Quantitative Assessment of Cardiac Hypermetabolism and Perfusion for Diagnosis of Cardiac Sarcoidosis.

BACKGROUND: Quantitative assessment of cardiac hypermetabolism from 18Flourodeoxy glucose (FDG) positron emission tomography (PET) may improve diagnosis of cardiac sarcoidosis (CS). We assessed different approaches for quantification of cardiac hypermetabolism and perfusion in patients with suspected CS. METHODS AND RESULTS: Consecutive patients undergoing 18FDG PET assessment for possible CS between January 2014 and March 2019 were included. Cardiac hypermetabolism was quantified using maximal standardized uptake value (SUVMAX), cardiometabolic activity (CMA) and volume of inflammation, using relative thresholds (1.3× and 1.5× left ventricular blood pool [LVBP] activity), and absolute thresholds (SUVMAX > 2.7 and 4.1). Diagnosis of CS was established using the Japanese Ministry of Health and Wellness criteria. In total, 69 patients were studied, with definite or possible CS in 29(42.0%) patients. CMA above 1.5× LVBP SUVMAX had the highest area under the receiver operating characteristic curve (AUC 0.92). Quantitative parameters using relative thresholds had higher AUC compared to absolute thresholds (p < 0.01). Interobserver variability was low for CMA, with excellent agreement regarding absence of activity (Kappa 0.970). CONCLUSIONS: Quantitation with scan-specific thresholds has superior diagnostic accuracy compared to absolute thresholds. Based on the potential clinical benefit, programs should consider quantification of cardiac hypermetabolism when interpreting 18F-FDG PET studies for CS.

99mTechnetium-labeled cardiac scintigraphy for suspected amyloidosis: a review of current and future directions.

Cardiac amyloidosis (CA) is an underdiagnosed form of restrictive cardiomyopathy leading to a rapid progression into heart failure. Evaluation of CA requires a multimodality approach making use of echocardiography, cardiac magnetic imaging, and nuclear imaging. Technetium (Tc)-labeled cardiac scintigraphy has witnessed a resurgence in its application for the workup of CA. Advancements in disease-modifying therapies have fueled the rapid adoption of cardiac scintigraphy using bone tracers and the need for transformative novel studies. The goal of this review is to present diagnostic utility, currently recommended protocols, as well as a glimpse into the rapid evolution of Tc-labeled cardiac scintigraphy in the diagnosis of CA.

Cardiac involvement in hospitalized patients with COVID-19 and its incremental value in outcomes prediction.

Recent reports linked acute COVID-19 infection in hospitalized patients to cardiac abnormalities. Studies have not evaluated presence of abnormal cardiac structure and function before scanning in setting of COVD-19 infection. We sought to examine cardiac abnormalities in consecutive group of patients with acute COVID-19 infection according to the presence or absence of cardiac disease based on review of health records and cardiovascular imaging studies. We looked at independent contribution of imaging findings to clinical outcomes. After excluding patients with previous left ventricular (LV) systolic dysfunction (global and/or segmental), 724 patients were included. Machine learning identified predictors of in-hospital mortality and in-hospital mortality + ECMO. In patients without previous cardiovascular disease, LV EF < 50% occurred in 3.4%, abnormal LV global longitudinal strain (< 16%) in 24%, and diastolic dysfunction in 20%. Right ventricular systolic dysfunction (RV free wall strain < 20%) was noted in 18%. Moderate and large pericardial effusion were uncommon with an incidence of 0.4% for each category. Forty patients received ECMO support, and 79 died (10.9%). A stepwise increase in AUC was observed with addition of vital signs and laboratory measurements to baseline clinical characteristics, and a further significant increase (AUC 0.91) was observed when echocardiographic measurements were added. The performance of an optimized prediction model was similar to the model including baseline characteristics + vital signs and laboratory results + echocardiographic measurements.

Diagnostic and prognostic value of Technetium-99m pyrophosphate uptake quantitation for transthyretin cardiac amyloidosis.

