Citations

In 2005, the description of the JAK2V617F mutation for the first time provided a molecular key to enable more rapid diagnosis and target for novel therapeutics in the myeloproliferative neoplasms. In 2007, the first-in-class agent INC18424, ruxolitinib, JAKafi, or JAKAVI was first tested in patients with intermediate-risk 2 or high-risk myelofibrosis regardless of whether they possessed the JAK2V617F mutation. Patients treated with this agent had major reduction in splenomegaly as well as impressive reduction, and in some cases resolution, of symptoms. This study was followed by the two Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy (COMFORT) trials (the first-ever phase III trials in myelofibrosis), which confirmed results in these aspects were superior to either placebo or standard care, and updated results show a survival advantage with this therapy. This paper discusses these results and data from other JAK inhibitors while speculating on the future of these therapies. It also reflects on the fact that the true targets and agents' mode of action are uncertain. Unlike targeted therapy for chronic myeloid leukemia (CML), these agents do not deliver molecular remission, and it is not clear whether their predominant benefit is mediated via JAK2, JAK1, or both. Nonetheless, the advent of the JAK inhibitor is a welcome advance and has made a dramatic improvement to the therapeutic landscape of these conditions.

AbstractCurrently, the data on independent risk factors for the progression of kidney disease in type 2 diabetes mellitus (T2DM) patients with CKD are limited. This study aimed to investigate CKD progression in T2DM patients who have reduced kidney function with baseline estimated glomerular filtration rate (eGFRs) between 15 and 59 mL/min/1.73 m2. This study was composed of a nationwide retrospective cohort of adult T2DM patients from 831 public hospitals in Thailand during the year 2015. T2DM patients with CKD stages 3 and 4 were followed up, until development of CKD stage 5, requirement of chronic dialysis, loss to follow‐up, death, or 31 May 2018, whichever came first. Cox proportional hazard regression was utilized for analysis. A total of 8464 participants were included; 30.4% were male. The mean age was 69 ± 10 years. The mean eGFR was 45 ± 11 mL/min/1.73 m2. The incidence of CKD stage 5 or the need for chronic dialysis was 16.4 per 1000 person‐years. The annual rate of eGFR decline during a mean follow‐up of 29 months was −2.3 mL/min/1.73 m2; 14.4% had a rapid decline in eGFR. The risk factors associated with progression to CKD stage 5 or the need for chronic dialysis were diabetes duration, systolic blood pressure, serum uric acid, albuminuria, and baseline eGFR. Conversely, older age and the use of renin‐angiotensin aldosterone system blockade were associated with decreased risks for rapid CKD progression and incidence CKD stage 5 or dialysis. This study identifies multiple predictive risk factors that support a multifaceted approach to prevent progression of advanced CKD.

Background: Vascular and bleeding complications were commonly reported in transcatheter aortic valve replacement clinical trials. Little is known about complication rates in contemporary US clinical practice or clinical outcomes associated with these complications. Methods: In the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry, we evaluated patients undergoing transcatheter aortic valve replacement from November 1, 2011 to June 30, 2016. The primary outcomes were in-hospital vascular complications and bleeding events. Secondary outcomes included all-cause mortality, stroke, and rehospitalization at 1 year. P values for trends were calculated for rates over time, and multivariable logistic regression was used to determine the association between vascular/bleeding complications and in-hospital clinical outcomes. Results: Overall, 34 893 patients undergoing transcatheter aortic valve replacement at 445 hospitals were analyzed. Of these, 9.3% (n=3257) experienced a vascular complication while 7.6% (n=2651) had an in-hospital bleeding event. Rates of both vascular complications and bleeding events decreased over time ( P value for trend test <0.0001); however, there was significant variation in rates across hospital sites (adjusted median rate, 11.4%; IQR, 8.9–14.5). Vascular complications were independently associated with 30-day death (adjusted HR, 2.23 [95% CI, 1.80–2.77]) and death (adjusted HR, 1.17 [95% CI, 1.05–1.30]) and rehospitalization (adjusted HR, 1.14 [95% CI, 1.07–1.22]) at 1 year. Bleeding events were also associated with 30-day death (adjusted HR, 3.71 [95% CI, 2.94–4.69]), and with death (adjusted HR, 1.39 [95% CI, 1.23–1.56]) and hospital readmission (adjusted HR, 1.19 [95% CI, 1.11–1.27]) at 1 year. Conclusions: In patients undergoing transcatheter aortic valve replacement in the US, vascular complications and in-hospital bleeding events were common, but rates have declined over time with significant variation in complication rates across hospital sites. Vascular and bleeding complications are both associated with worse short- and long-term clinical outcomes including all-cause mortality. Further innovation to reduce sheath sizes and optimize antithrombotic therapy is necessary to reduce the incidence of these detrimental complications.

