We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly ...diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10−3 and MR5 for ratios <10−5. Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.
•Nilotinib plus multiagent chemotherapy was feasible and showed a comparable outcome to previous results with imatinib for Ph-pos ALL.•The achievement of deep MR with nilotinib at postremission correlated well with the clinical outcomes for Ph-pos ALL.
The Tokyo Guidelines 2013 (TG13) include new topics in the biliary drainage section. From these topics, we describe the indications and new techniques of biliary drainage for acute cholangitis with ...videos. Recently, many novel studies and case series have been published across the world, thus TG13 need to be updated regarding the indications and selection of biliary drainage based on published data. Herein, we describe the latest updated TG13 on biliary drainage in acute cholangitis with meta‐analysis. The present study showed that endoscopic transpapillary biliary drainage regardless of the use of nasobiliary drainage or biliary stenting, should be selected as the first‐line therapy for acute cholangitis. In acute cholangitis, endoscopic sphincterotomy (EST) is not routinely required for biliary drainage alone because of the concern of post‐EST bleeding. In case of concomitant bile duct stones, stone removal following EST at a single session may be considered in patients with mild or moderate acute cholangitis except in patients under anticoagulant therapy or with coagulopathy. We recommend the removal of difficult stones at two sessions after drainage in patients with a large stone or multiple stones. In patients with potential coagulopathy, endoscopic papillary dilation can be a better technique than EST for stone removal. Presently, balloon enteroscopy‐assisted endoscopic retrograde cholangiopancreatography (BE‐ERCP) is used as the first‐line therapy for biliary drainage in patients with surgically altered anatomy where BE‐ERCP expertise is present. However, the technical success rate is not always high. Thus, several studies have revealed that endoscopic ultrasonography‐guided biliary drainage (EUS‐BD) can be one of the second‐line therapies in failed BE‐ERCP as an alternative to percutaneous transhepatic biliary drainage where EUS‐BD expertise is present.
HighlightThe Tokyo Guidelines 2013 are due for an update based on newly published data. On behalf of the Tokyo Guidelines Revision Committee, Mukai and colleagues describe the latest drainage techniques for acute cholangitis and treatment methods for stone removal based on a meta‐analysis as part of the Tokyo Guidelines 2018.
Background and Aims Although fully covered self-expandable metal stents (FCSEMSs) have been commonly used for EUS-guided biliary drainage (EUS-BD), FCSEMS migration is a main limitation of this ...procedure. In the present study we evaluated the technical and clinical success rates, adverse events, and long-term outcomes of a newly developed hybrid stent that has been customized for EUS-BD. Methods From September 2011 to May 2015, 54 consecutive patients with biliary obstruction were enrolled in this prospective, observational study. These patients were candidates for alternative BD techniques because of failed ERCP. The hybrid metal stent used for EUS-BD in this study was partially covered, had anchoring flaps, and is commercially available in Korea. Results EUS-guided hepaticogastrostomy (EUS-HGS) was performed in 21 patients and EUS-guided choledochoduodenostomy (EUS-CDS) in 33 patients. The technical and clinical success rates of EUS-BD were 100% (54/54) and 94.4% (51/54), respectively. Immediate adverse events developed after EUS-BD in 9 patients (16.6%; cholangitis in 3, bleeding in 2, self-limited pneumoperitoneum in 3, and abdominal pain in 1). Proximal or distal stent migration was not observed during the follow-up period (median, 148.5 days; IQR, 79.7-244), and the mean stent patency duration was 166.3 days and 329.1 days in the EUS-HGS and EUS-CDS groups, respectively. Conclusions EUS-BD with the hybrid metal stent is technically feasible and can effectively treat biliary obstruction after failed ERCP. EUS-BD with the hybrid metal stent can reduce stent-related adverse events, especially stent migration.
Owing to the extreme toxicity of mercury, methods for its selective and sensitive sensing in solutions, and in live cells and tissues are in great demand. In this study, we developed a ...naphthalimide-based diphenylphosphinothioyl group-containing fluorescent and colorimetric probe that selectively detects mercury (Hg2+). Upon addition of mercury (Hg2+) to a solution of the probe, both a colorimetric change from colorless to yellow and a fluorescence change from blue to green (under a 365 nm hand-held UV lamp) occur, both of which can be observed using the "naked-eye". Furthermore, the probe possesses the capability of sensing intracellular mercury in both live cells and tissues using dual-emission channels and two-photon microscopy.