BACKGROUND: 99mTc-pyrophosphate imaging has emerged as an important non-invasive method to diagnose transthyretin cardiac amyloidosis (ATTR-CM). Quantitation of 99mTc-pyrophosphate activity, on SPECT images, could be a marker of ATTR-CM disease burden. We assessed the diagnostic accuracy and clinical significance of 99mTc-pyrophosphate quantitation. METHODS AND RESULTS: Patients who underwent 99mTc-pyrophosphate imaging for suspected ATTR-CM were included. Using SPECT images, radiotracer activity in the myocardium was calculated using cardiac pyrophosphate activity (CPA) and volume of involvement (VOI), with thresholds for abnormal activity derived from LVBP activity. Diagnostic accuracy was assessed using area under the receiver operating characteristic curve (AUC). In total, 124 patients were identified, mean age 73.9 ± 11.4, with ATTR-CM diagnosed in 43 (34.7%) patients. CPA had the highest diagnostic accuracy (AUC .996, 95% CI .987-1.00), and was significantly higher compared to the Perugini score (AUC .952, P = .016). In patients with ATTR-CM, CPA was associated with reduced left ventricular ejection fraction (adjusted odds ratio 1.28, P = .035) and heart failure hospitalizations (adjusted hazard ratio 1.29, P = .006). CONCLUSION: Quantitative assessment of myocardial radiotracer activity with CPA or VOI have high diagnostic accuracy for ATTR-CM. Both measures are potential non-invasive markers to follow progression of disease or response to therapy.

Frequency of injuries associated with syncope in the prevention of syncope trials.

AIMS: Syncope can lead to injuries. We determined the frequency, severity, and predictors of injuries due to syncope in cohorts of syncope patients. METHODS AND RESULTS: Participants were enrolled in the POST2 (fludrocortisone) and POST4 (midodrine) vasovagal syncope (VVS) randomized trials, and POST3 enrolled patients with bifascicular block and syncope. Injury was defined as minor (bruising, abrasions), moderate (lacerations), and severe (fractures, burns, joint pain), and recorded up to 1 year after enrolment. A total of 459 patients (median 39 years) were analysed. There were 710 faints occurred in 186 patients during a 1-year follow-up. Fully 56/186 (30%) of patients were injured with syncope (12% of overall group). There were 102 injuries associated with the 710 faints (14%), of which 19% were moderate or severe injuries. Neither patient age, sex, nor the presence of prodromal symptoms associated with injury-free survival. Patients with bifascicular block were more prone to injury (relative risk 1.98, P = 0.018). Patients with ≥4 faints in the prior year had more injuries than those with fewer faints (relative risk 2.97, P < 0.0001), but this was due to more frequent syncope, and not more injuries per faint. In VVS patients, pharmacological therapy significantly reduced the likelihood of an injury due to a syncopal spell (relative risk 0.64, P = 0.015). Injury severity did not associate with age, sex, or prior-year syncope frequency. CONCLUSION: Injuries are frequent in syncope patients, but only 4% of injuries were severe. None of age, sex, and prodromal symptoms associate with injury.

Characterization of Right Ventricular Deformation in Pulmonary Arterial Hypertension Using Three-Dimensional Principal Strain Analysis.

