LINKED CONTENT
This article is linked to Schreiner et al papers. To view these articles, visit https://doi.org/10.1111/apt.16145 and https://doi.org/10.1111/apt.16190
Background Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series ...contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. Study Design We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. Results Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (≥10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio HR 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. Conclusions Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size ≥ 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years.
Summary Background Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived ...growth factor receptor α proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. Methods We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov , number NCT00041197. Findings All randomised patients were included in the analysis. At median follow-up of 19·7 months (minimum–maximum 0–56·4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% 95% CI 96–100 vs 83% 78–88 at 1 year; hazard ratio HR 0·35 0·22–0·53; one-sided p<0·0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 3% vs 0), abdominal pain (12 3% vs six 1%), and diarrhoea (ten 2% vs five 1%) in the imatinib group and hyperglycaemia (two <1% vs seven 2%) in the placebo group. Interpretation Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. Funding US National Institutes of Health and Novartis Pharmaceuticals.
In 2014, we then brought the e-learning team into the Education Committee with a plan to develop education further, to provide accessible and up to date information to all UEG Member Societies, and ...to ensure that the content provided was always cutting edge and up to date. With a great deal of work and collaboration with multiple experts in their fields, we increased the online users of our courses from a number of over 40 in 2013, to nearly 13,000 unique users today. The second Masterclass on Colorectal Cancer is imminent, and with the ability to blend online and classroom learning with experts in the field, the offerings are taking the education we provide to the next level. ...as my term comes to an end, it is with great pride and gratitude that I look back on the last 4 years as UEG Education Committee Chair, and nearly a decade of involvement in education in UEG.
Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We ...sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections.
Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020.
Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001).
Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy.
ISRCTN45176516.
The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have ...rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.
Summary
The accurate assembly of the system matrix is an important step in any code that solves partial differential equations on a mesh. We either explicitly set up a matrix, or we work in a ...matrix‐free environment where we have to be able to quickly return matrix entries upon demand. Either way, the construction can become costly due to nontrivial material parameters entering the equations, multigrid codes requiring cascades of matrices that depend upon each other, or dynamic adaptive mesh refinement that necessitates the recomputation of matrix entries or the whole equation system throughout the solve. We propose that these constructions can be performed concurrently with the multigrid cycles. Initial geometric matrices and low accuracy integrations kickstart the multigrid iterations, while improved assembly data is fed to the solver as and when it becomes available. The time to solution is improved as we eliminate an expensive preparation phase traditionally delaying the actual computation. We eliminate algorithmic latency. Furthermore, we desynchronize the assembly from the solution process. This anarchic increase in the concurrency level improves the scalability. Assembly routines are notoriously memory‐ and bandwidth‐demanding. As we work with iteratively improving operator accuracies, we finally propose the use of a hierarchical, lossy compression scheme such that the memory footprint is brought down aggressively where the system matrix entries carry little information or are not yet available with high accuracy.
Linked ContentThis article is linked to Singh et al papers. To view these articles, visit https://doi.org/10.1111/apt.15214 and https://doi.org/10.1111/apt.15283.
To explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis (SSc) in a phenome-wide association study (PheWAS), using real-world clinical records data.
Twelve ...thousand five hundred thirty-five documented clinical assessments of 2058 consenting individuals with SSc at the Royal Free Hospital (UK) were available for detailed phenotyping. Diagnoses and drugs were mapped to structured dictionaries of terms (Disease Ontology project and DrugBank Open Data, respectively). A PheWAS model was used to explore links between 6 important SSc-GI domains (constipation, diarrhea, dysmotility, incontinence, gastroesophageal reflux, and small intestinal bacterial overgrowth SIBO) and exposure to various comorbidities and drugs. "Hits" from the PheWAS model were confirmed and explored in a subcohort reporting quantitative GI symptom scores from the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (GIT 2.0) questionnaire.
One thousand five hundred forty-six individuals were entered into the PheWAS analysis. Six hundred seventy-three distinct diagnoses and 634 distinct drugs were identified in the dataset, as well as SSc-specific phenotypes such as antinuclear antibodies (ANA). PheWAS analysis revealed associations between drugs, diagnoses, and ANAs with 6 important SSc-GI outcomes: constipation, diarrhea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores links with SSc-GI were confirmed for 22 drugs, 4 diagnoses, and 3 ANAs.
Using a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, antimuscarinic, and endothelin receptor antagonist, and ANA subgroup.
Summary
Multigrid solvers face multiple challenges on parallel computers. Two fundamental ones read as follows: Multiplicative solvers issue coarse grid solves which exhibit low concurrency and many ...multigrid implementations suffer from an expensive coarse grid identification phase plus adaptive mesh refinement overhead. We propose a new additive multigrid variant for spacetrees, that is, meshes as they are constructed from octrees and quadtrees: It is an additive scheme, that is, all multigrid resolution levels are updated concurrently. This ensures a high concurrency level, while the transfer operators between the mesh levels can still be constructed algebraically. The novel flavor of the additive scheme is an augmentation of the solver with an additive, auxiliary damping parameter per grid level per vertex that is in turn constructed through the next coarser level—an idea which utilizes smoothed aggregation principles or the motivation behind AFACx: Per level, we solve an additional equation whose purpose is to damp too aggressive solution updates per vertex which would otherwise, in combination with all the other levels, yield an overcorrection and, eventually, oscillations. This additional equation is constructed additively as well, that is, is once more solved concurrently to all other equations. This yields improved stability, closer to what is seen with multiplicative schemes, while pipelining techniques help us to write down the additive solver with single‐touch semantics for dynamically adaptive meshes.
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