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Abstract Background Studies on oral health status of adults are sparse and rarely include data on endodontic treatment and trauma. In the military, those data are available because recruits are routinely assessed with a clinical and radiological examination at the start of their career. This study aimed to identify differences in oral health status of Dutch Armed Forces recruits between cohorts, departments, sex, age and rank, with DMF-T, endodontic treatment and dental trauma as outcome measures. Methods Data from Electronic Patient Files from all recruits enlisted in 2000, 2010 and 2020 were used for analysis in a hurdle model resulting in the estimated cohort effect, controlled for the demographic variables. The total number of recruits was 5,764. Due to the retrospective character of the study a proxy was used to compose D-T and dental trauma. Results The mean DMF-T number in recruits decreases from 5.3 in cohort 2000 to 4.13 in cohort 2010 and 3.41 in cohort 2020. The percentage of endodontically treated teeth increases from 6% in cohort 2000 to respectively 9% in 2010 and 8% in 2020. The percentage of recruits showing signs of dental trauma did not change significantly between cohort 2000 (3.1%) and cohort 2010 and 2020 (both 2.7%). Conclusions Oral health in Armed Forces recruits is improving over the years, following a similar trend as the general population in the Netherlands. Lower SES represented by enlisted rank showed substantial lower oral health status.

Summary: The primary objective of the prospective, randomized, multicenter, phase 3 biomarker Microarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens trial (MATADOR: ISRCTN61893718) is to generate a gene expression profile that can predict benefit from either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense scheduled doxorubicin and cyclophosphamide (ddAC). Patients with a pT1-3, pN0-3 tumor were randomized 1:1 between ddAC and TAC. The primary endpoint was a gene profile-treatment interaction for recurrence-free survival (RFS). We observed 117 RFS events in 664 patients with a median follow-up of 7 years. Hallmark gene set analyses showed significant association between enrichment in immune-related gene expression and favorable outcome after TAC in hormone receptor-negative, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) (triple-negative breast cancer [TNBC]). We validated this association in TNBC patients treated with TAC on H&E slides; stromal tumor-infiltrating lymphocytes (sTILs) ≥20% was associated with longer RFS (hazard ratio 0.18, p = 0.01), while in patients treated with ddAC no difference in RFS was seen (hazard ratio 0.92, p = 0.86, pinteraction = 0.02).

Abstract Background Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. Methods We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models. Results Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and

Abstract Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico‐designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER‐positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer‐driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER‐positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER‐positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.

Abstract Background In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. Patients and methods Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. Results Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. Conclusion Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Trial registration Clinical trial registration: NCT02925234. First registration date: 05/10/2016.

Cancer transmission from deceased donors is an exceedingly rare but potentially fatal complication in transplant recipients. We aimed to quantify the likelihood of non-utilization of kidneys for transplantation from donors with a prior cancer history. We included all intended and actual deceased donors in Australia and New Zealand between 1989 and 2017. Association between prior cancer history and non-utilization of donor kidneys was examined using adjusted logistic regression. Of 9,485 deceased donors, 345 (4%) had a prior cancer history. Of 345 donors with a prior cancer history, 197 (57%) were utilized for transplantation. Donor characteristics of age, sex and comorbidities were similar between utilized and non-utilized donors with prior cancer. The time from cancer to organ donation was similar between utilized and non-utilized donors, irrespective of cancer subtypes. Donors with a prior cancer history were less likely to be utilized [adjusted OR (95% CI) 2.29 (1.68–3.13)] than donors without prior cancer. Of all actual donors, the adjusted OR for non-utilization among those with prior cancer was 2.36 (1.58–3.53). Non-melanoma skin cancer was the most frequent prior cancer type for utilized and non-utilized potential donors. Donors with prior cancers were less likely to be utilized for transplantation, with no discernible differences in cancer characteristics between utilized and non-utilized donors.