Although percutaneous transhepatic biliary drainage (PTBD) is the standard method for draining a malignant biliary obstruction after failed endoscopic retrograde cholangiopancreatographies (ERCPs), ...use of endoscopic ultrasound-guided transmural biliary drainage (EUS-BD) is increasing. We performed a multicenter, open-label, randomized trial to compare EUS-BD vs PTBD for malignant distal biliary obstruction after a failed ERCP.
Patients with unresectable malignant distal biliary obstructions and failed primary ERCP, caused by inaccessible papilla, were assigned to groups that underwent EUS-BD with an all-in-one device for direct deployment of a partially covered metal stent (without further fistula tract dilation, n = 34) or PTBD (n = 32). The procedures were performed at 4 tertiary academic referral centers in South Korea from October 2014 through March 2015; patients were followed up through June 2015. The primary end point was technical success, which was calculated using a noninferiority model. Secondary end points were functional success, procedure-related adverse events, rate of unscheduled re-intervention, and quality of life (QOL).
The rates of primary technical success were 94.1% (32 of 34) in the EUS-BD group and 96.9% (31 of 32) in the PTBD group (1-sided 97.5% confidence interval lower limit, -12.7%; P = .008 for a noninferiority margin of 15%). The rates of functional success were 87.5% (28 of 32) in the EUS-BD group and 87.1% (27 of 31) in the PTBD group (P = 1.00). The proportions of procedure-related adverse events were 8.8% in the EUS-BD group vs 31.2% in the PTBD group (P = .022); the mean frequency of unscheduled re-intervention was 0.34 in the EUS-BD group vs 0.93 in the PTBD group (P = .02). The QOL was similar between groups.
EUS-BD and PTBD had similar levels of efficacy in patients with unresectable malignant distal biliary obstruction and inaccessible papilla based on rates of technical and functional success and QOL. However, EUS-BD produced fewer procedure-related adverse events and unscheduled re-interventions. Clinical trial registration no: cris.nih.go.kr/KCT0001370.
Commensal bacteria are critically involved in the establishment of tolerance against inflammatory challenges, the molecular mechanisms of which are just being uncovered. All kingdoms of life produce ...aminoacyl-tRNA synthetases (ARSs). Thus far, the non-translational roles of ARSs have largely been reported in eukaryotes. Here, we report that the threonyl-tRNA synthetase (AmTARS) of the gut-associated bacterium Akkermansia muciniphila is secreted and functions to monitor and modulate immune homeostasis. Secreted AmTARS triggers M2 macrophage polarization and orchestrates the production of anti-inflammatory IL-10 via its unique, evolutionary-acquired regions, which mediates specific interactions with TLR2. This interaction activates the MAPK and PI3K/AKT signaling pathways, which converge on CREB, leading to an efficient production of IL-10 and suppression of the central inflammatory mediator NF-κB. AmTARS restores IL-10-positive macrophages, increases IL-10 levels in the serum, and attenuates the pathological effects in colitis mice. Thus, commensal tRNA synthetases can act as intrinsic mediators that maintain homeostasis.
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•Gut-associated Akkermansia muciniphila secretes threonyl-tRNA synthetase (AmTARS)•Secreted AmTARS targets macrophages and activates the anti-inflammatory TLR2-CREB axis•An evolutionarily acquired region in AmTARS mediates specific interactions with TLR2•AmTARS restores macrophage homeostasis, increases IL-10, and attenuates colitis in mice
Kim et al. report that the gut-associated bacterium A. muciniphila secretes threonyl-tRNA synthetase (AmTARS) to monitor and modulate host immune homeostasis. Secreted AmTARS activates anti-inflammatory signaling, restores macrophage homeostasis, increases IL-10, and attenuates colitis in mice. Commensal tRNA synthetases may act as intrinsic mediators that maintain homeostasis.
