Citations

SummaryThe hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets—“WHO Targets” (65% reduction in HCV‐related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

Abstract TARGET POPULATION Adults diagnosed with vestibular schwannomas. QUESTION 1 What is the prognostic significance of Antoni A vs B histologic patterns in vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 2 What is the prognostic significance of mitotic figures seen in vestibular schwannoma specimens? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 3 Are there other light microscopic features that predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 4 Does the KI-67 labeling index predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 5 Does the proliferating cell nuclear antigen labeling index predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. QUESTION 6 Does degree of vascular endothelial growth factor expression predict clinical behavior of vestibular schwannomas? RECOMMENDATION No recommendations can be made due to a lack of adequate data. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter_6.

Key Points Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies. Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.

AbstractNeurogenesis in the subependymal zone (SEZ) declines across the human lifespan, and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full‐length (TrkB‐TK+) and truncated TrkB receptors (TrkB‐TK‐) in the human SEZ from infancy to middle age (n = 26–35, 41 days to 43 years). We further measured TrkB‐TK+ and TrkB‐TK‐ mRNAs in the SEZ from young adulthood into ageing (n = 50, 21–103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB‐TK‐ mRNA increased in the SEZ from young adulthood into ageing, whereas TrkB‐TK+ mRNA remained stable. TrkB‐TK‐ mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete‐scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB‐TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ.

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein–coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m‐tolyl 5‐chloro‐2‐[ethylsulfonyl] pyrimidine‐4‐carboxylate [SBI‐115]), and (3) a combination of SBI‐115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA‐treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5−/− ;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2‐fold to 3‐fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5‐deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2‐fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI‐115 alone and by ∼50% when SBI‐115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197‐1218).

Abstract Background Thyroid carcinoma, which is rare in pediatric patients (age 0–18 years) but more common in adolescent and young adult (AYA) patients (age 15–39 years), carries the potential for morbidity and mortality. Methods Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC). Results GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment. Conclusion CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy.

Abstract Acute myelogenous leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT–driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT–null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT–driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug–resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT–driven myeloid leukemia. Mol Cancer Ther; 15(10); 2323–33. ©2016 AACR.

Objective The aim of this study was to compare 2-dimensional (2D) gradient recalled echo (GRE) and 2D spin echo echoplanar imaging (SE-EPI) magnetic resonance elastography (MRE) sequences of the liver in terms of image quality and quantitative liver stiffness (LS) measurement. Materials and Methods This prospective study involved 50 consecutive subjects (male/female, 33/17; mean age, 58 years) who underwent liver magnetic resonance imaging at 3.0 T including 2 MRE sequences, 2D GRE, and 2D SE-EPI (acquisition time 56 vs 16 seconds, respectively). Image quality scores were assessed by 2 independent observers based on wave propagation and organ coverage on the confidence map (range, 0–15). A third observer measured LS on stiffness maps (in kilopascal). Mean LS values, regions of interest size (based on confidence map), and image quality scores between SE-EPI and GRE-MRE were compared using paired nonparametric Wilcoxon test. Reproducibility of LS values between the 2 sequences was assessed using intraclass coefficient correlation, coefficient of variation, and Bland-Altman limits of agreement. T2* effect on image quality was assessed using partial Spearman correlation. Results There were 4 cases of failure with GRE-MRE and none with SE-EPI-MRE. Image quality scores and region of interest size were significantly higher using SE-EPI-MRE versus GRE-MRE (P < 0.0001 for both measurements and observers). Liver stiffness measurements were not significantly different between the 2 sequences (3.75 ± 1.87 kPa vs 3.55 ± 1.51 kPa, P = 0.062), were significantly correlated (intraclass coefficient correlation, 0.909), and had excellent reproducibility (coefficient of variation, 10.2%; bias, 0.023; Bland-Altman limits of agreement, −1.19; 1.66 kPa). Image quality scores using GRE-MRE were significantly correlated with T2* while there was no correlation for SE-EPI-MRE. Conclusions Our data suggest that SE-EPI-MRE may be a better alternative to GRE-MRE. The diagnostic performance of SE-EPI-MRE for detection of liver fibrosis needs to be assessed in a future study.

PurposeTo assess interplatform reproducibility of liver stiffness (LS) and spleen stiffness (SS) measured with magnetic resonance elastography (MRE) based on a 2D gradient echo (GRE) sequence.Materials and MethodsThis prospective Health Insurance Portability and Accountability Act (HIPAA)‐compliant and Institutional Review Board (IRB)‐approved study involved 12 subjects (five healthy volunteers and seven patients with liver disease). A multislice 2D‐GRE‐based MRE sequence was performed using two systems from different vendors (3.0T GE and 1.5T Siemens) on the same day. Two independent observers measured LS and SS on confidence maps. Bland–Altman analysis (with coefficient of reproducibility, CR), coefficient of variability (CV), and intraclass correlation (ICC) were used to analyze interplatform, intra‐ and interobserver variability. Human data were validated using a gelatin‐based phantom.ResultsThere was excellent reproducibility of phantom stiffness measurement (CV 4.4%). Mean LS values were 3.44–3.48 kPa and 3.62–3.63 kPa, and mean SS values were 7.54–7.91 kPa and 8.40–8.85 kPa at 3.0T and 1.5T for observers 1 and 2, respectively. The mean CVs between platforms were 9.2%–11.5% and 13.1%–14.4% for LS and SS, respectively, for observers 1 and 2. There was excellent interplatform reproducibility (ICC >0.88 and CR <36.2%) for both LS and SS, and excellent intra‐ and interobserver reproducibility (intraobserver: ICC >0.99, CV <2.1%, CR <6.6%; interobserver: ICC >0.97, CV and CR <16%).ConclusionThis study demonstrates that 2D‐GRE MRE provides platform‐ and observer‐independent LS and SS measurements. J. Magn. Reson. Imaging 2016;43:1064–1072.