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Supplementary Figure 3: Gating strategy for a representative sample

Supplementary Tables S1-S2

Purpose:Patients with cancer display reduced humoral responses after double-dose COVID-19 vaccination, whereas their cellular response is more comparable with that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and patients with cancer. Because of the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in patients with cancer.Experimental Design:A total of 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs. 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARS-CoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T-cell responses against SARS-CoV-2–specific S1 and S2 peptides.Results:Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects [GMT 1,755.90 BAU/mL (95% CI, 1,276.95–2,414.48) vs. 1,495.82 BAU/mL (95% CI, 1,131.48–1,977.46)]. However, homologous-boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels.Conclusions:In patients with cancer who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response.

Purpose: Patients with cancer display reduced humoral responses after double-dose COVID-19 vaccination, whereas their cellular response is more comparable with that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and patients with cancer. Because of the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in patients with cancer. Experimental Design: A total of 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs. 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARS-CoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T-cell responses against SARS-CoV-2–specific S1 and S2 peptides. Results: Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects [GMT 1,755.90 BAU/mL (95% CI, 1,276.95–2,414.48) vs. 1,495.82 BAU/mL (95% CI, 1,131.48–1,977.46)]. However, homologous-boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels. Conclusions: In patients with cancer who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response.

As solid organ recipients are at high risk of severe COVID-19 and respond poorly to primary SARS-CoV-2 mRNA vaccination, they have been prioritized for booster vaccination. However, an immunological correlate of protection has not been identified in this vulnerable population. We conducted a prospective monocentric cohort study of 65 kidney transplant recipients who received three doses of SARS-CoV-2 BNT162b2 mRNA vaccination. Associations between symptomatic breakthrough infection (BTI) and vaccine responses, patient demographic and clinical characteristics were explored. Symptomatic COVID-19 was diagnosed in 32% of kidney transplant recipients during a period of six months after the administration of the third vaccine dose. During this period, SARS-CoV-2 delta and omicron were the dominant variants in the general population. Univariate analyzes identified avidity of SARS-CoV-2 receptor binding domain (RBD) binding IgG, neutralizing antibodies and SARS-CoV-2 S2 domain-specific IFN-γ responses as correlates of protection against BTI. Some demographic and clinical parameters correlated with vaccine responses, but none correlated with the risk of BTI. In multivariate analysis, the risk of BTI was best predicted by neutralizing antibody and S2-specific IFN-γ responses, adjusting for age, graft function and mycophenolate mofetil use. In conclusion, both antibody and T cell responses predict the risk of BTI in kidney transplant recipients who received three doses of SARS-CoV-2 mRNA vaccine. T cell responses may help compensate for the suboptimal antibody response to vaccination in this vulnerable population.One Sentence SummaryAntibody and T cell responses to booster SARS-CoV-2 vaccination predict the risk of symptomatic breakthrough infection in kidney transplant recipients

Background: Nursing home residents, a frail and old population group, respond poorly to primary mRNA COVID-19 vaccination. A third dose has been shown to boost protection against severe disease and death in this immunosenescent population, but limited data is available on the immune responses it induces.Methods: In this observational cohort study, peak humoral and cellular immune responses were com-pared 28 days after the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in residents and staff members of two Belgian nursing homes. Only individuals without evidence of previous SARS-CoV-2 infection at third dose administration were included in the study. In addition, an extended cohort of residents and staff members was tested for immune responses to a third vaccine dose and was mon-itored for vaccine breakthrough infections in the following six months. The trial is registered on ClinicalTrials.gov (NCT04527614).Findings: All included residents (n = 85) and staff members (n = 88) were SARS-CoV-2 infection naive at third dose administration. Historical blood samples from 28 days post second dose were available from 42 residents and 42 staff members. Magnitude and quality of humoral and cellular immune responses were strongly boosted in residents post third compared to post second dose. Increases were less pro-nounced in staff members than in residents. At 28 days post third dose, differences between residents and staff had become mostly insignificant. Humoral, but not cellular, responses induced by a third dose were predictive of subsequent incidence of vaccine breakthrough infection in the six months following vaccination.Interpretation: These data show that a third dose of mRNA COVID-19 vaccine largely closes the gap in humoral and cellular immune response observed after primary vaccination between NH residents and staff members but suggest that further boosting might be needed to achieve optimal protection against variants of concern in this vulnerable population group.(c) 2023 Published by Elsevier Ltd.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented itself as one of the most important health concerns of the 2020's, and hit the geriatric population the hardest. The presence of co-morbidities and immune ageing in the elderly lead to an increased susceptibility to COVID-19, as is the case for other influenza-like illnesses (ILI) or acute respiratory tract infections (ARI). However, little is known, about the impact of a previous or current infection on the other in terms of susceptibility, immune response, and clinical course. The aim of the "Prior Infection with SARS-COV-2" (PICOV) study is to compare the time to occurrence of an ILI or ARI between participants with a confirmed past SARS-CoV-2 infection (previously infected) and those without a confirmed past infection (naïve) in residents and staff members of nursing homes. This paper describes the study design and population characteristics at baseline., info:eu-repo/semantics/published

