Main Recommendations
ESGE recommends the use of a graded pneumatic dilation protocol in achalasia, starting with a 30-mm dilation and followed by a 35-mm dilation at a planned interval of 2 – 4 ...weeks, with a subsequent 40-mm dilation when there is insufficient relief, over both a single balloon dilation procedure or the use of a larger balloon from the outset.
Strong recommendation, high quality of evidence, level of agreement 100 %.
ESGE recommends being cautious in treating spastic motility disorders other than achalasia with peroral endoscopic myotomy (POEM).
Strong recommendation, very low quality of evidence, level of agreement 87.5 %.
ESGE recommends against the routine use of botulinum toxin injections to treat patients with non-achalasia hypercontractile esophageal motility disorders (Jackhammer esophagus, distal esophageal spasm). However, if, in individual patients, endoscopic injection of botulinum toxin is chosen, ESGE recommends performing injections into four quadrants of the lower esophageal sphincter and in the lower third of the esophagus.
Strong recommendation, low quality of evidence, level of agreement 78.6 %.
ESGE recommends that endoscopic pylorus-directed therapy should be considered only in patients with symptoms suggestive of gastroparesis in combination with objective proof of delayed gastric emptying using a validated test, and only when medical therapy has failed.
Strong recommendation, very low quality of evidence, level of agreement 100 %.
ESGE recommends against the use of botulinum toxin injection in the treatment of unselected patients with gastroparesis.
Strong recommendation, high quality of evidence, level of agreement 92.9 %.
ESGE recommends consideration of gastric peroral endoscopic myotomy (G-POEM) in carefully selected patients only, because it is an emerging procedure with limited data on effectiveness, safety, and durability. G-POEM should be performed in expert centers only, preferably in the context of a clinical trial.
Strong recommendation, low quality of evidence, level of agreement 100 %.
Germ cells are unique in engendering totipotency, yet the mechanisms underlying this capacity remain elusive. Here, we perform comprehensive and in‐depth nucleome analysis of mouse germ‐cell ...development in vitro, encompassing pluripotent precursors, primordial germ cells (PGCs) before and after epigenetic reprogramming, and spermatogonia/spermatogonial stem cells (SSCs). Although epigenetic reprogramming, including genome‐wide DNA de‐methylation, creates broadly open chromatin with abundant enhancer‐like signatures, the augmented chromatin insulation safeguards transcriptional fidelity. These insulatory constraints are then erased en masse for spermatogonial development. Notably, despite distinguishing epigenetic programming, including global DNA re‐methylation, the PGCs‐to‐spermatogonia/SSCs development entails further euchromatization. This accompanies substantial erasure of lamina‐associated domains, generating spermatogonia/SSCs with a minimal peripheral attachment of chromatin except for pericentromeres—an architecture conserved in primates. Accordingly, faulty nucleome maturation, including persistent insulation and improper euchromatization, leads to impaired spermatogenic potential. Given that PGCs after epigenetic reprogramming serve as oogenic progenitors as well, our findings elucidate a principle for the nucleome programming that creates gametogenic progenitors in both sexes, defining a basis for nuclear totipotency.
Synopsis
Multi‐omics profiling of an in vitro system for mouse germ‐cell development delineates key principles of nucleome programming, including progressive euchromatization and dynamic insulation, as a basis for nuclear totipotency.
3D genome matures unidirectionally over epigenetic reprogramming and programming.
Epigenetic reprogramming creates broadly open chromatin with enhanced insulation.
Spermatogonia show minimal, peripherally‐positioned, and pericentromeric LADs.
Nucleome mis‐programming leads to impaired spermatogenic potential.
Progressive euchromatization and insulation dynamics safeguard nuclear totipotency during gametogenesis.
Summary
Reinduction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second‐line standard of care for transplant‐eligible patients with ...relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high‐dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant‐eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase‐I‐part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end‐point of computed tomography (CT)‐based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT‐based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end‐point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.
Objectives
Patients with classical Hodgkin lymphoma (cHL) relapsing after second‐line therapy have a dismal prognosis and novel approaches are required for this patient group. Based on promising ...(pre‐)clinical data and the favourable toxicity profile, we performed a phase II clinical trial with the JAK inhibitor ruxolitinib in patients with relapsed or refractory cHL (r/r cHL).
Methods
Patients ≥18 years with histologically confirmed r/r cHL who failed second‐line treatment were included. Ruxolitinib was given orally at a dose of 25 mg twice daily in continuous 28‐day cycles until progression or unacceptable toxicity. Primary endpoint was the PET/CT‐based overall response rate (ORR; complete response (CR) or partial response (PR)) after 2 cycles; secondary endpoints included progression‐free (PFS) and overall survival (OS) as well as feasibility. The Jericho Trial adopted a 2‐stage phase 2 design (Simon 1989).
Results
Among the 12 included patients in stage 1, 2 had a PR, 3 had a stable disease (SD) and 6 had progressive disease (PD) after two treatment cycles (ORR: 2/12 evaluable patients, 16.7%). Median PFS was 3.6 months, the 1‐year OS estimate was 50.6% (median not reached). The toxicity profile was favourable with only one grade IV adverse event (7.1%) reported.
Conclusion
Ruxolitinib exhibited a favourable side effect profile but modest activity in r/r cHL. Although the formal stopping criterion after stage 1 was not met, the trial did not continue to stage 2 due to the low response and PFS rates observed in stage 1.