BACKGROUND: Pulmonary arterial hypertension (PAH) can cause maladaptive right ventricular (RV) functional changes associated with adverse prognosis that are challenging to accurately quantify noninvasively. The aim of this study was to explore principal strain (PS) with contraction angle analysis using three-dimensional echocardiography to characterize RV deformation changes in patients with PAH. METHODS: Three-dimensional echocardiography was performed in 37 patients with PAH and 20 healthy control subjects with two-component (primary and secondary) PS and principal contraction angle analysis. Patients were stratified according to World Health Organization (WHO) functional class. RESULTS: Primary PS differed significantly between patients with PAH and healthy control subjects (-20.2 ± 3.3% vs -26.8 ± 3.3%, P = .01), while secondary PS was not significantly different (3.6 ± 5.1% vs -2.5 ± 4.7%, P = .12). Principal contraction angle was significantly lower in patients with PAH (63 ± 22° vs 71 ± 7°, P = .01), with the greatest reduction for the RV free wall. Primary PS and principal contraction angle differed significantly between WHO class I and II and class III and IV patients (-23.9 ± 4.7% vs -18.1 ± 4.8% [P = .03] and 69 ± 9° vs 58 ± 14° [P = .03], respectively), while secondary PS was not significantly different between groups (P = .13). Compared with healthy control subjects, septal principal contraction angle was not different in patients with WHO class I and II PAH (P = .62), but it was significantly reduced in those with WHO class III and IV PAH (P < .01). The area under the curve for primary PS to differentiate patients with PAH by WHO functional class was 0.81 (95% CI, 0.77-0.89; P = .01). Primary PS intraclass correlation coefficients for intraobserver and interobserver variability were 0.91 (95% CI, 0.88-0.93) and 0.86 (95% CI, 0.81-0.88), respectively. CONCLUSIONS: PS analysis using three-dimensional echocardiography provides comprehensive quantification of RV deformation and characterizes alterations occurring in PAH that are associated with WHO functional class.

Effects of a reminder to initiate oral anticoagulation in patients with atrial fibrillation/atrial flutter discharged from the emergency department: REMINDER study.

OBJECTIVE: Oral anticoagulation (OAC) reduces stroke risk in patients with atrial fibrillation (AF) or atrial flutter (AFL). However, OAC initiation rates in patients discharged directly from the emergency department (ED) are low. We aimed to address this care gap by implementing a quality improvement intervention. METHODS: The study was performed in four Canadian urban EDs between 2015 and 2016. Patients were included if they had an electrocardiogram (ECG) documenting AF/AFL in the ED, were directly discharged from the ED, and were alive after 90 days. Baseline rates of OAC initiation were determined prior to the intervention. Between June and December 2016, we implemented our intervention in two EDs (ED-intervention), with the remaining sites acting as controls (ED-control). The intervention included a reminder statement prompting OAC initiation according to guideline recommendations, manually added to ECGs with a preliminary interpretation of AF/AFL, along with a decision-support algorithm that included a referral sheet. The primary outcome was the rate of OAC initiation within 90 days of the ED visit. RESULTS: Prior to the intervention, 37.2% OAC-naïve patients with ECG-documented AF/AFL were initiated on OAC. Following implementation of the intervention, the rate of OAC initiation increased from 38.6% to 47.5% (absolute increase of 8.5%; 95% CI, 0.3% to 16.7%, p=0.04) among the ED-intervention sites, whereas the rate remained unchanged in ED-control sites (35.3% to 35.9%, p=0.9). CONCLUSIONS: Implementation of a quality improvement intervention consisting of a reminder and decision-support tool increased initiation of OAC in high-risk patients. This support package can be readily implemented in other jurisdictions to improve OAC rates for AF/AFL.

What is the Impact of Frailty on Prescription of Anticoagulation in Elderly Patients with Atrial Fibrillation? A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) and frailty are both associated with advanced age. Oral anticoagulants (OAC) effectively prevent strokes in AF patients but are underutilized in the elderly, possibly due to misperception of frailty. OBJECTIVE: We performed a systematic review to determine the prevalence of frailty in patients with AF, and whether frailty was associated with reduced prescription of OAC. METHODS: We systematically searched Cochrane, MEDLINE, EMBASE, and PubMed databases. Search terms combined relevant words and MeSH headings: 1) atrial fibrillation, 2) frail elderly, and 3) geriatric assessments. Studies that measured frailty using a validated instrument, and involved OAC for AF in frail and non-frail patients were eligible for inclusion. Pooled odds ratios were calculated using random-effects model. RESULTS: Of 166 reviewed titles, only 3 studies (1204 patients) met the inclusion criteria. Two used the Reported Edmonton Frail Scale (total 509 patients), and one used the Canadian Study of Health and Aging Clinical Frailty Scale (682 patients). All 3 studies involved hospitalized patients with an average age of 85 ± 6 and 45% were male. The weighted mean prevalence of frailty in patients with atrial fibrillation was 39% (95%CI 36-42). The weighted mean rate of OAC use was 57±11%. Frailty was associated with non-prescription of OAC compared to non-frail (OR 0.49, 95% CI 0.32-0.74, I2 =45%). CONCLUSION: The prevalence of frailty in hospitalized elderly patients with AF is high, and the use of OAC is low in these patients. Frail elderly are significantly less likely to receive OAC.