N‐Heterocyclic carbene (NHC) boranes undergo oxidative hydrolysis to give imidazolium salts with excellent kinetic selectivity for HOCl over other reactive oxygen species (ROS), including peroxides ...and peroxynitrite. Selectivity for HOCl results from the electrophilic oxidation mechanism of NHC boranes, which stands in contrast to the nucleophilic oxidation mechanism of arylboronic acids with ROS. The change in polarity that accompanies the conversion of NHC boranes to imidazolium salts can control the formation of emissive excimers, forming the basis for the design of the first fluorescence probe for ROS based on the oxidation of B−H bonds. Two‐photon microscope (TPM) ratiometric imaging of HOCl in living cells and tissues is demonstrated.
Bleached boranes: NHC boranes are oxidatively hydrolyzed to imidazolium salts with high kinetic selectivity for HOCl over other reactive oxygen species (ROS). This reactivity is harnessed in the two‐photon fluoresence imaging probe 1⋅BH3, the first ROS‐responsive material that rely on a B−H bond oxidation as triggering event.
Background and Aim
EB‐RFA with self‐expandable metal stent (SEMS) may improve the stent patency and patient survival in malignant extrahepatic biliary obstruction. However, there are few studies on ...the role of EB‐RFA for malignant hilar obstruction (MHO). This study aimed to assess the feasibility, efficacy, and safety of EB‐RFA for MHO.
Methods
We retrospectively compared the stent patency and survival among 79 consecutive patients with MHO who underwent bilateral uncovered SEMS placement without and with EB‐RFA between April 2016 and January 2020.
Results
Fifty‐one patients (64.6%) underwent SEMS placement alone (stent alone group), whereas 28 (35.4%) underwent SEMS placement after EB‐RFA (RFA‐stent group). All procedures were successful (100%). During follow‐up, stent occlusion occurred in 59 patients (74.7%), of which 40 (78.4%) and 19 (67.9%) were in the stent alone and RFA‐stent groups, respectively. There was no difference in stent patency (192 ± 39.2 days vs 140 ± 53.7 days, P = 0.41) and survival (311 ± 24.7 days vs 311 ± 46.9 days, P = 0.73) between the stent alone and RFA‐stent groups. Multivariate cox analysis showed a hazard ratio (HR) of 2.892 (1.579–5.294, P = 0.001) for stent occlusion in patients who did not receive chemotherapy. EB‐RFA had no significant effect on stent occlusion (HR, 1.150, 0.644–2.053, P = 0.636).
Conclusions
SEMS placement after EB‐RFA in MHO was not associated with improvement in the stent patency or patient survival. Further prospective randomized studies are necessary to establish the effectiveness of EB‐RFA with stents in MHO.
Many aspects of cell metabolism are controlled by acidic pH. We report a new family of small molecule and ratiometric two photon (TP) probes derived from benzimidazole (BH1–3 and BH1L) for monitoring ...acidic pH values. These probes are characterized by a strong two-photon excited fluorescence, a marked blue-to-green emission color change in response to pH, pK a values ranging from 4.9 to 6.1, a distinctive isoemissive point, negligible cytotoxicity, and high photostability, thereby allowing quantitative analysis of acidic pH. Moreover, we show that BH1L optimized as a lysosomal-targeted probe allows for direct, real-time estimation of the pH values inside lysosomal compartments in live cells as well as in living mouse brain tissues through the use of two-photon microscopy. These findings demonstrate that these probes will find useful applications in biomedical research.
International consensus for the treatment of autoimmune pancreatitis Okazaki, Kazuichi; Chari, Suresh T; Frulloni, Luca ...
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... et al.,
01/2017, Letnik:
17, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
Abstract Background and aims The International Consensus Diagnostic Criteria (ICDC) for AIP has proposed two distinctive type of AIP, type 1 and type 2, and enabled us first to differentiate two ...types of AIP each other. By initial steroid treatment for induction of remission, remission can be successfully induced in almost all subjects with type 1 and type 2 AIP. As relapse rate in type 1 AIP is significantly higher than in type 2 AIP, there has been ongoing debate on how to treat effectively relapse of type 1 AIP. Methods By a modified Delphi approach, a panel of international experts has proposed an international consensus on the treatment of AIP after intense discussion and deliberation during an international consensus symposium of the International Association of Pancreatology (IAP) 2016. Results Individual statements for nine clinical questions with recommendation levels and the therapeutic strategy have been proposed. Conclusion The recommendations are based on the available evidence, and eastern and western experts' opinions to find standard treatment of AIP worldwide. These recommendations can be tailored according to the local expertise and context in the management of individual patients.
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