BackgroundImplementation of eHealth is progressing slowly. In-depth insight into patients’ preferences and needs regarding eHealth might improve its use. ObjectiveThis study aimed to describe when patients want to use eHealth, how patients want to communicate and receive information digitally, and what factors influence the use of eHealth in clinical practice. MethodsA multimethod study was conducted. Two meetings of ~5.5 hours with plenary information sessions and focus groups were held with 22 patients from the rheumatology, orthopedics, and rehabilitation departments of a Dutch hospital specialized in musculoskeletal disorders. Assignments were performed during the focus groups in which qualitative (eg, semistructured interview questions) and quantitative (ie, voting and ranking factors) data were collected. ResultsThe way patients want to use eHealth varies between patients and moments of a patient’s care pathway. Patients’ digital channel preferences depended on the need for interaction with a health care provider (HCP). The interaction need is in turn influenced by the degree to which information or communication is specific to an individual patient and leads to consequences for the patient. The 5 most important factors influencing the use of eHealth were access to medical information (eg, electronic health records), perceived control over disease management, correctness and completeness of information, data security, and access to information or an HCP at any time. The 5 least important factors influencing eHealth use were help with using digital devices, having internet or equipment, digital skills, attitude or emotions toward eHealth, and societal benefits. ConclusionsPatients identified opportunities for using eHealth during all moments of their care pathway. However, preferences for eHealth varied between patients and phases in the care pathway. As a consequence, eHealth should be tailored to fit individual patients’ preferences but also the need for interaction regarding different topics by offering a variety of digital channels with a gradient of interaction possibilities. Furthermore, digital skills and access to the internet might become less important to focus on in the future. Improving eHealth use by patients may be achieved by providing patients access to correct and safe (medical) information and more control over their care.

Abstract Breast cancer tumor grade is strongly associated with patient survival. In current clinical practice, pathologists assign tumor grade after visual analysis of tissue specimens. However, different studies show significant inter-observer variation in breast cancer grading. Computer-based breast cancer grading methods have been proposed but only work on specifically selected tissue areas and/or require labor-intensive annotations to be applied to new datasets. In this study, we trained and evaluated a deep learning-based breast cancer grading model that works on whole-slide histopathology images. The model was developed using whole-slide images from 706 young (

Objective: Transmission of SARS-CoV-2 during oral health care is potentially increased compared to regular social activities. Specific amendments to the Dutch national infection control guidelines were promulgated. This study aimed to map the impact of the coronavirus pandemic on providing oral health care during the first wave of the coronavirus pandemic in 2020 in the Netherlands. Methods: A cross-sectional web-based survey was sent via email to a representative sample of dental hygienists and dentists in the Netherlands. Results: Of the 1700 oral health care practitioners approached, 440 (25.9%) responded to the survey. Patient access to oral health care was severely restricted during the lockdown in the spring of 2020. A total of 1.6% of the oral health care practitioners had laboratory-confirmed COVID-19 during the study period, although this is likely to be an underrepresentation due to limited access to testing at that time. Over half of the participants perceived an increased risk of virus transmission during aerosol-generating treatments in their practices. A large majority (65.0%–87.1%) of the oral health care practitioners followed the COVID-19-specific amendments to the national infection control guidelines. Compared to the pre-pandemic period, additional personal protective equipment and protocols were applied. Factors related with compliance with the additional recommendations were age, employment status, and occupation. Conclusions: The pandemic had a profound impact on both the accessibility and practice of oral health care. This survey study found that most Dutch oral health care practitioners paid extra attention to hygiene and infection control. Also, a low number of COVID-19 infections detected amongst Dutch oral health care practitioners was reported in the Netherlands. These overall outcomes suggest that safe oral health care can be provided when following the current infection control recommendations.

Background. This report contains recommendations from 1 of 7 domains of the International Donation and Transplantation Legislative and Policy Forum (the Forum). The purpose is to provide expert guidance on the structure and function of Organ and Tissue Donation and Transplantation (OTDT) systems. The intended audience is OTDT stakeholders working to establish or improve existing systems. Methods. The Forum was initiated by Transplant Québec and co-hosted by the Canadian Donation and Transplantation Program partnered with multiple national and international donation and transplantation organizations. This domain group included administrative, clinical, and academic experts in OTDT systems and 3 patient, family, and donor partners. We identified topic areas and recommendations through consensus, using the nominal group technique. Selected topics were informed by narrative literature reviews and vetted by the Forum’s scientific committee. We presented these recommendations publicly, with delegate feedback being incorporated into the final report. Results. This report has 33 recommendations grouped into 10 topic areas. Topic areas include the need for public and professional education, processes to assure timely referral of patients who are potential donors, and processes to ensure that standards are properly enforced. Conclusions. The recommendations encompass the multiple roles organ donation organizations play in the donation and transplantation process. We recognize the diversity of local conditions but believe that they could be adapted and applied by organ donation organizations across the world to accomplish their fundamental objectives of assuring that everyone who desires to become an organ donor is given that opportunity in a safe, equitable, and transparent manner.