Factors Influencing Oral Anticoagulation Prescription for Patients Presenting to Emergency Departments With Atrial Fibrillation and Flutter.

Atrial fibrillation and atrial flutter (AF/AFL) are associated with an increased risk of stroke and systemic embolism. However, many patients are not started on guideline-recommended oral anticoagulation (OAC). We determined factors associated with initiation of OAC in eligible patients presenting to emergency departments. This retrospective cohort included patients with electrocardiogram (ECG)-documented AF/AFL presenting to 4 urban emergency departments in 2015. Presenting diagnoses, admission status, and comorbidities were determined by chart review. The primary outcome was OAC prescription within 90 days of ED presentation in guideline-eligible patients not previously on OAC. Of 4948 patients presenting to emergency departments with ECG-documented AF/AFL, we identified 2059 patients with Congestive Heart failure, Age (≥65),Diabetes, and Stroke (CHADS-65) score ≥1 not previously on OAC. Of those patients, 1287 (62.5%) were admitted, and 772 (37.5%) were discharged from the emergency department. Within 90 days of discharge, 663 (32.2%) patients were initiated on OAC. On multivariable analysis, hospitalization (odds ratio [OR] 1.31; 95% confidence interval [CI] 1.05-1.63, P = 0.02), presenting diagnosis of AF/AFL (OR 4.56, 95% CI 3.60-5.79, P < 0.01), and higher CHADS-65 score (OR 1.14 per point, 95% CI 1.04-1.25, P < 0.01) were associated with increased rates of OAC initiation. However, there was no association with individual components of the CHADS-65 score. Guideline-directed OAC is infrequently initiated in eligible patients within 90 days of presenting to emergency departments. The strongest factors associated with OAC initiation rates were hospitalization or having primary presenting diagnoses in emergency departments of AF/AFL after adjusting for other important characteristics. New interventions are required to improve appropriate OAC initiation in patients with AF/AFL.

Diagnostic Value of Neurological Studies in Diagnosing Syncope: A Systematic Review.

BACKGROUND: Syncope is common and approaches to establishing etiology remain a matter of clinical and financial importance. Patients often undergo comprehensive neurologic investigations despite a lack of compelling indications. The aim was to determine the prevalence of use and diagnostic yield of electroencephalography (EEG), head computed tomography (CT), head magnetic resonance imaging (MRI), and carotid Doppler ultrasound (CUS) examinations. METHODS: We conducted a systematic search in EMBASE, PubMed, and Cochrane from 1970 to 2015 for studies reporting on the use of EEG, CT, MRI, and CUS in diagnosing the cause of syncope. The inclusion criteria were: (1) observational and randomized trials; (2) frequency of use of investigations; and (3) diagnostic yield. Diagnostic studies of the more general transient loss of consciousness were excluded. RESULTS: Of 149 screened studies, 15 studies having 6944 patients met the criteria. No studies met all 6 prespecified quality descriptors. The mean prevalence of test use were: EEG, 17.0%; CT, 57.3%; MRI, 10.5%; and CUS, 17.8%. The articles reported the likelihoods of a test providing diagnostic information for syncope etiology were: EEG, 1.35%; CT, 1.18%; MRI, 3.74%; and CUS, 2.4%. Only 2 new and informative results were noted in 6334 tests. CONCLUSIONS: Neurologic investigations for assessment of patients deemed to have syncope are used widely and are widely ineffective. Neurologic investigations should be obtained only with a very high degree of clinical suspicion.

High Remission Rates in Vasovagal Syncope: Systematic Review and Meta-Analysis of Observational and Randomized Studies.

