JAK2-, and FLT3-inhibitors for the treatment of chronic myeloid leukemia, myeloproliferative neoplasms, and acute myeloid leukemia, respectively. More recently, gene panel sequencing has been introduced in clinical routine to identify genetic alterations with diagnostic, prognostic and predictive impact, and more sensitive techniques to monitor minimal residual disease are emerging. Whole genome and transcriptome sequencing are currently evaluated as the next diagnostic tool. Finally, a large number of targeted therapies are currently under development and/or undergoing clinical trials.
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May 2021

Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG).

Haematologica 2020 11 1;105(11):2598-2607. Epub 2020 Nov 1.

Department of Internal Medicine III, Ulm University, Ulm, Germany.

Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.
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http://dx.doi.org/10.3324/haematol.2019.231027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604575PMC
November 2020

Higher-order immunoglobulin repertoire restrictions in CLL: the illustrative case of stereotyped subsets 2 and 169.

Blood 2021 Apr;137(14):1895-1904

Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.

Chronic lymphocytic leukemia (CLL) major stereotyped subset 2 (IGHV3-21/IGLV3-21, ∼2.5% of all cases of CLL) is an aggressive disease variant, irrespective of the somatic hypermutation (SHM) status of the clonotypic IGHV gene. Minor stereotyped subset 169 (IGHV3-48/IGLV3-21, ∼0.2% of all cases of CLL) is related to subset 2, as it displays a highly similar variable antigen-binding site. We further explored this relationship through next-generation sequencing and crystallographic analysis of the clonotypic B-cell receptor immunoglobulin. Branching evolution of the predominant clonotype through intraclonal diversification in the context of ongoing SHM was evident in both heavy and light chain genes of both subsets. Molecular similarities between the 2 subsets were highlighted by the finding of shared SHMs within both the heavy and light chain genes in all analyzed cases at either the clonal or subclonal level. Particularly noteworthy in this respect was a ubiquitous SHM at the linker region between the variable and the constant domain of the IGLV3-21 light chains, previously reported as critical for immunoglobulin homotypic interactions underlying cell-autonomous signaling capacity. Notably, crystallographic analysis revealed that the IGLV3-21-bearing CLL subset 169 immunoglobulin retains the same geometry and contact residues for the homotypic intermolecular interaction observed in subset 2, including the SHM at the linker region, and, from a molecular standpoint, belong to a common structural mode of autologous recognition. Collectively, our findings document that stereotyped subsets 2 and 169 are very closely related, displaying shared immunoglobulin features that can be explained only in the context of shared functional selection.
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http://dx.doi.org/10.1182/blood.2020005216DOI Listing
April 2021

Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy.

Blood 2021 01;137(2):216-231

School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.

Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.
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http://dx.doi.org/10.1182/blood.2020006073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820876PMC
January 2021

Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL.

Blood 2021 03;137(10):1365-1376

Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine, Masaryk University-University Hospital Brno, Brno, Czech Republic.

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed "satellites," were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.
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http://dx.doi.org/10.1182/blood.2020007039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976441PMC
March 2021

Concordance in survival among first-degree relatives diagnosed with indolent lymphoid malignancies including chronic lymphocytic leukemia.

Eur J Haematol 2020 Dec 29;105(6):779-785. Epub 2020 Sep 29.

Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden.

Objectives: To investigate concordance in survival time among first-degree relatives with lymphoid malignancies.

Methods: By linkage of national Swedish registers, we identified 66 430 patients diagnosed with a lymphoid malignancy 1958-2016 with information on first-degree relationships and follow-up until 2017. Among these, we identified pairs of first-degree relatives with any (N = 3326) or a similar (N = 690) lymphoid malignancy subtype. We defined survival in the first-degree relative as good, expected, or poor based on tertiles of deviance residuals from a multivariable Cox regression model. Next, we used Cox regression to estimate hazard ratios (HR) of death with 95% confidence intervals (CI) among patients, using the survival of their first-degree relative as exposure and adjusting for confounders.

Results: There was no concordance in survival among first-degree relatives with any lymphoid malignancy (HR  = 1.00 (reference), HR  = 1.02, 95% CI: 0.89-1.17, HR  = 1.12, 95% CI: 0.98-1.27, P  = .08). Among first-degree relatives with indolent lymphoma, including chronic lymphocytic leukemia, those with a first-degree relative to an expected or poor survival had worse outcome compared to those with a first-degree relative with good survival (HR  = 1.44, 95% CI: 0.82-2.53, HR  = 1.79, 95% CI: 1.07-3.00, P  = .03).

