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Abstract Background The Cancer Genome Atlas (TCGA) recognizes four molecular subgroups of gastric cancer: Epstein-Barr virus (EBV) positive, microsatellite instable (MSI), genomically stable (GS), and chromosomal instable (CIN). Since a GS/CIN classifier is lacking, alternative markers such as Lauren’s histopathology or CDH1/p53 immunohistochemistry are commonly applied. Here we compared survival of gastric cancer subgroups determined by four methods. Methods 309 EBV negative and microsatellite stable tumors were included from the Dutch D1/D2 trial and assigned to subgroups by: (i) TCGA’s specific chromosomal copy number aberrations, (ii) genome instability index (GII), (iii) Lauren’s classification, and (iv) CDH1/p53 immunohistochemistry. Subgroups were associated with cancer-related survival (CRS). Results Five-year CRS was 42.0% for diffuse and 49.5% for patients with intestinal type tumors, and 57.8% for GS and 41.6% for patients with CIN tumors. Classification by GII or CDH1/p53 IHC did not correlate with CRS. The combination of TCGA and Lauren classifications resulted in four distinct subgroups. Five-year CRS for GS-intestinal (n = 24), GS-diffuse (n = 57), CIN-intestinal (n = 142) and CIN-diffuse (n = 86) was 61.4%, 56.5%, 47.6%, and 31.5%, respectively. Conclusions TCGA’s GS and CIN subgroups have additional prognostic value to Lauren’s classification in resectable gastric cancer. GS-intestinal, GS-diffuse, CIN-intestinal and CIN-diffuse are suggested stratification variables for future studies.

Background: The prognostic significance of T-cell densities in gastric cancer (GC) was previously demonstrated in surgical resection specimens. For prognosis or response prediction, it is preferable to identify biomarkers in pre-treatment biopsies; yet, its representativeness of the tumor immune microenvironment is unclear. Objectives: This study aimed to evaluate the concordance and prognostic value of T-cell densities in paired biopsies and resections. Methods: Paired diagnostic biopsies and surgical resections were available for 131 patients with resectable GC who were treated with surgery alone in the D1/D2 trial. T-cell markers such as CD3, CD45RO, CD8, FOXP3, and Granzyme B were assessed by immunohistochemistry and digitally quantified. Tumors were categorized into high and low subgroups for each marker. The concordance between biopsies and resections was determined for each marker with Cohen’s κ. To determine the prognostic value of T cells in biopsies, Cox regression was performed. Results: The concordance of T-cell high and low tumors was moderate for CD8 (κ = 0.58) and weak for other markers (κ

Abstract Background Magnetic resonance (MR) imaging is the modality used for baseline assessment of locally advanced rectal cancer (LARC) and restaging after neoadjuvant treatment. The overall audited quality of MR imaging in large multicentre trials on rectal cancer is so far not routinely reported. Materials and methods We collected MR images obtained within the Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation (RAPIDO) trial and performed an audit of the technical features of image acquisition. The required MR sequences and slice thickness stated in the RAPIDO protocol were used as a reference. Results Out of 920 participants of the RAPIDO study, MR investigations of 668 and 623 patients in the baseline and restaging setting, respectively, were collected. Of these, 304/668 (45.5%) and 328/623 (52.6%) MR images, respectively, fulfilled the technical quality criteria. The main reason for non-compliance was exceeding slice thickness 238/668, 35.6% in the baseline setting and 162/623, 26.0% in the restaging setting. In 166/668, 24.9% and 168/623, 27.0% MR images in the baseline and restaging setting, respectively, one or more of the required pulse sequences were missing. Conclusion Altogether, 49.0% of the MR images obtained within the RAPIDO trial fulfilled the image acquisition criteria required in the study protocol. High-quality MR imaging should be expected for the appropriate initial treatment and response evaluation of patients with LARC, and efforts should be made to maximise the quality of imaging in clinical trials and in clinical practice. Critical relevance statement This audit highlights the importance of adherence to MR image acquisition criteria for rectal cancer, both in multicentre trials and in daily clinical practice. High-resolution images allow correct staging, treatment stratification and evaluation of response to neoadjuvant treatment. Key points - Complying to MR acquisition guidelines in multicentre trials is challenging. - Neglection on MR acquisition criteria leads to poor staging and treatment. - MR acquisition guidelines should be followed in trials and clinical practice. - Researchers should consider mandatory audits prior to study initiation. Graphical Abstract