Although several promising approaches for the treatment of relapsed/refractory diffuse large B‐cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately ...achieve long‐term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost‐ and time‐sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof‐of‐principle for its ability to predict outcomes.
In this paper, a viscoelastic model able to capture important mechanical features of a wide class of glassy polymers is presented. Among them, the ability of reproducing the highly nonlinear ...rate-dependent stress response and the post-yield strain softening phenomenon. The simplicity of the proposition allows to recover the same mathematical structure of classical constitutive approaches, well suited for the use of implicit finite element codes. To this aim, the
flow resistance
concept, elsewhere known as
shear strength
, is reframed as a state variable of an accumulated strain measure. Three alternative expressions for this function are presented. The model is cast within a variational framework in which consistent constitutive updates are obtained by a minimization procedure. Convenient choices for the conservative and dissipative potentials reduce the local constitutive problem to the solution of a single nonlinear scalar equation, emulating the simplest case of viscoelastic models. Numerical tests on the constitutive model show excellent agreement with experimental data. Finally, a 3D simulation of a standard specimen with heterogeneous material properties illustrates the ability of the present proposition to be implemented in implicit finite element codes.
The influence of commercially pure Titanium microstructure on fatigue properties and their improvement or deterioration is analyzed, in the presented contribution. One tested material was after cold ...drawing, the other after severe plastic deformation by Equal Channel Angular Pressing (ECAP). Intense plastic deformation (ECAP) resulted in yield point 100% higher and UTS 97% higher than obtained by traditional cold drawing. The ductility was 57% lower than for cold drawing. However, the fatigue properties namely; the degradation of fatigue properties were influenced by sever plastic deformation in a way not consistent with the usually counted influence on mechanical properties and more, the fatigue limit was lower for high numbers of loading cycles. For N = 5.5 x 10^sup 5^, the fatigue limits in torsion τ^sub C^ for Ti after ECAP and after cold drawing were identical. For N < 5.5 x 10^sup 5^ cycles, the τ^sub C^ for Ti after ECAP was higher, but for N > 5.5 x 10^sup 5^ cycles it was lower.
•Tumor-agnostic ctDNA sequencing in CNSL is feasible and allows for detection of PRD.•We propose the molecular prognostic index for CNSL, a model integrating clinical and molecular features for ...improved risk profiling in CNSL.
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State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment.
Heger et al report on a novel risk stratification schema for patients with central nervous system lymphoma (CNSL) using ultrasensitive circulating tumor DNA (ctDNA) sequencing in 67 patients at baseline and after therapy. Undetectable plasma ctDNA predicts favorable outcomes while persistence of peripheral residual disease following therapy predicts for relapse. The authors developed a molecular prognostic index for CNSL that could improve standard risk stratification and allow for more individualized treatment.
Purpose
To demonstrate a physiologically induced alternative to the typical methods of reducing cardiac output during deployment of stent-grafts in the aortic arch and proximal aorta.
Technique
A ...modified Valsalva maneuver, the Munich Valsalva implantation technique (MuVIT), to raise the intrathoracic pressure, minimize backflow, and reduce the cardiac output is illustrated in a patient undergoing a triple-branch thoracic endovascular aortic repair (TEVAR). During manual mechanical ventilation, the adjustable pressure-limiting valve is carefully closed to 25 mm Hg, creating “manual bloating” of the lungs and sustained apnea. The increased intrathoracic pressure causes compression of the vena cava and pulmonary veins, reducing the venous backflow and gradually decreasing the arterial pressure. Once the desired pressure is obtained, the stent-graft is accurately deployed. The airway pressure is thereupon slowly reduced, and the patient is taken back to normal ventilation. The procedure is then finished following standard practice.
Conclusion
The MuVIT is a simple, noninvasive technique for cardiac output reduction during aortic arch TEVAR, eliminating the need for other invasive techniques.
What Might Machines Mean? Green, Mitchell; Michel, Jan G.
Minds and machines (Dordrecht),
2022/6, Letnik:
32, Številka:
2
Journal Article
Recenzirano
Odprti dostop
This essay addresses the question whether artificial speakers can perform speech acts in the technical sense of that term common in the philosophy of language. We here argue that under certain ...conditions artificial speakers can perform speech acts so understood. After (§1) explaining some of the issues at stake in these questions, we (§2) elucidate a relatively uncontroversial way in which machines can communicate, namely through what we call verbal signaling. But verbal signaling is not sufficient for the performance of a speech act. To explain the difference, we (§3) elucidate the notion of a speech act developed by Austin (
How to Do Things with Words
, 1962) in the mid-twentieth century and then discuss Strawson’s ("Intention and Convention in Speech Acts", 1964) influential proposal for how that notion may be related to Grice’s ("Meaning", 1957) conception of speaker meaning. We then refine Strawson’s synthesis in light of Armstrong’s ("Meaning and Communication", 1971) reconceptualization of speaker meaning in terms of objectives rather than intentions. We next (§4) extend this conception of speech acts to the cases of recorded, proxy, and conditional speech acts. On this basis, we propose (§5) that a characteristic role for artificial speakers is as proxies in the performance of speech acts on behalf of their human creators. We (§6) also consider two objections to our position, and compare our approach with others: while other authors appeal to notions such as “quasi-assertion,” we offer a sharp characterization of what artificial speakers can do that does not impute intentions or similarly controversial powers to them. We conclude (§7) by raising doubts that our strategy can be applied to speech acts generally.
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