Citations

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a low-grade B-cell neoplasm and ∼2% to 9% patients develop an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (Richter transformation, DLBCL-RT). Programmed death-1 (PD-1) pathway plays a crucial role in tumor host immunity evasion and its blockade has emerged as an effective anti-cancer immunotherapy. PD-L1 and PD-1 expression has shown predictive value in anti-PD cancer immunotherapy; however, it has not been well documented in CLL/SLL and DLBCL-RT. We evaluated PD-1 and PD-L1 expression by immunohistochemistry in 39 CLL/SLL, 15 DLBCL-RT, and 26 other DLBCL. In CLL/SLL, neoplastic B-cell PD-1 expression was weak and restricted to prolymphocytes/paraimmunoblasts within proliferation centers (PCs) and accentuated PCs of all sizes. Neoplastic B-cell PD-1 expression was highly prevalent and demonstrated increased intensity in DLBCL-RT, but in contrast was only rarely seen in other DLBCL (12/15 vs. 1/26; P<0.0001). An excellent correlation (90% concordance) was observed between neoplastic B-cell PD-1 immunohistochemistry positivity and molecularly defined CLL/SLL clonal relatedness in DLBCL-RT. PD-L1 expression was observed on the neoplastic B cells in rare DLBCL-RT and other DLBCL cases (1/15 vs. 1/26; P>0.05) as well as background histiocytes and dendritic cells. Overall survival of DLBCL-RT was significantly inferior to that of the other DLBCL (median, 16.9 vs. 106.1 mo; P=0.002). Our findings suggest a biological continuum from prolymphocytes/paraimmunoblasts in CLL/SLL PCs to the neoplastic B-cells in DLBCL-RT. The characteristic PD-1 expression in DLBCL-RT makes it a potential surrogate marker for determining clonal relatedness to CLL/SLL, which may have important prognostic and therapeutic implications.

Abstract Early allograft dysfunction (EAD) identifies allografts with marginal function soon after liver transplantation (LT) and is associated with poor LT outcomes. The impact of EAD on post-LT renal recovery, however, has not been studied. Data on 69 primary LT recipients (41 with and 28 without history of renal dysfunction) who received renal replacement therapy (RRT) for a median (range) of 9 (13-41) days before LT were retrospectively analyzed. Primary outcome was renal nonrecovery defined as RRT requirement 30 days from LT. Early allograft dysfunction developed in 21 (30%) patients, and 22 (32%) patients did not recover renal function. Early allograft dysfunction was more common in the renal nonrecovery group (50% vs 21%, P = 0.016). Multivariate logistic regression analysis demonstrated that EAD (odds ratio, 7.25; 95% confidence interval, 2.0-25.8; P = 0.002) and baseline serum creatinine (odds ratio, 3.37; 95% confidence interval, 1.4-8.1; P = 0.007) were independently associated with renal nonrecovery. History of renal dysfunction, duration of renal dysfunction, and duration of RRT were not related to renal recovery ( P > 0.2 for all). Patients who had EAD and renal nonrecovery had the worst 1-, 3-, and 5-year patient survival, whereas those without EAD and recovered renal function had the best outcomes ( P < 0.001). Post-LT EAD was independently associated with renal nonrecovery in LT recipients on RRT for a short duration before LT. Furthermore, EAD in the setting of renal nonrecovery resulted in the worst long-term survival. Measures to prevent EAD should be undertaken in LT recipients on RRT at time of LT.

Background Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change. Methods and Results Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR ‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P <5×10 −8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS 2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P =4.17×10 −8 ). G‐allele carriers of HMGCS 2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P =0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10 −8 . HMGCS 2 , a part of the HMG ‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis. Conclusions These results suggest that HMGCS 2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 00246519 and NCT 01203852.

PurposeTo develop a reconstruction pipeline that intrinsically accounts for both simultaneous multislice echo planar imaging (SMS‐EPI) reconstruction and dynamic slice‐specific Nyquist ghosting correction in time‐series data.MethodsAfter 1D slice‐group average phase correction, the separate polarity (i.e., even and odd echoes) SMS‐EPI data were unaliased by slice GeneRalized Autocalibrating Partial Parallel Acquisition. Both the slice‐unaliased even and odd echoes were jointly reconstructed using a model‐based framework, extended for SMS‐EPI reconstruction that estimates a 2D self‐phase map, corrects dynamic slice‐specific phase errors, and combines data from all coils and echoes to obtain the final images.ResultsThe percentage ghost‐to‐signal ratios (%GSRs) and its temporal variations for MB3Ry2 with a field of view/4 shift in a human brain obtained by the proposed dynamic 2D and standard 1D phase corrections were 1.37 ± 0.11 and 2.66 ± 0.16, respectively. Even with a large regularization parameter λ applied in the proposed reconstruction, the smoothing effect in fMRI activation maps was comparable to a very small Gaussian kernel size 1 × 1 × 1 mm3.ConclusionThe proposed reconstruction pipeline reduced slice‐specific phase errors in SMS‐EPI, resulting in reduction of GSR. It is applicable for functional MRI studies because the smoothing effect caused by the regularization parameter selection can be minimal in a blood‐oxygen‐level–dependent activation map.

