Early detection of esophageal and gastric cancers offers the possibility of curative treatments with less-invasive interventions than traditional surgical approaches. This review highlights the main ...endoscopic therapeutic modalities used for early esophageal and gastric malignancies. Endoscopic resection techniques include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). EMR is beneficial for smaller, well-defined lesions and involves resecting the superficial layer of the mucosa. In contrast, ESD permits en bloc resection of larger lesions, including those involving the superficial submucosa, offering precise histopathological assessments and reduced recurrence rates. As such, multidisciplinary collaboration is essential to achieve optimal outcomes.
•Extensive review of Sequentially Linear Analysis (SLA) type solution procedures.•Comparison between two sequentially linear methods: SLA and Force-Release method.•Illustration using ...non-proportionally loaded experiments with real brittle collapse.•Differences in redistribution to simulate dynamic failures in a quasi-static setup.
Sequentially linear solution procedures provide a robust alternative to their traditional incremental-iterative counterparts for finite element simulation of quasi-brittle materials. Sequentially linear analysis (SLA), one such non-incremental (total) approach, has been extended to non-proportional loading situations in the past few years. Although the process of damage propagation and localisation is often dynamic in nature, the simulation being quasi-static poses a fundamental problem. This article gives an overview of the different approaches to address non-proportional loading in SLA and other sequentially linear methods, and their corresponding redistribution methodologies to address the dynamic phenomenon. Furthermore, the inherent differences between two such methods: SLA (total) and the Force-Release method (incremental), and their suitability to structural continuum models involving non-proportional loading, are illustrated using real-life concrete and masonry experimental benchmarks tested up to and beyond brittle collapse. In each illustration, SLA is shown to enforce equilibrium during dynamic failure by load reduction, using the intermittent proportional loading, while allowing for active damage propagation resulting in a relaxed failure mechanism which manifests as snap-back(s). Contrarily, the Force-Release method is shown to describe the collapse through states of disequilibrium.
Colonic stent placement in patients with large-bowel obstruction (LBO) secondary to extracolonic malignancy (ECM) has been evaluated in small series with heterogeneous results. Our aim is to better ...characterize the technical and clinical success of colonic stent placement and to identify factors that affect this success in ECM patients.
All patients at a single high-volume center who presented for colonic stent placement for LBO because of ECM between 2001 and 2012 were retrospectively identified. The outcomes of interest were technical success, clinical success, stent occlusion rate, and overall survival.
A total of 187 patients were identified. Mean age was 61.9 years (range, 23-89), and 150 (80.2%) were women. The most common malignancy type was urogynecologic (n = 104) and most common location sigmoid colon (n = 128). Overall, 142 patients (75.9%) achieved technical success and 102 patients (54.5%) clinical success. Radiographic presence of peritoneal carcinomatosis (P < .001) and multifocal disease (P < .001) were associated with both decreased technical and clinical success. Procedure-related adverse events were seen in 12 patients (6.4%). In patients with clinical success, the incidence of stent occlusion at 3 months was 14.7% (95% confidence interval, 7.8%-21.6%) and was higher in patients with prior radiation therapy (P = .011). The median overall survival for all patients from time of attempted stent placement was 3.3 months (95% confidence interval, 3.0-4.1).
This study represents the largest retrospective series of colonic stent placement for LBO in ECM patients in the literature. Our technical success rate of 75.9%, clinical success rate of 54.5%, and 3-month stent occlusion rate of 14.7% suggest that stent placement is a viable palliative option for patients with advanced disease because of ECM. Patients with peritoneal carcinomatosis and multifocal disease have reduced technical and clinical success. However, these factors should not dissuade an attempt at stent placement, if risk-to-benefit analysis is favorable.
•Discretised composite failure surfaces for line and planar interfaces.•Suitable to simulate local cracking, crushing and shearing failures in masonry.•Suitable to load-unload (total) and incremental ...sequentially linear methods.•Helps capture localised brittle collapse mechanisms in a robust manner.
