Richard Rosenquist | Uppsala University (original) (raw)

Papers by Richard Rosenquist

British Journal of Haematology, 2011

Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the ris... more Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0·1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of ≥0·1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ-PCR, a higher MRD cut-off (≥0·2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of ≥0·1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR.

British Journal of Haematology, 2008

The Iowa orthopaedic journal

Elite wrestlers place tremendous stress through their cervical spine. These athletes are at risk ... more Elite wrestlers place tremendous stress through their cervical spine. These athletes are at risk for cervical trauma and may develop radiculopathy from recurrent episodes of injury. Team physicians and athletic trainers are faced with the challenge of treating these injuries in such a way as to allow the athlete to safely and expeditiously return to competition. Epidural steroid injections can be a successful complement to a conservative treatment algorithm for these complex injuries. Case Series. Five upper-level NCAA collegiate wrestlers who experienced symptomatic cervical radiculopathy were identified from an archival review. The majority of the athletes had MRI evidence of cervical disc disease, with corresponding subjective complaints and physical examination findings including pain and weakness that precluded continued competition. All athletes were treated conservatively with initial activity modification, strengthening, rehabilitation, NSAIDs, and, ultimately, cervical epid...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 2, 2015

The role of antigen(s) in shaping the T-cell repertoire in chronic lymphocytic leukemia, though r... more The role of antigen(s) in shaping the T-cell repertoire in chronic lymphocytic leukemia, though relevant for understanding malignant cell interactions with cognate T cells, is largely unexplored. Here we profiled the T-cell receptor β chain gene repertoire in 58 chronic lymphocytic leukemia patients, focusing on cases assigned to well-characterized subsets with stereotyped clonotypic B-cell receptor immunoglobulins, therefore those cases most evidently selected by antigen (subsets #1, #2 and #4). Remarkable repertoire skewing and oligoclonality were observed, and differences between subsets were noted regarding both T-cell receptor β chain gene usage and the extent of clonality, with subset #2 being the least oligoclonal. Longitudinal analysis of subset #4 cases revealed that although the repertoire may fluctuate over time, certain clonotypes persist, thus alluding to persistent antigenic stimulation. Shared ("stereotyped") clonotypes were found between different patients,...

Spine

Clinical practice guideline. To develop evidence-based recommendations on use of interventional d... more Clinical practice guideline. To develop evidence-based recommendations on use of interventional diagnostic tests and therapies, surgeries, and interdisciplinary rehabilitation for low back pain of any duration, with or without leg pain. Management of patients with persistent and disabling low back pain remains a clinical challenge. A number of interventional diagnostic tests and therapies and surgery are available and their use is increasing, but in some cases their utility remains uncertain or controversial. Interdisciplinary rehabilitation has also been proposed as a potentially effective noninvasive intervention for persistent and disabling low back pain. A multidisciplinary panel was convened by the American Pain Society. Its recommendations were based on a systematic review that focused on evidence from randomized controlled trials. Recommendations were graded using methods adapted from the US Preventive Services Task Force and the Grading of Recommendations, Assessment, Develo...

Blood, Jan 8, 2015

Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized... more Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more ring sideroblasts in the bone marrow. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 has been reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with a myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129/159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P<.001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (HR .37, P=.003) and lower c...

The American journal of pathology, Jan 2, 2015

To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed... more To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-ΔE4a, AID-ΔE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microen...

Haematologica, 2014

Chronic lymphocytic leukemia B cells express auto/xeno antigen-reactive antibodies that bind to s... more Chronic lymphocytic leukemia B cells express auto/xeno antigen-reactive antibodies that bind to self-epitopes and resemble natural IgM antibodies in their repertoire. One of the antigenic structures recognized is oxidation-induced malonedialdehyde that is present on low-density lipoprotein, apoptotic blebs, and on certain microbes. The poor-prognostic stereotyped subset #1 (Clan I IGHV genes-IGKV1(D)-39) express IgM B-cell receptors that bind oxidized low-density lipoprotein. In this study, we have used for the first time this authentic cognate antigen for analysis of downstream B-cell receptor-signal transduction events, since it is more faithful to B-cell physiology than anti-IgM. Multivalent oxidized low-density lipoprotein showed specific binding to subset #1 IgM/IgD B-cell receptors, whereas native low-density lipoprotein did not. The antigen binding induced prompt receptor clustering followed by internalization. However, the receptor-signal transduction was silenced, revealing...

Cancer research, Jan 15, 2014

Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IG) has prov... more Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IG) has proved instrumental in dissecting chronic lymphocytic leukemia (CLL) pathogenesis. Initially, it was the finding that the level of somatic hypermutations in rearranged IG heavy-chain genes could define two CLL subtypes associated with a different clinical course that drew attention. As the years ensued, this not only continued to hold strong, but also revealed an unprecedented BcR restriction (aptly coined as "stereotypy"), thus cementing the idea that antigenic elements select the leukemic clones. With all this in mind, in the present review, we focus on the CLL BcR IG, a molecule that clearly lies at the heart of disease pathogenesis, and attempt to distil from past and emerging biologic knowledge the most relevant aspects in the context of the immunogenetics of CLL, while at the same time provoking questions that remain unanswered. We juxtapose CLL with mutated BcR IGs against C...