Conclusion: Our results support a role of inherited factors in the outcome of indolent lymphoma, including chronic lymphocytic leukemia.
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http://dx.doi.org/10.1111/ejh.13510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702025PMC
December 2020

Risk-adapted bendamustine + rituximab is a tolerable treatment alternative for elderly patients with chronic lymphocytic leukaemia: a regional real-world report on 141 consecutive Swedish patients.

Br J Haematol 2020 11 10;191(3):426-432. Epub 2020 Aug 10.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Bendamustine + rituximab (BR) is the current first-line standard-of-care for chronic lymphocytic leukaemia (CLL) in fit patients aged 66-70 years, whereas chlorambucil + CD20 antibody is recommended in older patients with co-morbidities. This retrospective real-world study investigated whether risk-adapted BR was safe and effective in elderly patients. All 141 CLL patients in the Stockholm region (diagnosed from 2007 to 2016, identified from regional registries) who had received BR as first (n = 84) or later line (n = 57) were analysed. Median age was 72 years, 49% had Binet stage C, 40% had Cumulative Illness Rating Scale (CIRS) score ≥ 6, 20% Eastern Cooperative Oncology Group (ECOG) score 2. None had del(17p). Only 15% of patients aged ≥80 years received full-dose bendamustine and 65% of them postponed rituximab until cycle 2. Corresponding numbers in patients 73-79 years were 21% and 36% and in <73 years, 63% and 33%. Overall response rate was 83% (first line) and 67% (later line) (P < 0·022) equally distributed between age subsets. ECOG, immunoglobulin heavy chain variable region (IGHV) mutational status and cytogenetics, but not treatment line and age, were significant factors on progression-free survival (PFS) in multivariate analysis. Infections and neutropenia/thrombocytopenia (≥grade 3) were similar across age subgroups. In summary, BR was well tolerated even in patients ≥80 years, with similar efficacy and safety as in less old patients, provided that carefully adapted dosing was applied.
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http://dx.doi.org/10.1111/bjh.17032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689859PMC
November 2020

Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing.

Leukemia 2020 10 19;34(10):2545-2551. Epub 2020 Jun 19.

Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece.

Twenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend. There is indeed a growing demand for shifting practice and using NGS for IGHV gene SHM assessment, although it is debatable whether it is always justifiable, at least taking into account financial considerations for laboratories with limited resources. Nevertheless, as this analysis impacts on treatment decisions, standardization of both technical aspects, and data interpretation becomes essential. Also, the need for establishing new recommendations and providing dedicated education and training on NGS-based immunogenetics is greater than ever before. Here we address potential and challenges of NGS-based immunogenetics in CLL. We are convinced that this perspective helps the hematological community to better understand the pros and cons of this new technological development for CLL patient management.
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http://dx.doi.org/10.1038/s41375-020-0923-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515836PMC
October 2020

Multimodal analgesia using opioid-sparing regimen in patients undergoing left ventricular assist device implantation.

J Heart Lung Transplant 2020 09 24;39(9):977-979. Epub 2020 May 24.

Department of Cardiovascular Medicine, Kaufman Center for Heart Failure Treatment and Recovery, Heart, Vascular & Thoracic Institute, Cleveland, Ohio.

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http://dx.doi.org/10.1016/j.healun.2020.05.009DOI Listing
September 2020

Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study.

Haematologica 2021 03 1;106(3):682-691. Epub 2021 Mar 1.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

Next-generation sequencing (NGS) has transitioned from research to clinical routine, yet the comparability of different technologies for mutation profiling remains an open question. We performed a European multicenter (n=6) evaluation of three amplicon-based NGS assays targeting 11 genes recurrently mutated in chronic lymphocytic leukemia. Each assay was assessed by two centers using 48 pre-characterized chronic lymphocytic leukemia samples; libraries were sequenced on the Illumina MiSeq instrument and bioinformatics analyses were centralized. Across all centers the median percentage of target reads ≥100x ranged from 94.2- 99.8%. In order to rule out assay-specific technical variability, we first assessed variant calling at the individual assay level i.e., pairwise analysis of variants detected amongst partner centers. After filtering for variants present in the paired normal sample and removal of PCR/sequencing artefacts, the panels achieved 96.2% (Multiplicom), 97.7% (TruSeq) and 90% (HaloPlex) concordance at a variant allele frequency (VAF) >0.5%. Reproducibility was assessed by looking at the inter-laboratory variation in detecting mutations and 107 of 115 (93% concordance) mutations were detected by all six centers, while the remaining eight variants (7%) were undetected by a single center. Notably, 6 of 8 of these variants concerned minor subclonal mutations (VAF <5%). We sought to investigate low-frequency mutations further by using a high-sensitivity assay containing unique molecular identifiers, which confirmed the presence of several minor subclonal mutations. Thus, while amplicon-based approaches can be adopted for somatic mutation detection with VAF >5%, after rigorous validation, the use of unique molecular identifiers may be necessary to reach a higher sensitivity and ensure consistent and accurate detection of low-frequency variants.
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http://dx.doi.org/10.3324/haematol.2019.234716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927885PMC
March 2021

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia.