In the finite element modelling of masonry structures, the micro-modelling technique of differentiating the continuum into a linear elastic bulk, and interfaces representing non-linear joints is common. However, this approach of simulating cracking-crushing-shearing failure possibilities in interfaces, typical of damage in masonry, also poses numerical stability issues due to the quasi-brittle nature of the failure. In this regard, the article proposes the use of numerically robust sequentially linear procedures and a suitable discretised tension-shear-compression failure model for interfaces. Sequentially linear solution procedures describe the nonlinear response of a specimen/structure through a sequence of scaled linear analyses, each of which represents locally applied damage increments, using secant-stiffness based discretised constitutive relations called saw-tooth laws. The constitutive formulation proposed herein includes a tension cut-off criterion combined with a uniaxial discretised softening law, a Coulomb friction criterion with a discretised cohesion softening law, and a compression cut-off criterion combined with a uniaxial discretised hardening–softening law. It is presented for both two-dimensional (2D) line interfaces and three-dimensional (3D) planar interfaces. The applicability of these formulations are illustrated using 2D and 3D models of a pushover analysis on a squat unreinforced masonry wall. The simulations are made using Sequentially Linear Analysis (SLA) and the Force-Release method, which are total (load-unload) and incremental sequentially linear methods respectively. The clear global softening in the force–displacement evolution and the localised brittle shear failure observed in the experiment are reproduced well and in a stable manner.
STUDY QUESTION
Do reproductive risk factor associations differ across subgroups of invasive epithelial ovarian cancer (EOC) defined by the dualistic model (type I/II) or a histologic pathway-based ...classification?
SUMMARY ANSWER
Associations with parity, history of endometriosis, tubal ligation and hysterectomy were found to differ in the context of the type I/II and the histologic pathways classification of ovarian cancer.
WHAT IS KNOWN ALREADY
Shared molecular alterations and candidate precursor lesions suggest that tumor histology and grade may be used to classify ovarian tumors into likely etiologic pathways.
DESIGN
This case–control study included 1571 women diagnosed with invasive EOC and 2100 population-based controls that were enrolled from 1992 to 2008. Reproductive risk factors as well as other putative risk factors for ovarian cancer were assessed through in-person interviews.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Eligible cases were diagnosed with incident ovarian cancer, were aged 18 and above and resided in eastern Massachusetts or New Hampshire, USA. Controls were identified through random digit dialing, drivers' license and town resident lists and were frequency matched with the cases based on age and study center.
MAIN RESULTS AND THE ROLE OF CHANCE
We used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for type I/II EOC or using a pathway-based grouping of histologic subtypes. In multivariate analyses, we observed that having a history of endometriosis (OR = 1.92, 95% CI: 1.36–2.71) increased the risk for a type I tumor. Factors that were strongly inversely associated with risk for a type I tumor included parity (≥3 versus 0 children, OR = 0.15, 95% CI: 0.11–0.21), having a previous tubal ligation (OR = 0.40, 95% CI: 0.26–0.60) and more weakly hysterectomy (OR = 0.71, 95% CI: 0.45–1.13). In analyses of histologic pathways, parity (≥3 versus 0 children, OR = 0.13, 95% CI: 0.10–0.18) and having a previous tubal ligation (OR = 0.41, 95% CI: 0.28–0.60) or hysterectomy (OR = 0.54, 95% CI: 0.34–0.86) were inversely associated with risk of endometrioid/clear cell tumors. Having a history of endometriosis strongly increased the risk for endometrioid/clear cell tumors (OR = 2.41, 95% CI: 1.78–3.26). We did not observe significant differences in the risk associations across these tumor classifications for age at menarche, menstrual cycle length or infertility.
LIMITATIONS, REASONS FOR CAUTION
A potential limitation of this study is that dividing the cases into subgroups may limit the power of these analyses, particularly for the less common tumor types. Since cases were enrolled after their diagnosis, it is possible that the most aggressive cases were not included in the study.
WIDER IMPLICATIONS OF THE FINDINGS
This study provides insights about the role of reproductive factors in relation to risk of pathway-based subgroups of ovarian cancer that with further confirmation may assist with the development of improved strategies for the prevention of these different tumor types.
STUDY FUNDING/COMPETING INTEREST(S)
This research is funded by grants from the National Cancer Institute, the Department of Defense Ovarian Cancer Research Program and the Ovarian Cancer Research Fund. The authors have no competing interests to declare.
TRIAL REGISTRATION NUMBER
Not applicable.
