Citations

SummaryPatients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow‐up of 9·5 [8·1–11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β2‐microglobulin (β2M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time‐to‐progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7–8·7) vs. 4·7 (2·4–7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C‐X‐C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT, P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age‐, sex‐ and calendar year‐matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β2M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre‐emptive intervention in this patient population.

Abstract Pneumocystis species interaction with myeloid cells is well known, especially in macrophages; however, how the organism binds to lung epithelial cells is incompletely understood. Ephrin type-A receptor 2 (EphA2) has been previously identified as a lung epithelial pattern recognition receptor that binds to fungal β-glucans. Herein, we also report that EphA2 can also bind Pneumocystis β-glucans, both in isolated forms and also on exposed surfaces of the organism. Furthermore, binding of Pneumocystis β-glucans resulted in phosphorylation of the EphA2 receptor, which has been shown to be important for downstream proinflammatory response. Indeed, we also show that interleukin 6 cytokine is significantly increased when lung epithelial cells are exposed to Pneumocystis β-glucans, and that this response could be blocked by preincubation with a specific antibody to EphA2. Our study presents another Pneumocystis lung epithelial cell receptor with implications for initial colonization and possible therapeutic intervention.

Abstract Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning has been shown to be predictive of patient outcomes throughout the disease course. We sought to corroborate these findings by examining the prognostic impact of PET/CT scanning in the posttransplant setting. We retrospectively analyzed PET/CT scans in 229 MM patients receiving an autologous stem cell transplant (ASCT) near day 100, and correlated these findings with time to progression(TTP) and overall survival (OS) to assess the impact of day 100 PET/CT scan findings as an independent prognostic factor. The median OS for the entire cohort was 61.5 months (95% confidence interval [CI], 49-75) and the median TTP was 18.5 months (95% CI, 15.4-21.8). Among patients with abnormal day 100 PET findings (PET+), median TTP was 12.4 months vs 24 months among those with normal PET findings (PET−) (P < .0001). The median OS in the PET+ group was 46 months compared with 99 months in the PET− group (P < .0001). We conclude that an abnormal PET/CT scan near day 100 post-ASCT is predictive of shorter TTP and OS, with prognostic significance retained after adjusting for disease response and other prognostic variables in MM.

Background While venous congestion in the peripheral vasculature has been described and accepted, intracranial venous congestion remains poorly understood. The characteristics, pathophysiology, and management of cerebral venous stasis, venous hypertension and venous congestion remain controversial, and a unifying conceptual schema is absent. The cerebral venous and lymphatic systems are part of a complex and dynamic interaction between the intracranial compartments, with interplay between the parenchyma, veins, arteries, cerebrospinal fluid, and recently characterized lymphatic-like systems in the brain. Each component contributes towards intracranial pressure, occupying space within the fixed calvarial volume. This article proposes a framework to consider conditions resulting in brain and neck venous congestion, and seeks to expedite further study of cerebral venous diagnoses, mechanisms, symptomatology, and treatments. Methods A multi-institution retrospective review was performed to identify unique patient cases, complemented with a published case series to assess a spectrum of disease states with components of venous congestion affecting the brain. These diseases were organized according to anatomical location and purported mechanisms. Outcomes of treatments were also analyzed. Illustrative cases were identified in the venous treatment databases of the authors. Conclusion This framework is the first clinically structured description of venous pathologies resulting in intracranial venous and cerebrospinal fluid hypertension. Our proposed system highlights unique clinical symptoms and features critical for appropriate diagnostic work-up and potential treatment. This novel schema allows clinicians effectively to approach cases of intracranial hypertension secondary to venous etiologies, and furthermore provides a framework by which researchers can better understand this developing area of cerebrovascular disease.

BACKGROUND: Idiopathic recurrent pericarditis (IRP) is a debilitating condition that can be recalcitrant to conventional therapy. Some patients develop steroid dependency with the attendant risks of systemic side effects and increased future recurrence. Anakinra is a recombinant human interleukin-1 receptor antagonist that reduces systemic inflammatory responses. The aim of this study was to evaluate the therapeutic role of anakinra in IRP. Methods: We retrospectively studied consenting patients with treatment refractory IRP who received anakinra, between January 2009 and November 2013. The primary end points were symptom resolution and steroid discontinuation. Results: Nine patients were followed for a median of 16.8 (IQR 1.3-24) months. Study subjects were predominantly female (7 [78%]) with a median age of 53 (IQR 38 - 58) years. All 9 patients had failed maximum tolerated doses of NSAIDs, colchicine and prednisone (median dose 20 mg [IQR 15 - 22.5]). Primary symptom was chest pain in 9 (100%), with concurrent dyspnea in 5 (56%) patients. Symptom duration prior to anakinra initiation was 24 (IQR 13 - 71) months. Indication for anakinra was steroid sparing agent in 7 (78%) and symptom control in 2 (22%) patients. The dosage was 100 mg once daily via subcutaneous injection. Baseline LVEF was 62% (IQR 59% - 67%). Echocardiographic findings include pericardial effusion in 3 (33%), pericardial thickening in 6 (67%), and constrictive physiology in 4 (44%). Pericardial enhancement on cardiac MRI was seen in 7 (78%) patients. All 9 patients (100%) had symptom improvement with complete resolution in 8 (89%) and partial resolution in 1 (11%) patient. At last follow up, all 9 (100%) patients had discontinued NSAIDs and colchicine, 5 (56%) patients discontinued and 4 (44%) had reduced prednisone dosage. All patients remained on anakinra at the end of follow up. The only reported side effect was transient injection site reaction in 4 (44%) patients. In 2 (22%) patients, attempted anakinra weaning was unsuccessful due to symptomatic flare after 6 weeks. Conclusion: Anakinra is an effective alternative agent for the management of steroid dependent IRP. It provides remarkable symptomatic amelioration, limits steroid dependency, and is associated with minimal side effects.