OBJECTIVES: The aims of this study were to quantify the degree of improvement in vasovagal syncope after assessment and to identify predictive factors. BACKGROUND: No treatments for vasovagal syncope have been proved effective, but patients in all prospective studies appear to show a reduction in the likelihood of fainting. METHODS: A systematic review and meta-analysis was performed of studies published from 1993 through 2013. Inclusion criteria were: 1) vasovagal syncope frequency in the preceding 1 to 2 years; and 2) the proportion of subjects with syncope in at least the first follow-up year. Random-effects methods were used. RESULTS: Of 338 screened studies, 17 were analyzed, with a mean of 112 subjects (range 9 to 511 subjects). In the preceding epoch, 97% of subjects fainted, with 2.6 ± 1.0 syncopal spells per year. In the follow-up year, the proportion of patients with ≥1 syncope recurrence was 677 of 1,912 (35.4%), and in the meta-analysis, the proportion of subjects fainting was only 0.44 (95% confidence interval: 0.41 to 0.46; p < 0.001). Subjects in larger studies were less likely to faint than those in randomized trials (relative risk: 0.35 vs. 0.55; p = 0.004). The probabilities of ≥1 syncope recurrence in the observational versus randomized studies were 0.30 (95% confidence interval: 0.24 to 0.37) and 0.54 (95% confidence interval: 0.46 to 0.62), respectively (p < 0.001). None of the degree of blinding, type of intervention, age, sex, and number of recent faints predicted the probability of syncope recurrence. Heterogeneity was very high in all analyses (I2 = 60% to 96%). CONCLUSIONS: The spontaneous remission rate in highly symptomatic syncope patients is high, and remission occurs in all types of studies. Improvement was more likely in larger and observational studies.

Clusters, Gaps, and Randomness: Vasovagal Syncope Recurrence Patterns.

OBJECTIVES: This study elucidated the temporal recurrence patterns of syncope in patients with frequent vasovagal syncope (VVS). BACKGROUND: Understanding the temporal distribution of fainting spells in syncope patients may illuminate biological processes and inform decision making. METHODS: Patients from the POST 2 (Prevention of Syncope Trial 2) were included; all had VVS and fainted ≥4 times in the study year, providing ≥3 interevent intervals (IEIs). Only fainting spells separated by ≥1 day were included. IEI distributions were analyzed using Poisson modeling and cumulative sum distributions. RESULTS: Twenty-four patients (5 males, 19 females; mean 33 years of age) had a total of 286 syncopal events and 262 IEIs, with a median 6 IEI. They resembled excluded subjects in age and sex but fainted more often in their lives (median: 57 vs. 13 fainting spells, respectively; p < 0.0001) and in the previous year (median: 23 vs. 3 fainting spells, respectively; p < 0.0001). Subjects had a median IEI duration of 8 (interquartile range: 4 to 19) days. The IEI distributions were fit well by Poisson models with a median r2 of 0.94 (95% confidence interval: 0.91 to 0.97). The patients' Poisson rate constant frequencies were 7 to 263 fainting spells/year with a median rate of 19 fainting spells/year. The modal syncope frequency was 10 to 15 fainting spells per year. Seven patients had biexponential distributions, and many patients fainted in clusters. CONCLUSIONS: Patients with frequent VVS have fainting spells that occur randomly in time. Clusters of syncope occur, and in this population, there is a central tendency to 10 to 15 fainting spells per year. This provides a quantitative measure of frequency and predictability that may afford individualized treatment goals.

Acute myeloid leukaemia: expression of MYC protein and its association with cytogenetic risk profile and overall survival.