Esophageal cancer is the 8th most common cancer worldwide and the 6th most common cause of cancer-related death. Its two main subtypes, esophageal adenocarcinoma (EAC) and esophageal squamous cell ...carcinoma (ESCC), have varying incidences globally, but recent decades have seen a demonstrated rise of EAC in Western countries whereas ESCC remains highly prevalent in Eastern Africa, Central Asia, and China. Screening interventions have focused on using endoscopy to identify Barrett's esophagus (BE) as a precursor to EAC, and squamous cell dysplasia prior to onset of ESCC. However, additional cost-effective screening interventions that can be applied to larger populations at risk for esophageal cancer are needed. Advances in endoscopic ablative techniques and endoscopic resection via endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have proven to be effective in eradicating dysplasia and early stage cancer. Preventive strategies involving reduction in tobacco and alcohol consumption as well as regular use of proton pump inhibitors and nonsteroidal anti-inflammatory drugs are aimed at reducing the incidence of dysplasia and esophageal cancer, but require further study before being recommended for widespread use.
Summary
Sequentially linear analysis (SLA), an event‐by‐event procedure for finite element (FE) simulation of quasi‐brittle materials, is based on sequentially identifying a critical integration ...point in the FE model, to reduce its strength and stiffness, and the corresponding critical load multiplier (λcrit), to scale the linear analysis results. In this article, two strategies are proposed to efficiently reuse previous stiffness matrix factorisations and their corresponding solutions in subsequent linear analyses, since the global system of linear equations representing the FE model changes only locally. The first is based on a direct solution method in combination with the Woodbury matrix identity, to compute the inverse of a low‐rank corrected stiffness matrix relatively cheaply. The second is a variation of the traditional incomplete LU preconditioned conjugate gradient method, wherein the preconditioner is the complete factorisation of a previous analysis step's stiffness matrix. For both the approaches, optimal points at which the factorisation is recomputed are determined such that the total analysis time is minimised. Comparison and validation against a traditional parallel direct sparse solver, with regard to a two‐dimensional (2D) and three‐dimensional (3D) benchmark study, illustrates the improved performance of the Woodbury‐based direct solver over its counterparts, especially for large 3D problems.
Surgery has traditionally been the preferred treatment for early stage esophageal cancer. Recent advances in endoscopic treatments have been shown to be effective and safe. Endoscopic mucosal ...resection (EMR) and endoscopic submucosal dissection (ESD) allow endoscopists to remove small, superficial lesions, providing tumor specimen that can be examined for accurate pathologic tumor staging and assessment of adequacy of resection. Endoscopic ablation procedures, including photodynamic therapy (PDT) and radio frequency ablation (RFA), have also been shown to safely and effectively treat esophageal dysplasia and early stage neoplasia, with excellent long-term disease control. Both approaches are becoming more widely available around the world, and provide an alternative, safe, low risk strategy for treating early stage disease, making combined endoscopic therapy the recommended treatment of choice for early stage esophageal cancers.
In patients with locally advanced esophageal adenocarcinoma, response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore ...sought to discover meaningful predictors of response in these patients.
We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (i) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (ii) underwent prospective sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response.
In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy OR, 0.10 (95% confidence interval, 0.01-0.55); P = 0.032, when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (P = 0.004, q = 0.07). Patients with MDM2 amplifications or truncating biallelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes.
MDM2 amplification and TP53 status are associated with response to therapy in patients with esophageal adenocarcinoma. Given the dearth of actionable targets in esophageal adenocarcinoma, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.
The ENUBET project is aimed at designing and experimentally demonstrating the concept of monitored neutrino beams. These novel beams are enhanced by an instrumented decay tunnel, whose detectors ...reconstruct large-angle charged leptons produced in the tunnel and give a direct estimate of the neutrino flux at the source. These facilities are thus the ideal tool for high-precision neutrino cross-section measurements at the GeV scale because they offer superior control of beam systematics with respect to existing facilities. In this paper, we present the first end-to-end design of a monitored neutrino beam capable of monitoring lepton production at the single particle level. This goal is achieved by a new focusing system without magnetic horns, a 20 m normal-conducting transfer line for charge and momentum selection, and a 40 m tunnel instrumented with cost-effective particle detectors. Employing such a design, we show that percent precision in cross-section measurements can be achieved at the CERN SPS complex with existing neutrino detectors.
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