Blood 2020 05;135(21):1859-1869

University of Texas MD Anderson Cancer Center, Houston, TX.

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.
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http://dx.doi.org/10.1182/blood.2019003453DOI Listing
May 2020

Multimodal Analgesic Regimen for Spine Surgery: A Randomized Placebo-controlled Trial.

Anesthesiology 2020 05;132(5):992-1002

From the Department of General Anesthesiology (K.M., R.A., D.T., S.R., M.M., S.M., A. Kurz) Department of Quantitative Health Sciences (N.M.) Department of Neurosurgery (A. Krishnaney, A.M.) Department of Pain Management (R.R.) Department of Outcomes Research (K.M., D.I.S., N.M., M.T., S.R., A. Kurz), Cleveland Clinic, Cleveland, Ohio.

Background: Various multimodal analgesic approaches have been proposed for spine surgery. The authors evaluated the effect of using a combination of four nonopioid analgesics versus placebo on Quality of Recovery, postoperative opioid consumption, and pain scores.

Methods: Adults having multilevel spine surgery who were at high risk for postoperative pain were double-blind randomized to placebos or the combination of single preoperative oral doses of acetaminophen 1,000 mg and gabapentin 600 mg, an infusion of ketamine 5 µg/kg/min throughout surgery, and an infusion of lidocaine 1.5 mg/kg/h intraoperatively and during the initial hour of recovery. Postoperative analgesia included acetaminophen, gabapentin, and opioids. The primary outcome was the Quality of Recovery 15-questionnaire (0 to 150 points, with 15% considered to be a clinically important difference) assessed on the third postoperative day. Secondary outcomes were opioid use in morphine equivalents (with 20% considered to be a clinically important change) and verbal-response pain scores (0 to 10, with a 1-point change considered important) over the initial postoperative 48 h.

Results: The trial was stopped early for futility per a priori guidelines. The average duration ± SD of surgery was 5.4 ± 2.1 h. The mean ± SD Quality of Recovery score was 109 ± 25 in the pathway patients (n = 150) versus 109 ± 23 in the placebo group (n = 149); estimated difference in means was 0 (95% CI, -6 to 6, P = 0.920). Pain management within the initial 48 postoperative hours was not superior in analgesic pathway group: 48-h opioid consumption median (Q1, Q3) was 72 (48, 113) mg in the analgesic pathway group and 75 (50, 152) mg in the placebo group, with the difference in medians being -9 (97.5% CI, -23 to 5, P = 0.175) mg. Mean 48-h pain scores were 4.8 ± 1.8 in the analgesic pathway group versus 5.2 ± 1.9 in the placebo group, with the difference in means being -0.4 (97.5% CI; -0.8, 0.1, P = 0.094).

Conclusions: An analgesic pathway based on preoperative acetaminophen and gabapentin, combined with intraoperative infusions of lidocaine and ketamine, did not improve recovery in patients who had multilevel spine surgery.
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http://dx.doi.org/10.1097/ALN.0000000000003143DOI Listing
May 2020

A Systematic Literature Review of Spine Neurostimulation Therapies for the Treatment of Pain.

Pain Med 2020 11;21(7):1421-1432

Pain Specialists Australia, Richmond, Monash University, Victoria, Australia.

Objective: To conduct a systematic literature review of spinal cord stimulation (SCS) for pain.

Design: Grade the evidence for SCS.

Methods: An international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year's duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.

Results: SCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT).

Conclusions: High-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.
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http://dx.doi.org/10.1093/pm/pnz353DOI Listing
November 2020

Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study.

Haematologica 2021 01 1;106(1):87-97. Epub 2021 Jan 1.

MLL Munich Leukemia Laboratory, Munich, Germany.

Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as ≥5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.
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http://dx.doi.org/10.3324/haematol.2019.239947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776256PMC
January 2021

The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome.

Clin Cancer Res 2020 03 9;26(6):1507-1515. Epub 2020 Jan 9.

Department of Hematology, Rigshospitalet, Copenhagen, Denmark.

Purpose: Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear.

Experimental Design: We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing.

Results: Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways.

Conclusions: We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4158DOI Listing
March 2020

DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy.

Clin Epigenetics 2019 12 2;11(1):177. Epub 2019 Dec 2.