Abstract Objective Gout and diabetes mellitus type 2 (DM) frequently co-exist. The pharmacological effects of metformin may include anti-inflammatory and urate lowering effects. The objective of this study was to test these effects in patients with gout starting uric acid lowering treatment (ULT) in secondary care. Methods Retrospective cohort study including patients with gout and DM starting ULT. Differences in the incidence density of gout flares, proportion of patients reaching target sUA in the first six months after starting ULT, and difference in mean allopurinol dose at sUA target were compared between users of metformin and users of other or no anti-diabetic drugs (control group). Correction for confounding was applied. Results A total of 307 patients were included, of whom 160 (52.1%) used metformin. The incidence of flares was 1.61 and 1.70 in the first six months for respectively the metformin group and control group. The incidence rate ratio for gout flares was not significant (0.95, 95% CI 0.78 to 1.14). At six months, 62.8% and 54.9% reached target sUA in the metformin and control group respectively, corrected odds ratio of 1.09 (95% CI 0.66 to 1.80). There was no difference in mean allopurinol dose at sUA target 266 mg for metformin users and 236 mg for the control group, difference 30 mg (95% CI − 4.7 to 65.5). Conclusions In conclusion we could not confirm a clinically relevant anti-inflammatory or urate lowering effect of metformin in patients starting ULT treatment and receiving usual care flare prophylaxis.

Background The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.Methods GSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.Conclusions GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration number NCT02528357.

Background:. Unexpected donor-derived infections of hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV are rare but important potential complications of deceased organ transplantation. The prevalence of recently acquired (yield) infections has not been previously described in a national cohort of Australian deceased organ donors. Donor yield infections are of particularly significance, as they can be used to gain insights in the incidence of disease in the donor pool and in turn, estimate the risk of unexpected disease transmission to recipients. Methods:. We conducted a retrospective review of all patients who commenced workup for donation in Australia between 2014 and 2020. Yield cases were defined by having both unreactive serological screening for current or previous infection and reactive nucleic acid testing screening on initial and repeat testing. Incidence was calculated using a yield window estimate and residual risk using the incidence/window period model. Results:. The review identified only a single yield infection of HBV in 3724 persons who commenced donation workup. There were no yield cases of HIV or HCV. There were no yield infections in donors with increased viral risk behaviors. The prevalence of HBV, HCV, and HIV was 0.06% (0.01–0.22), 0.00% (0–0.11), and 0.00% (0–0.11), respectively. The residual risk of HBV was estimated to be 0.021% (0.001–0.119). Conclusions:. The prevalence of recently acquired HBV, HCV, and HIV in Australians who commence workup for deceased donation is low. This novel application of yield-case-methodology has produced estimates of unexpected disease transmission which are modest, particularly when contrasted with local average waitlist mortality. Supplemental Visual Abstract; http://links.lww.com/TXD/A503.

Background. We aimed to facilitate the donation of tissue samples for research by establishing a centralized system integrated in the organ donation program for collection, storage, and distribution of samples (the Australian Donation and Transplantation Biobank [ADTB]). Methods. Feasibility of a research biobank integrated within the deceased organ and tissue donation program was assessed. DonateLife Victoria sought consent for ADTB donation after consent was received for organ donation for transplantation from the donor’s senior available next of kin. ADTB samples were collected during donation surgery and distributed fresh to researchers or stored for future research. The main outcome measures were ADTB donation rates, ADTB sample collection, ADTB sample use, and to identify ethical considerations. Results. Over 2 y, samples were collected for the ADTB from 69 donors (28% of 249 donors). Samples were obtained from the spleen (n = 59, 86%), colon (n = 57, 83%), ileum (n = 56, 82%), duodenum (n = 55, 80%), blood (n = 55, 80%), bone marrow (n = 55, 80%), skin (n = 54, 78%), mesenteric lymph nodes (n = 56, 81%), liver (n = 21, 30%), lung (n = 29, 42%), and lung-draining lymph node (n = 29, 42%). Heart (n = 20), breast (n = 1), and lower urinary tract (n = 1) samples were obtained in the second year. Five hundred fifty-six samples were used in 19 ethics-approved research projects spanning the fields of immunology, microbiology, oncology, anatomy, physiology, and surgery. Conclusions. The integration of routine deceased donation and transplantation activities with a coordinated system for retrieval and allocation of donor samples for use in a range of research projects is feasible and valuable.