Acute myeloid leukaemia (AML) is a clinically aggressive disease with marked genetic heterogeneity. Cytogenetic abnormalities provide the basis for risk stratification into clinically favourable, intermediate, and unfavourable groups. There are additional genetic mutations, which further influence the prognosis of patients with AML. Most of these result in molecular aberrations whose downstream target is MYC. It is therefore logical to study the relationship between MYC protein expression and cytogenetic risk groups. We studied MYC expression by immunohistochemistry in a large cohort (n = 199) of AML patients and correlated these results with cytogenetic risk profile and overall survival (OS). We illustrated differential expression of MYC protein across various cytogenetic risk groups (p = 0.03). Highest expression of MYC was noted in AML patients with favourable cytogenetic risk group. In univariate analysis, MYC expression showed significant negative influence of OS in favourable and intermediate cytogenetic risk group (p = 0.001). Interestingly, MYC expression had a protective effect in the unfavourable cytogenetic risk group. In multivariate analysis, while age and cytogenetic risk group were significant factors influencing survival, MYC expression by immunohistochemistry methods also showed some marginal impact (p = 0.069). In conclusion, we have identified differential expression of MYC protein in relation to cytogenetic risk groups in AML patients and documented its possible impact on OS in favourable and intermediate cytogenetic risk groups. These preliminary observations mandate additional studies to further investigate the routine clinical use of MYC protein expression in AML risk stratification. Copyright © 2016 John Wiley & Sons, Ltd.

CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series.

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarely CD10 positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics. AIMS AND METHODS: A series of nine CD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) of CD10-negative MCL cases (controls), which were randomly selected from our institutional registry. RESULTS: GEP showed distinct expression of a GC signature in CD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between our CD10-positive and CD10-negative MCL cases. The frequency of SHM was comparable with established data. CONCLUSIONS: This study provides convincing evidence that CD10 expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications.

Protein Expression for Novel Prognostic Markers (Cyclins D1, D2, D3, B1, B2, ITGß7, FGFR3, PAX5) Correlate With Previously Reported Gene Expression Profile Patterns in Plasma Cell Myeloma.

Among plasma cell myeloma (PCM) patients, gene expression profiling (GEP)-based molecular classification has proven to be an independent predictor of survival, after autologous stem cell transplantation. However, GEP has limited routine clinical applicability given its complex methodology, high cost, and limited availability in clinical laboratories. In this study, we have evaluated biomarkers identified from GEP discoveries, utilizing immunohistochemistry (IHC) platform in a cohort of PCM patients. IHC staining for cyclins B1, B2, D1, D2, D3, FGFR3, PAX5, and integrin ß7 (ITGß7) was performed on the bone marrow biopsies of 93 newly diagnosed PCM patients. Expression of FGFR3 was noted in 10 (11%) samples correlating completely with t(4;14)(p16;q32) results (P<0.001); however, the association between FGFR3 and cyclin D2 expression was not significant (P=0.14). ITGß7 expression was present in 9/93 (9%) patients and all these samples also demonstrated upregulated expression of cyclin D2 (P=0.014). Expression of cyclins D1, D2, and D3 was variable in this cohort. Positive protein expression of cyclin D1 was noted in 30/93 (32%), D2 in 17/93 (18%), and D3 in 5/93 (5%) samples. Coexpression of cyclins D1 and D2 was observed in 13/93 (14%) samples, whereas 28 (30%) samples were negative for all the 3 cyclin D proteins. Cyclin B1 was not expressed in any sample, despite adequate staining in positive controls. Cyclin B2 was expressed in 33/93 (35%) and PAX5 protein was noted in 7/93 (8%) samples. In summary, we have demonstrated that mRNA-based prognostic markers can be detected by routine IHC in decalcified bone marrow samples. This approach may provide a useful tool for the wider adoption of prognostic makers for risk stratification of PCM patients. We anticipate that such an approach might allow patients with high-risk immunoprofiles to be considered for other potential novel therapeutic agents, potentially sparing some patients the toxicity of stem cell transplant.

Clinical improvement of vasovagal syncope in the absence of specific therapies: The Seinfeld effect.