International anesthesiology clinics, 2011

British journal of cancer, Jan 17, 2007

B-cell chronic lymphocytic leukaemia (B-CLL) is characterised by the progressive accumulation of ... more B-cell chronic lymphocytic leukaemia (B-CLL) is characterised by the progressive accumulation of monoclonal CD5(+) B cells. In a previous study, we have analysed the expression profile of apoptosis-regulating genes using a cDNA-based microarray and found overexpression of the antiapoptotic bcl-2 family member, bfl-1, in B-CLL cells with an apoptosis-resistant phenotype. In this study, bfl-1 mRNA levels have been determined by competitive PCR in an extended population of B-CLL patients to characterise its role in disease progression and development of chemoresistance. bfl-1 levels were significantly higher in patients with no response (NR) to last chemotherapy than in patients responding (partial response (PR)) to last chemotherapy (P<0.05) and in patients who had not required treatment (P<0.05). We found no correlation between bfl-1 mRNA levels and disease progression, IGHV mutational status or other clinical parameters. In addition, bfl-1 mRNA levels were inversely correlated...

Medical oncology (Northwood, London, England), 2005

B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with many patient... more B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with many patients surviving for decades with minimal or no treatment, whereas others succumb rapidly to their disease despite therapy. In recent years, new molecular prognostic factors have emerged in CLL that have significantly improved the subgrouping of the disease. One of the most important molecular predictors, the immunoglobulin V(H) gene mutation status, divides CLL into two prognostic groups, depending on the presence or absence of somatic hypermutation, where unmutated V(H) genes are associated with considerably worse prognosis than mutated V(H) genes. An exception to this appears to be CLL patients utilizing the V(H)3-21 gene as they have poor outcome irrespective of mutation status. Surrogate markers for the VH gene mutation status have been suggested, such as CD38 and ZAP-70 expression. However, the CD38 level was later shown to display poor correlation to the mutation status, although it ma...

British journal of cancer, Jan 24, 2003

The immunoglobulin V(H) gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL... more The immunoglobulin V(H) gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V(H) genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated V(H) genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and V(H) gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between V(H) gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 6...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 16, 2015

Mounting evidence supports the clinical significance of gene mutations and immunogenetic features... more Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted re-sequencing and explored potential clinical implications in a multinational cohort of 175 SMZL patients. We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%) and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time-to-first-treatment (0.12 vs. 1.11 yrs; P=0.01). In multivariate analysis mutations in NOTCH2 (HR 2.12, 95%CI 1.02-4.4, P=0.044) and 100% germline IGHV gene identity (HR 2.19, 95%CI 1.05-4.55, P=0.036) were independent markers of short time-to-first-treatment, while TP53 m...

Hereditary Cancer in Clinical Practice, 2007

H He er re ed di it ta ar ry y C Ca an nc ce er r i in n C Cl li in ni ic ca al l P Pr ra ac ct t... more H He er re ed di it ta ar ry y C Ca an nc ce er r i in n C Cl li in ni ic ca al l P Pr ra ac ct ti ic ce e 2007; 5(1)

Transactions of the American Ophthalmological Society, 2008

To report a retrospective case series of 1127 Trabectome surgical procedures, including 738 Trabe... more To report a retrospective case series of 1127 Trabectome surgical procedures, including 738 Trabectome-only and 366 Trabectome-phacoemulsification surgeries. Electroablation of meshwork via a temporal corneal incision. Outcomes included changes in intraocular pressure (IOP) and medication use, complications, and Kaplan-Meier success estimates. For all cases, mean preoperative IOP of 23.8 +/- 7.7 mm Hg decreased by 39% to 16.5 +/- 4.0 mm Hg at 24 months (n = 50). Intraoperative reflux bleeding occurred in 77.6%. Medications decreased from 2.8 to 1.2 by 24 months. Sixty-five patients (5.8%) had IOP elevation > 10 mm Hg above baseline on day 1. Failure led to trabeculectomy in 5.9% (n = 67) and shunt installation in 1.6% (n = 18). Kaplan-Meier failure was defined across groups with at least 2 weeks follow-up as IOP > 21 mm Hg with or without medications and not reduced by 20% below baseline on 2 consecutive visits or repeat surgery. For Trabectome-only cases, mean preoperative IO...

Genome Biology, 2008

We present a strategy for detection of loss-of-heterozygosity and allelic imbalance in cancer cel... more We present a strategy for detection of loss-of-heterozygosity and allelic imbalance in cancer cells from whole genome single nucleotide polymorphism genotyping data. Using a dilution series of a tumor cell line mixed with its paired normal cell line and data generated on Affymetrix and Illumina platforms, including paired tumor-normal samples and tumors characterized by fluorescent in situ hybridization, we demonstrate a high sensitivity and specificity of the strategy for detecting both minute and gross allelic imbalances in heterogeneous tumor samples.

Blood, Jan 29, 2015

An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in gene... more An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, c...