Abstract Purpose: With increasing incidence of renal mass, it is important to make a pretreatment differentiation between benign renal mass and malignant tumor. We aimed to develop a deep learning model that distinguishes benign renal tumors from renal cell carcinoma (RCC) by applying a residual convolutional neural network (ResNet) on routine MR imaging. Experimental Design: Preoperative MR images (T2-weighted and T1-postcontrast sequences) of 1,162 renal lesions definitely diagnosed on pathology or imaging in a multicenter cohort were divided into training, validation, and test sets (70:20:10 split). An ensemble model based on ResNet was built combining clinical variables and T1C and T2WI MR images using a bagging classifier to predict renal tumor pathology. Final model performance was compared with expert interpretation and the most optimized radiomics model. Results: Among the 1,162 renal lesions, 655 were malignant and 507 were benign. Compared with a baseline zero rule algorithm, the ensemble deep learning model had a statistically significant higher test accuracy (0.70 vs. 0.56, P = 0.004). Compared with all experts averaged, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.60, P = 0.053), sensitivity (0.92 vs. 0.80, P = 0.017), and specificity (0.41 vs. 0.35, P = 0.450). Compared with the radiomics model, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.62, P = 0.081), sensitivity (0.92 vs. 0.79, P = 0.012), and specificity (0.41 vs. 0.39, P = 0.770). Conclusions: Deep learning can noninvasively distinguish benign renal tumors from RCC using conventional MR imaging in a multi-institutional dataset with good accuracy, sensitivity, and specificity comparable with experts and radiomics.

PurposePhysical and digital phantoms play a key role in the development and testing of nuclear medicine instrumentation and processing algorithms for clinical and research applications, including neuroimaging using positron emission tomography (PET). We have developed and tested a digital reference object (DRO) version of the original segmented magnetic resonance imaging (MRI) data used for the three‐dimensional (3D) PET brain phantom developed by Hoffman et al., which is used as the basis of a commercially available physical test phantom.MethodsThe DRO was constructed by subdividing the MRI image planes the original phantom was based on to create equal‐thickness slices and re‐labeling voxels. The digital data was then embedded in a PET Digital Imaging and Communications in Medicine format and tested for compliance.ResultsWe then tested the DRO by comparing it to computed tomography (CT) images of the physical phantom summed to form composite slices with axial extent similar to the DRO, but with a factor of two better in‐slice resolution. For composite slices, 91% of voxels were labeled in full agreement, 5% of the voxels were 50–75% accurate, and the remaining 4% of voxels had 25% or less agreement.ConclusionsThis DRO can be used as an input for PET scanner simulation studies or for comparing simulations to measured Hoffman phantom images.

ABSTRACTBlood smear evaluation of two baboons (Papio cynocephalus) experiencing acute hemolytic crises following experimental stem cell transplantation revealed numerous intraerythrocytic organisms typical of the genusBabesia. Both animals had received whole-blood transfusions from two baboon donors, one of which was subsequently found to display rare trophozoites ofEntopolypoides macaci. An investigation was then undertaken to determine the prevalence of hematozoa in baboons held in our primate colony and to determine the relationship, if any, between the involved species. Analysis of thick and thin blood films from 65 healthy baboons (23 originating from our breeding facility, 26 originating from an out-of-state breeding facility, and 16 imported from Africa) for hematozoa revealed rareE. macaciparasites in 31%, with respective prevalences of 39, 35, and 12%. Phylogenetic analysis of nuclear small-subunit rRNA gene sequences amplified from peripheral blood of a baboon chronically infected withE. macacidemonstrated this parasite to be most closely related toBabesia microti(97.9% sequence similarity); sera from infected animals did not react in indirect fluorescent-antibody tests withBabesia microtiantigen, however, suggesting that they represent different species. These results support an emerging view that the genusEntopolypoidesMayer 1933 is synonymous with that of the genusBabesiaStarcovici 1893 and that the morphological variation noted among intracellular forms is a function of alteration in host immune status. The presence of an underrecognized, but highly enzootic,Babesiasp. in baboons may result in substantial, unanticipated impact on research programs. The similarity of this parasite to the known human pathogenB. microtimay also pose risks to humans undergoing xenotransplantation, mandating effective screening of donor animals.

Purpose: To demonstrate the utility of an ultrasonic aspirator (Sonopet, Stryker Corporation; Kalamazoo, MI) for debulking firm, soft tissue masses of the orbit. Methods: Case series. The ultrasonic aspirator was used to debulk firm, soft tissue masses in 3 cases. The initial patient had a large orbitofacial mass extending to the inferior and lateral orbital apex secondary to IgG4 disease. The second patient had a lacrimal sac adenocarcinoma extending to the medial orbital apex. The third patient had a large orbital mass extending to the apex secondary to granulomatosis with polyangiitis. Results: The ultrasonic aspirator facilitated debulking of infiltrative firm soft tissue masses of the orbit. The device’s ability to emulsify, irrigate, and aspirate, along with its small footprint, facilitated precise sculpting and debulking to an extent which would have been difficult otherwise due to location. Conclusions: The ultrasonic aspirator allows precise sculpting of infiltrative firm soft tissue masses in the orbit and is particularly useful in cases with challenging anatomical access.