Background Factors affecting response to SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients remain to be elucidated. Methods Forty allo-HCT recipients were included in a study of immunization with BNT162b2 mRNA vaccine at days 0 and 21. Binding antibodies (Ab) to SARS-CoV-2 receptor binding domain (RBD) were assessed at days 0, 21, 28, and 49 while neutralizing Ab against SARS-CoV-2 wild type (NT50) were assessed at days 0 and 49. Results observed in allo-HCT patients were compared to those obtained in 40 healthy adults naive of SARS-CoV-2 infection. Flow cytometry analysis of peripheral blood cells was performed before vaccination to identify potential predictors of Ab responses. Results Three patients had detectable anti-RBD Ab before vaccination. Among the 37 SARS-CoV-2 naive patients, 20 (54%) and 32 (86%) patients had detectable anti-RBD Ab 21 days and 49 days postvaccination. Comparing anti-RBD Ab levels in allo-HCT recipients and healthy adults, we observed significantly lower anti-RBD Ab levels in allo-HCT recipients at days 21, 28 and 49. Further, 49% of allo-HCT patients versus 88% of healthy adults had detectable NT50 Ab at day 49 while allo-HCT recipients had significantly lower NT50 Ab titers than healthy adults ( P = 0.0004). Ongoing moderate/severe chronic GVHD ( P 0.5, P, info:eu-repo/semantics/published

BackgroundPatients with cancer, especially haematological cancer, are at increased risk for breakthrough COVID-19 infection. However, so far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed.MethodsHere, we employed machine learning approaches to identify a biomarker signature based on blood cytokine and growth factors linked to vaccine response from 199 cancer patients receiving BNT162b2 vaccine.ResultsWe show that C-reactive protein (CRP; general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) can correctly classify patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments.ConclusionWhile we propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at continued risk of COVID-19, our data also importantly suggest that such a signature could reflect the inherent make-up of some cancer patients who are also refractive to immunotherapy.

While the association between fruit consumption and bladder cancer risk has been extensively reported, studies have had inadequate statistical power to investigate associations between types of fruit and bladder cancer risk satisfactorily. Fruit consumption in relation to bladder cancer risk was investigated by pooling individual data from 13 cohort studies. Cox regression models with attained age as time scale were used to estimate hazard ratios (HRs) for intakes of total fruit and citrus fruits, soft fruits, stone fruits, tropical fruits, pome fruits and fruit products. Analyses were stratified by sex, smoking status and bladder cancer subtype. During on average 11.2 years of follow-up, 2836 individuals developed incident bladder cancer. Increasing fruit consumption (by 100 g/day) was inversely associated with the risk of bladder cancer in women (HR = 0.92; 95% CI 0.85-0.99). Although in women the association with fruit consumption was most evident for higher-risk nonmuscle invasive bladder cancer (NMIBC; HR = 0.72; 95% CI 0.56-0.92), the test for heterogeneity by bladder cancer subtype was nonsignificant (P-heterogeneity = .14). Increasing fruit consumption (by 100 g/day) was not associated with bladder cancer risk in men (HR = 0.99; 95% CI 0.94-1.03), never smokers (HR = 0.96; 95% CI 0.88-1.05), former smokers (HR = 0.98; 95% CI 0.92-1.05) or current smokers (HR = 0.95; 95% CI 0.89-1.01). The consumption of any type of fruit was not found to be associated with bladder cancer risk (P values > .05). Our study supports no evidence that the consumption of specific types of fruit reduces the risk of bladder cancer. However, increasing total fruit consumption may reduce bladder cancer risk in women.

We report the levels of neutralising antibodies against Wuhan, Delta and Omicron variants in unimmunized infected (group 1), immunised and boosted (group 2) and infected immunised and boosted (group 3) adult individuals. Our observations support the rapid administration of a booster vaccine dose to prevent infection and disease caused by Omicron.

We report the levels of neutralising antibodies against Wuhan, Delta and Omicron variants in healthy individuals pre-infected or not with SARS-CoV-2 and immunized with three doses of the BNT162b2 vaccine. Our observations support the rapid administration of a booster vaccine dose to prevent infection and disease caused by Omicron.