Plasmodium vivax remains a challenge for malaria elimination since it forms dormant liver stages (hypnozoites) that can reactivate after initial infection. 8-aminoquinolone drugs kill hypnozoites but can cause severe hemolysis in individuals with Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. The STANDARD G6PD test (Biosensor) is a novel point-of-care diagnostic capable of identifying G6PD deficiency prior to treatment. In 2021, Cambodia implemented the Biosensor to facilitate radical cure treatment for vivax malaria. To assess the Biosensor's implementation after its national rollout, a mixed-methods study was conducted in eight districts across three provinces in Cambodia. Interviews, focus group discussions, and observations explored stakeholders' experiences with G6PD testing and factors influencing its implementation. Quantitative data illustrative of test implementation were gathered from routine surveillance forms and key proportions derived. Qualitative data were analyzed thematically. The main challenge to implementing G6PD testing was that only 49.2% (437/888) of eligible patients reached health centers for G6PD testing following malaria diagnosis by community health workers. Factors influencing this included road conditions and long distances to the health center, compounded by the cost of seeking further care and patients' perceptions of vivax malaria and its treatment. 93.9% (790/841) of eligible vivax malaria patients who successfully completed referral (429/434) and directly presented to the health center (360/407) were G6PD tested. Key enabling factors included the test's acceptability among health workers and their understanding of the rationale for testing. Only 36.5% (443/1213) of eligible vivax episodes appropriately received primaquine. 70.5% (165/234) of female patients and all children under 20 kilograms never received primaquine. Our findings suggest that access to radical cure requires robust infrastructure and income security, which would likely improve referral rates to health centers enabling access. Bringing treatment closer to patients, through community health workers and nuanced community engagement, would improve access to curative treatment of vivax malaria.

Abstract Background Hormone receptor (HR)-positive, HER2/neu-negative breast cancers have a sustained risk of recurrence up to 20 years from diagnosis. TEAM (Tamoxifen, Exemestane Adjuvant Multinational) is a large, multi-country, phase III trial that randomized 9776 women for the use of hormonal therapy. Of these 2754 were Dutch patients. The current study aims for the first time to correlate the ten-year clinical outcomes with predictions by CanAssist Breast (CAB)—a prognostic test developed in South East Asia, on a Dutch sub-cohort that participated in the TEAM. The total Dutch TEAM cohort and the current Dutch sub-cohort were almost similar with respect to patient age and tumor anatomical features. Methods Of the 2754 patients from the Netherlands, which are part of the original TEAM trial, 592 patients’ samples were available with Leiden University Medical Center (LUMC). The risk stratification of CAB was correlated with outcomes of patients using logistic regression approaches entailing Kaplan–Meier survival curves, univariate and multivariate cox-regression hazards model. We used hazard ratios (HRs), the cumulative incidence of distant metastasis/death due to breast cancer (DM), and distant recurrence-free interval (DRFi) for assessment. Results Out of 433 patients finally included, the majority, 68.4% had lymph node-positive disease, while only a minority received chemotherapy (20.8%) in addition to endocrine therapy. CAB stratified 67.5% of the total cohort as low-risk [DM = 11.5% (95% CI, 7.6–15.2)] and 32.5% as high-risk [DM = 30.2% (95% CI, 21.9–37.6)] with an HR of 2.90 (95% CI, 1.75–4.80; P