Vasovagal syncope can persist for decades and recur sporadically but many patients appear to improve after being seen in specialty clinics. The absence of specific and proven effective therapy raises the possibility that this might be due to regression to the mean or to a placebo effect. However, analysis using the Poisson distribution indicates the extreme unlikeliness that regression to the mean is the explanation. A main cause of the placebo effect is expectancy. Subject expectancy is the influence of the subject's anticipation of benefit on outcomes, and observer expectancy is the influence of investigator or physician attitudes and behavior on subject response. Ample data support the role of expectancy in outcomes of syncope patients. Moreover, expectancy can vary depending on the type of ineffective intervention. Interestingly, studies in which patients are blinded but the investigator is not show similar patient benefits compared with completely open label studies consistent with a strong observer expectancy effect due to physician-subject interaction. These results suggest the paramount importance of properly conducted randomized clinical trials in assessing biomedical interventions, and also illuminate the powerful potential of studies aimed at enhancing the expectancy effect on patient outcome.

B-lymphoblastic leukemia/lymphoma: overexpression of nuclear DNA repair protein PARP-1 correlates with antiapoptotic protein Bcl-2 and complex chromosomal abnormalities.

Poly(ADP-ribose) polymerase-1 (PARP-1) and Bcl-2 are emerging as therapeutic targets in various cancers. The former is a DNA repair protein associated with genomic stability and apoptosis, whereas the latter is an antiapoptotic protein having a DNA repair function through inhibition of PARP-1. Because genomic stability is critical for prognosis in B-lymphoblastic leukemia/lymphoma (B-ALL), we studied the expression of PARP-1 and Bcl-2 proteins in patients with B-ALL of different ages and compared the results with cytogenetic data. The PARP-1 protein was overexpressed in about two-thirds (61%) of patients with B-ALL. It had a nuclear location, whereas Bcl-2 protein was cytosolic. Expression of the 2 proteins showed a highly positive correlation (ρ = 0.367; P < .001). Overexpression of PARP-1 correlated with a complex karyotype (P = .030), and this correlation remained significant for coexpression of PARP-1 and Bcl-2 proteins (χ(2) = 7.498; P = .024) as well as after exclusion of pediatric patients (n = 9, P = .042). Overexpression of PARP-1 was not significantly more common in diploid versus aneuploid karyotypes (50% versus 59%, P = .610). The PARP-1 protein showed no correlation with specific chromosomal abnormalities associated with prognosis in B-ALL, as defined by the World Health Organization. In conclusion, high expression of the PARP-1 protein among patients with B-ALL is related to a complex karyotype and Bcl-2 positivity. Although these findings require validation in a larger population, the observations will be valuable in planning therapeutic trials (such as of PARP inhibitors and BH3 mimetics).

LMO2 (LIM domain only 2) is expressed in a subset of acute myeloid leukaemia and correlates with normal karyotype.

AIM: LMO2 is a transcription factor that plays a key role in haematopoiesis. Expression of LMO2 has been demonstrated in germinal centre B cells, various B cell lymphomas and T lymphoblastic lymphoma/leukaemia (T-ALL), but has not been studied extensively in acute myeloid leukaemia (AML). METHODS: We studied LMO2 expression by immunohistochemistry in biopsies from a cohort of AML patients (n = 196) and correlated it with established prognostic factors such as age, bone marrow morphology and cytogenetic findings. RESULTS: Forty per cent (79 of 196) of the samples from AML patients showed moderate/strong expression of LMO2 protein. LMO2 expression showed a significant positive correlation with normal cytogenetics (65% versus 24%, P < 0.0001) and a moderately negative correlation with complex karyotype [rs (98) = -0.218, P < 0.002]. AML associated with core binding factor [(t(8;21)/inv(16)/t(16;16)] had low LMO2 expression compared to diploid karyotype (29% versus 65%; P = 0.013). Expression of LMO2 protein exhibited an insignificant association with age (P = 0.197). Lower expression of LMO2 protein was noted in AML associated with myelodysplasia-related changes, compared to AML subtypes based on FAB classification (M0-M7) (21% versus 44%, P = 0.0187). CONCLUSIONS: LMO2 is expressed in a subset of AML patients and is associated with normal karyotype, which is different from T-ALL, where specific translocation (11p13) mediates protein expression.