Institute of Applied Biosciences, Center for Research and Technology Hellas, 6th km Charilaou-Thermi Rd, 57001, Thermi, Thessaloniki, GR, Greece.

Background: In order to gain insight into the contribution of DNA methylation to disease progression of chronic lymphocytic leukemia (CLL), using 450K Illumina arrays, we determined the DNA methylation profiles in paired pre-treatment/relapse samples from 34 CLL patients treated with chemoimmunotherapy, mostly (n = 31) with the fludarabine-cyclophosphamide-rituximab (FCR) regimen.

Results: The extent of identified changes in CLL cells versus memory B cells from healthy donors was termed "epigenetic burden" (EB) whereas the number of changes between the pre-treatment versus the relapse sample was termed "relapse changes" (RC). Significant (p < 0.05) associations were identified between (i) high EB and short time-to-first-treatment (TTFT); and, (ii) few RCs and short time-to-relapse. Both the EB and the RC clustered in specific genomic regions and chromatin states, including regulatory regions containing binding sites of transcription factors implicated in B cell and CLL biology.

Conclusions: Overall, we show that DNA methylation in CLL follows different dynamics in response to chemoimmunotherapy. These epigenetic alterations were linked with specific clinical and biological features.
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http://dx.doi.org/10.1186/s13148-019-0783-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889736PMC
December 2019

Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma.

Am J Hematol 2020 01 7;95(1):57-67. Epub 2019 Nov 7.

Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.
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http://dx.doi.org/10.1002/ajh.25666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916573PMC
January 2020

p66Shc deficiency sets the scene for clinically aggressive chronic lymphocytic leukemia.

Haematologica 2019 10;104(10):1914-1916

Dept. of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.3324/haematol.2019.225904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886431PMC
October 2019

Clinical significance of DNA methylation in chronic lymphocytic leukemia patients: results from 3 UK clinical trials.

Blood Adv 2019 08;3(16):2474-2481

Cancer Genomics, Cancer Research UK Centre and Experimental Cancer Medicine Centre, Academic Unit of Cancer Sciences, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.

Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.
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http://dx.doi.org/10.1182/bloodadvances.2019000237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712529PMC
August 2019

Outcomes of Sympathetic Blocks in the Management of Complex Regional Pain Syndrome: A Retrospective Cohort Study.

Anesthesiology 2019 10;131(4):883-893

From the Departments of Pain Management (J.C., V.S., M.G., O.T.C., F.Z., R.W.R.) Neurosciences (J.C.) Quantitative Health Sciences and Outcomes Research (J.Y., D.Y., E.J.M.), Cleveland Clinic, Cleveland, Ohio Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, California (V.S.).

Background: Sympathetic dysfunction may be present in complex regional pain syndrome, and sympathetic blocks are routinely performed in practice. To investigate the therapeutic and predictive values of sympathetic blocks, the authors test the hypotheses that sympathetic blocks provide analgesic effects that may be associated with the temperature differences between the two extremities before and after the blocks and that the effects of sympathetic blocks may predict the success (defined as achieving more than 50% pain reduction) of spinal cord stimulation trials.

Methods: The authors performed a retrospective study of 318 patients who underwent sympathetic blocks in a major academic center (2009 to 2016) to assess the association between pain reduction and preprocedure temperature difference between the involved and contralateral limbs. The primary outcome was pain improvement by more than 50%, and the secondary outcome was duration of more than 50% pain reduction per patient report. The authors assessed the association between pain reduction and the success rate of spinal cord stimulation trials.

Results: Among the 318 patients, 255 were diagnosed with complex regional pain syndrome and others with various sympathetically related disorders. Successful pain reduction (more than 50%) was observed in 155 patients with complex regional pain syndrome (155 of 255, 61%). The majority of patients (132 of 155, 85%) experienced more than 50% pain relief for 1 to 4 weeks or longer. The degree and duration of pain relief were not associated with preprocedure temperature parameters with estimated odds ratio of 1.03 (97.5% CI, 0.95-1.11) or 1.01 (97.5% CI, 0.96-1.06) for one degree decrease (P = 0.459 or 0.809). There was no difference in the success rate of spinal cord stimulation trials between patients with or without more than 50% pain relief after sympathetic blocks (35 of 40, 88% vs. 26 of 29, 90%, P > 0.990).

Conclusions: The authors conclude that sympathetic blocks may be therapeutic in patients with complex regional pain syndrome regardless of preprocedure limb temperatures. The effects of sympathetic blocks do not predict the success of spinal cord stimulation.
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http://dx.doi.org/10.1097/ALN.0000000000002899DOI Listing
October 2019
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