AbstractPurposeMethodResultsConclusion\nIMPLICATIONS FOR REHABILITATIONChildren with congenital upper limb difference (CULD) in India have limited access to treatment with conventional prostheses. 3D printed prosthetic devices (3DPP) can function as transitional prostheses for growing children with congenital transverse deficiency. They are low-cost and the designs are easily customized. However, functional outcomes, access, and acceptability are still unexplored in many clinical settings. This qualitative study sought perspectives from Indian mothers of children with CULD using 3DPP for the first time. The objective was to enhance understanding of 3DPP acceptability and to explore how their children utilized these devices.Semi-structured interviews were conducted with seven mothers of children aged 3 to 11 years with varying levels of CULD who had been fitted with a 3DPP for at least 1 month prior. The interviews aimed to gather insights into the children’s daily experiences with the devices and the mothers’ perceptions of 3DPP. Thematic analysis was carried out using an inductive approach.Four major themes were identified through thematic analysis. They were: 1. Design and functionality of 3DPP, 2. Adaptation patterns, 3. Social attitudes and perceptions, and 4. Access to the Center for congenital hand differences: location and its services.Our study explores the early-stage use and acceptance of 3DPP in India. Mothers reported several reasons for prosthesis abandonment including functional limitations, pain, and unmet expectations. The acceptability of 3DPP was moderate among close family, but social stigmatization was still a barrier to continued use. Addressing these issues and offering tailored solutions could be important to achieve successful 3DPP adaptation.3D printed prostheses (3DPP) offer affordability and customizability. The current study explores their use and acceptability in a low-income setting in India.Specialized and individualized 3DPP design is essential. Given the identified limitations in functionality, prioritizing the patient’s needs for specific applications in daily activities or sports with improved grip is critical for optimal performance.Enhanced communication and collaboration among all stakeholders (parents, child, surgeon, and engineers) are necessary to prevent disappointment and improve overall usage rates of 3DPP.Implementing 3DPP in rehabilitation should account for local socioeconomic barriers and develop strategies to overcome these obstacles to achieve effective and functional outcomes.3D printed prostheses (3DPP) offer affordability and customizability. The current study explores their use and acceptability in a low-income setting in India.Specialized and individualized 3DPP design is essential. Given the identified limitations in functionality, prioritizing the patient’s needs for specific applications in daily activities or sports with improved grip is critical for optimal performance.Enhanced communication and collaboration among all stakeholders (parents, child, surgeon, and engineers) are necessary to prevent disappointment and improve overall usage rates of 3DPP.Implementing 3DPP in rehabilitation should account for local socioeconomic barriers and develop strategies to overcome these obstacles to achieve effective and functional outcomes. [ABSTRACT FROM AUTHOR]

Background: The prognostic significance of T-cell densities in gastric cancer (GC) was previously demonstrated in surgical resection specimens. For prognosis or response prediction, it is preferable to identify biomarkers in pre-treatment biopsies; yet, its representativeness of the tumor immune microenvironment is unclear. Objectives: This study aimed to evaluate the concordance and prognostic value of T-cell densities in paired biopsies and resections. Methods: Paired diagnostic biopsies and surgical resections were available for 131 patients with resectable GC who were treated with surgery alone in the D1/D2 trial. T-cell markers such as CD3, CD45RO, CD8, FOXP3, and Granzyme B were assessed by immunohistochemistry and digitally quantified. Tumors were categorized into high and low subgroups for each marker. The concordance between biopsies and resections was determined for each marker with Cohen's κ. To determine the prognostic value of T cells in biopsies, Cox regression was performed. Results: The concordance of T-cell high and low tumors was moderate for CD8 (κ = 0.58) and weak for other markers (κ < 0.3). CD8 and FOXP3 densities in biopsies were significantly associated with cancer-specific survival. Multivariable analysis showed that an Immunoscore incorporating CD8 and FOXP3 served as an independent prognostic marker (low vs high: hazard ratio 3.40, 95% confidence interval: 1.27–9.10; p = 0.015). Conclusion: Although the concordance in T-cell densities between biopsy and resection specimens is modest, a biopsy-based Immunoscore identified distinct biological subgroups with prognostic potential. To fully evaluate the prognostic performance of this biopsy Immunoscore, additional studies are warranted. [ABSTRACT FROM AUTHOR]