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), Myelofibrosis (Primary [PMF] and secondary to PV and ET [PPV-, PET-MF] and unclassified MPN (U-MPN), are associated with an increased risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT). SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites,hepatic failure and biliopathy. According to a meta-analysis MPN is the underlying cause of portal vein thrombosis (PVT) in 31.5% and Budd Chiari syndrome (BCS) in 40.9% of cases (Smalberg, 2012); a more in-depth analysis of clinical characteristics and evolution of MPN-associated SVT has been hampered by heterogeneity of cohorts comprising small number of cases. We conducted a retrospective multicenter study in patients (pts) with SVT associated with WHO2008-diagnosed MPN, with the aim to describe patient characteristics, disease course and prognostic factors with potential implications for clinical practice. Data were collected from 16 international hematologic centers in the framework of the Italian AGIMM and the IWG-MRT groups. We collected 519 cases of pts with PVT, splenic or mesenteric vein thrombosis (75.1%) and BCS (24.9%) associated with MPN. We used as comparator a cohort of 1686 controls (Ctr) represented by MPN without (w/o) SVT: 741 ET (43.9%), 684 PV (39.7%), 261 PMF (15.5%). Frequency of MPN associated with SVT was 37.8% ET (n=196), 36.8% PV (n=191), 15.4% MF (n=80), 10% U-MPN (n=52). Median follow-up was 89.9 months (mo) (range 0.5-430). For SVT vs Ctr group females were 54.5% vs 44.4% in PV (P=0.001), 68.4 vs 63.5% (p=0.13) in ET, 63.7% vs 29.1% in PMF (p<0.0001); median age at MPN diagnosis (dg) was 43.5 yr (range 12-90) vs 60.6 yr (range 12-93) (p<0.0001). Age at SVT dg was 44 yr (range 15-85). In 240 cases (46.7%) MPN and SVT dg were coincident, in 121 (23.6%) SVT occurred before MPN dg (median 26 mo, range 4-307) and in 153 (29.8%) during MPN follow up (median 68 mo, range 4-362). JAK2V617F mutation was found in 94% PV vs 94% in Ctr, 84% vs 61% ET (p<0.0001), 88.1% vs 68% PMF (p=0.006) and in 93% U-MPN. Erythropoietin-independent colonies (EEC) were evaluated in 111 SVT pts and found in 80 (72%), accounting for 38/48 PV (79%), 31/44 ET (70.5%), 9/12 PMF (75%) and 2/7 U-MPN (28.6%). At dg, SVT PV pts had lower hemoglobin levels than Ctr: median was 17.4 g/dL vs 18.5 g/dL (p<0.0001) in male, 16.9 g/dL vs 17.7 g/dL (p=0.0006) in female. A co-existing thrombophilic status was found in 38.5% SVT vs 11.8% of Ctr (p<0.0001). Recurrent SVT occurred in 12.2% of pts with a rate of 1.6% person/year (CI 1.2-2.1); risk of venous thrombosis other than SVT was increased in SVT group vs Ctr (p=0.02), with no difference for arterial thrombosis. Hemorrhage was more frequent in SVT group (32%) vs Ctr (7.2%)(p<0.0001), mainly related to esophageal varices, which were present in 66.9% of SVT pts. There was no difference in evolution to MF and acute leukemia (AL) for PV and ET pts with and w/o SVT, while risk of AL was lower in MF with SVT (p<0.00001). Overall survival was shorter in ET pts with SVT vs Ctr (p<0.0001). In PMF survival was better in SVT group (p<0.00001) and was associated with a higher proportion of SVT pts in lowest risk categories: IPSS low 65%, intermediate-1 20%, intermediate-2 10% and high 5% compared with 15%, 34%, 25% and 26% in Ctr group. At last FU, 79/519 pts (15.2%) had died; causes of death were evolution to AL (15.4%), other cancers (13.8%), disease progression without AL (10.8%), SVT (10.8%), hepatic failure and venous thrombosis other than SVT (7.7% each), heart failure and arterial thrombosis (6.2% each), hemorrhage (5.5%), renal failure and infection (4.6% each). Therapy after SVT included anticoagulation in 77%, antiaggregant in 21.2% and combination in 1.8%; 70% received cytotoxic drugs; 12.4% were treated with transjugular porto-systemic shunt. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) MPN associated with SVT correlated with younger age and female sex and might antedate the clinical phenotype in a quarter of the patients. MPN-associated SVT equally affected PV and ET, was more likely to occur in the presence of JAK2V617F or underlying thrombophilia and predicted recurrent venous but not arterial thrombosis. The apparent association of SVT with better or worse prognosis in PMF and ET, respectively, requires further investigation. Disclosures No relevant conflicts of interest to declare.