The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13 C stable isotope resolved metabolomics (SIRM) using U[ 13 C 6 ]Glucose and U[ 13 C 5 ]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle. Furthermore, the 13 C SIRM studies in HMCLs also demonstrate that glutamine is preferentially utilized by the TCA cycle compared with glucose. Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM. Thus, measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM patients offers potential early identification of those patients at high risk of progression to MM, who could benefit from early therapeutic intervention.

Abstract Electronic medical records (EMRs) have gained widespread use in clinical practice and by default serve as a large patient database with potential for use in clinical research. Although there remains significant interest in leveraging EMRs for research purposes, extraction of data has proven to be complex and with insufficient accuracy. We describe the limitations of an EMR in our attempt to conduct a seemingly simple study aimed at validating variables identified in the PRECiSE 3, a 7-year open label safety and efficacy study of certolizumab pegol in Crohn’s disease that identified clinical factors that predicted both short- and long-term efficacy. A multicenter, retrospective cohort study from 8 academic and large community practices was performed, and data were collected from each respective EMR. Significant challenges with reliable capture of key data elements were encountered, and overall a screen fail rate of 91.8% across all sites was seen. We describe these challenges and potential future directions to work together to advance accuracy and implementation of the use of EMRs in inflammatory bowel disease.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4‐week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: −9.6 ± 8.0 vs −5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: −18.7 ± 13.8 vs −13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (−17.0 ± 13.2/−9.6 ± 7.5 vs −7.0 ± 18.6/−6.7 ± 9.3 mm Hg, adjusted P<.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension.

AbstractTask-based functional magnetic resonance imaging (fMRI) is an imaging technique based on blood oxygenation level-dependent imaging. Maps of brain activation are generated during the performance of designated tasks involving eloquent functions, such as motor, sensory, visual, auditory, and/or language. Optimal performance of fMRI in children requires consideration of multiple psychological and physiological parameters. Also, a solid technical understanding is needed for appropriate study design, implementation, processing, and interpretation. In this article, the authors review the key principles of fMRI technique, study design, data processing, and interpretation. The important clinical applications in the pediatric population will be highlighted, accompanied by example cases from their institution.

Study Design: A multicenter retrospective case series was compiled involving 21 medical institutions. Inclusion criteria included patients who underwent cervical spine surgery between 2005 and 2011 and who sustained a vertebral artery injury (VAI). Objective: To report the frequency, risk factors, outcomes, and management goals of VAI in patients who have undergone cervical spine surgery. Methods: Patients were evaluated on the basis of condition-specific functional status using the Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA) score, the Nurick scale, and the 36-Item Short-Form Health Survey (SF-36). Results: VAIs were identified in a total of 14 of 16 582 patients screened (8.4 per 10 000). The mean age of patients with VAI was 59 years (±10) with a female predominance (78.6%). Patient diagnoses included myelopathy, radiculopathy, cervical instability, and metastatic disease. VAI was associated with substantial blood loss (770 mL), although only 3 cases required transfusion. Of the 14 cases, 7 occurred with an anterior-only approach, 3 cases with posterior-only approach, and 4 during circumferential approach. Fifty percent of cases of VAI with available preoperative imaging revealed anomalous vessel anatomy during postoperative review. Average length of hospital stay was 10 days (±8). Notably, 13 of the 14 (92.86%) cases resolved without residual deficits. Compared to preoperative baseline NDI, Nurick, mJOA, and SF-36 scores for these patients, there were no observed changes after surgery ( P = .20-.94). Conclusions: Vertebral artery injuries are potentially catastrophic complications that can be sustained from anterior or posterior cervical spine approaches. The data from this study suggest that with proper steps to ensure hemostasis, patients recover function at a high rate and do not exhibit residual deficits.