Introduction Anastomotic leakage (AL) is one of the major complications after colorectal surgery. Compromised tissue perfusion at the anastomosis site increases the risk of AL. Several cohort studies have shown that indocyanine green (ICG) combined with fluorescent near-infrared imaging is a feasible and reproducible technique for real-time intraoperative imaging of tissue perfusion, leading to reduced leakage rates after colorectal resection. Unfortunately, these studies were not randomised. Therefore, we propose a randomised controlled trial to assess the value of ICG-guided surgery in reducing AL after colorectal surgery.Methods and analysis A multicentre, randomised controlled clinical trial will be conducted to assess the benefit of ICG-guided surgery in preventing AL. A total of 978 patients scheduled for colorectal surgery will be included. Patients will be randomised between the Fluorescence Guided Bowel Anastomosis group and the Conventional Bowel Anastomosis group. The primary endpoint is clinically relevant AL (defined as requiring active therapeutic intervention or reoperation) within 90 days after surgery. Among the secondary endpoints are 30-day clinically relevant AL, all-cause postoperative complications, all-cause and AL-related mortality, surgical and non-surgical reinterventions, total surgical time, length of hospital stay and all-cause and AL-related readmittance.Ethics and dissemination This protocol has been approved by the Medical Ethical Committee Leiden-Den Haag-Delft (METC-LDD) and is registered at ClinicalTrials.gov and trialregister.nl. The results of this study will be reported through peer-reviewed publications and conference presentations.Trial registration number NCT04712032; NL7502.

(Series Information) European Papers - A Journal on Law and Integration, 2021 6(1), 831-868 | Article | (Table of Contents) I. Introduction. - II. Legal structures of military integration and cooperation in the EU. - II.1. The Treaty of Rome (1957): economic Europe as an alternative to the failed European Defence Community. - II.2. After the Lisbon Treaty (2009): strategic autonomy based on national or supranational responsibilities? - II.3. The legal roots of the NATO constraint on EU military integration. - II.4. Interim conclusion: national capability commitments vs the internal market? - III. The function of military procurement in foreign policy. - III.1. Overcoming the "realist challenge" in EU law: from realism to functionalism. - III.2. Systemic constraints on international cooperation and European integration. - III.3. Balance of power and troubled alliance. - III.4. Balance of power and military-industrial policymaking. - III.5. EDA's intergovernmental approach to offsets. - III.6. Interdependence and institutionalism: finding certainty in legal regimes. - III.7. The role of international institutions. - III.8. Issue linkage as a prerequisite for institutionalism. - III.9. Interim conclusion: linking military security to the internal market? - IV. The Commission's pursuit of EU strategic autonomy by industrial and procurement policies. - IV.1. The Defence Procurement Directive (DPD 2009). - IV.2. The European Defence Fund (EDF 2021-2027). - IV.3. The legal fiction of "economies of scale" by cooperation. - IV.4. From fragmentation to "European champions"? - IV.5. Interim conclusion: the problem of linking military security with the internal market. - V. A theoretical basis for EU military procurement law. - V.1. The primary role of military-industrial capabilities and balance of power. - V.2. General implication for EU supranational regulation. - V.3. The need for a dynamic armaments exception to the military procurement regime. - VI. Concluding remarks. | (Abstract) Ever since the Maastricht Treaty, the EU has been increasingly engaged in the military domain. More recently, many initiatives on intergovernmental EU cooperation have emerged in the area of Common Security and Defence Policy, such as those initiatives in the context of permanent structured cooperation (PESCO). At the same time, the Commission initiated policies and legislation on military industries based on the supranational regime of the internal market, such as the Defence Procurement Directive (DPD) which was adopted by the European Parliament and the Council in 2009. The EU Treaties, however, include a clear exception for military equipment and recognise national security as the sole responsibility of the Member States. The DPD aims to liberalise European armaments industries by imposing public procurement obligations on Member States for their military procurement. Such obligations, however, may conflict with the national security strategies of the Member States aimed at the survival of domestic industry. Consequently, Member States often still rely on the Treaty-based exception. This Article aims to provide a new legal approach to this conflict by, first, looking at the historic and legal context in which policies and legislation came about, secondly, determining the function of military procurement based on international relations theories and, thirdly, evaluating the internal market policies and legislation within this context. Finally, the author sets out a theoretical basis for legal interpretation of EU military procurement law. To overcome the conflict, the author argues for reconsideration of the internal market legal base of the military procurement regime and regulation of the legally controversial offset agreements.

Abstract The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N = 807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480–0.989, P = 0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411–0.923, P = 0.019) and multivariate analyses (HR 0.571, 95% CI 0.380–0.856, P = 0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR + breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research.