Background: Apical hypertrophic cardiomyopathy (apical HCM) is a less common subtype of HCM characterized by a focal thickening in the left ventricular apex. “Classic” ECG features have been described, however, apical HCM can persist for many years without detection. We investigated the relationship between ECG findings and echocardiographic morphometry in a large referral series of patients with apical HCM. Methods: We enumerated all patients diagnosed with apical HCM prior to Sept. 30, 2006 using the Mayo Clinic HCM database. We compared echocardiographic measures separately for patients with positive status for two ECG indices of left ventricular hypertrophy (LVH); the Sokolow-Lyon index and the Romhilt-Estes (RE) point-score. We also compared echocardiographic measurements in patients with and without negative T-waves in the precordial leads. Results: Apical HCM was detected in 177 patients (111 men and 68 women). Only 51% had positive Sokolow criteria and 51% had positive RE criteria. The agreement between Sokolow and RE status was high (agreement = 75.0%; kappa = 0.50; 95% CI = 0.38 – 0.62). In particular, Sokolow positive patients had increased LV ejection fraction (P = 0.02), and decreased LV end-systolic diameter (P = 0.03) compared with Sokolow negative patients. The prevalence of right atrial enlargement (47 vs. 28%; P = 0.02) and intracavity obstruction (22 vs. 8%; P = 0.01) were more common in Sokolow positive patients. Positive RE criteria was associated with a greater thickness of the basal septal and basal posterior walls (P = 0.001 and 0.02, respectively), and with a higher frequency of intracavity obstruction (21 vs. 9%; P = 0.04). Most patients (89%) exhibited at least one negative T-wave in the precordial leads; however, only 10% of patients had a negative T-wave of greater than 1.0 mV. We found that patients with an inverted T-wave larger than 0.4 mV (median) had a significantly increased LV ejection fraction (P = 0.03) compared with patients who had smaller or no negative T-waves. Conclusions: Among patients with apical HCM, nearly half do not have ECG evidence of LVH based on classic criteria and most do not have marked T-wave inversions. However, the majority did have at least a mild expression of negative T-waves.

Introduction: Papillary fibroelastomas (PFEs) are the 3rd most common primary cardiac tumors with a prevalence of around 0.01% in patients with echocardiograms. The pathogenesis is controversial but endocardial trauma has been implicated. We hypothesized that increased turbulence in hypertrophic cardiomyopathy (HCM) would be a risk factor for PFE development and characterized PFEs in HCM. Around 5% of HCM patients had neurologic events. We postulated that patients with both PFE and HCM had a higher risk of neurologic events. Methods: We reviewed pathology records from 1990 –2006 and identified 129 subjects with PFEs and 2479 patients with HCM. We then identified the subjects who had both HCM and PFE (n = 19). All subjects signed release for use of their medical records for research. Results: 19 subjects (68.4% female) had both HCM and PFE. Mean age at diagnosis of HCM was 49 (range 21– 81) years. All had outflow tract obstruction with resting gradient >/=30 mm Hg except 2 who had resting gradients <30 mm Hg but elevated gradients on provocation. PFE diagnosis was after a mean of 9.7 years (SD 8.3) following HCM diagnosis. 5 subjects were diagnosed pre-operatively by transthoracic echocardiography, 2 subjects by transesophageal echocardiography and 12 subjects at surgery only. Most subjects had only 1 PFE (57.9%) but 1 subject had as many as 40 tumors. Most PFEs were on the aortic valve (47.4%) and the left ventricular side of the septum and left ventricular outflow tract (42.1%). Only 2 patients had right heart lesions that were presumably unrelated to HCM. 3 patients had previous septal myectomies and all 3 had PFEs near the previous resection. 5 of 19 subjects (26.3%) with PFE and HCM had neurologic events (either strokes or transient ischemic attacks) compared to 199 of 2261 subjects (8.8%) with HCM alone (OR = 4.1; 95% CI 1.4 –11.4, p < 0.05). Conclusion: Nearly 90% of PFEs in HCM are located in the septum, left ventricular outflow tract and aortic valve. This may be supportive of endocardial trauma as a risk factor for PFE development in HCM. About a quarter of patients with PFEs and HCM had neurologic events. This may indicate that these lesions are not innocuous and should perhaps be actively searched for in patients with HCM and unexplained neurologic events.