Background: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. Patients and methods: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. Results: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (

BackgroundResidents of nursing homes (NH) are at high risk of COVID-19 related morbidity and death and may respond poorly to vaccination because of old age and frequent comorbidities.MethodsForty residents and forty staff members either naïve or previously infected with SARS-CoV-2 were recruited in two NH in Belgium before immunization with two doses of 30µg BNT162b2 mRNA vaccine at day 0 and day 21. Binding antibodies (Ab) to SARS-CoV-2 receptor binding domain (RBD), spike domains S1 and S2, RBD Ab avidity, and neutralizing Ab against SARS-CoV-2 wild type and B.1.351 variant were assessed at days 0, 21, 28, and 49.ResultsSARS-CoV-2 naïve residents had lower Ab responses to BNT162b2 mRNA vaccination than naïve staff. These poor responses involved lower levels of IgG to all domains of the vaccine antigen, lower avidity of RBD IgG, and lower levels of Ab neutralizing the vaccine strain. No naïve resident had detectable neutralizing Ab to the B.1.351 variant. High and comparable Ab responses were observed in residents and staff previously infected with SARS-CoV-2. Clustering analysis revealed that poor vaccine responders not only included naïve residents but also naïve staff, emphasizing the heterogeneity of responses to mRNA vaccination in the general population.ConclusionsThe poor Ab responses to mRNA vaccination observed in infection naïve residents and in some naïve staff members of NH suggest suboptimal protection against breakthrough infection, especially with variants of concern. Adapted vaccination regimens may be needed to provide optimal protection against COVID-19 to vulnerable populations.SummaryPoor antibody responses to COVID-19 mRNA vaccination were observed in SARS-CoV-2 infection naïve residents and some naïve staff members of nursing homes. This suggests suboptimal protection against breakthrough infection, especially with variants of concern, and the need for adapted vaccination regimens.

Background: COVID-19 has presented itself as one of the most important health concerns of 2020. The geriatric population is arguably hit the hardest by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ”Prior Infection with SARS-COV-2” (PICOV) study investigates both residents and staff members from nursing homes. The primary aim of the study is to compare the time to occurrence of an influenza-like illness (ILI) or acute respiratory infection (ARI) between participants with a confirmed past SARS-CoV-2 infection and those without an infection. This paper details the study design, sampling scheme, biological measurements, and population characteristics at baseline.Methods: In 26 Belgian nursing homes, all eligible residents and staff members with or without a past SARS-CoV-2 infection (ratio 40/60) were invited to participate. Consent was obtained from 1,375 participants and 1,226 completed the baseline questionnaire. Prevalence of symptoms during a prior SARS-CoV-2 infection was compared between residents and staff members with χ2 statistics.Results: Nursing home residents (both with and without a prior SARS-CoV-2 infection) systematically reported fewer symptoms than staff members. Moreover, results from prior nasopharyngeal RT-qPCR and baseline serology show that antibody development after a SARS-CoV-2 infection differs between residents and staff members.Conclusions: We can postulate that disease development and symptoms is different between a geriatric and younger population. Therefore, the occurrence and severity of a future ILI and/or ARI might vary from resident to staff.

OBJECTIVES: Assess the performance of five SARS-CoV-2 rapid serological tests (RST) using finger prick (FP) blood on-site to evaluate their usability for exposure assessment in population-based seroprevalence studies. STUDY DESIGN: Since cross-reactivity with common cold human coronaviruses occurs, serological testing includes a risk of false-positive results. Therefore, the selected cohort for RST-validation was based on combined immunoassay (presence of specific antibodies) and RT-qPCR (presence of SARS-CoV-2) data. RST-performance for FP blood and serum was assessed by performing each RST in two groups, namely SARSCoV- 2 positive (n=108) and negative healthcare workers (n=89). Differences in accuracy and positive and negative predictive values (PPV, NPV) were calculated for a range (1-50%) of SARS-CoV-2 prevalence estimates. RESULTS: The OrientGene showed overall acceptable performance, with sensitivities of 94.4% and 100%, and specificities of 96.6% and 94.4%, using FP blood and serum, respectively. Although three RST reach optimal specificities (100%), the OrientGene clearly outperforms in sensitivity. At a SARS-CoV-2 prevalence rate of 40%, this RST outperforms the other tests in NPV (96.3%) and reaches comparable PPV (94.9%). Although the specificity of the Covid-Presto is excellent when using FP blood or serum (100% and 97.8%, respectively), its sensitivity decreases when using FP blood (76.9%) compared to serum (98.1%). CONCLUSIONS: Performances of the evaluated RST differ largely. Only one out of five RST (OrientGene) had acceptable sensitivity and specificity using FP blood. Therefore, the latter could be used for seroprevalence studies in a high-prevalence situation. The OrientGene, which measures anti-RBD antibodies, can be valuable after vaccination as well. ispartof: JOURNAL OF CLINICAL VIROLOGY vol:142 ispartof: location:Netherlands status: published

Background: Cancer patients are at higher risk of developing severe COVID-19. However, safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment is unclear. Methods: In this interventional prospective multi-cohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted- or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Primary endpoint was anti-SARS-CoV-2 receptor binding domain (RBD) antibody level at 28 days post-booster. Anti-RBD IgG titers above 200 IU/ml was used to define high-responders as it leads to a neutralization response required for 50% protection against symptomatic SARS-CoV-2 infection in 268 independent subjects. Secondary endpoints included self-reported adverse events (AEs), antibody response over time and number of breakthrough infections after vaccination. Findings: 28 days post-booster vaccination of 197 cancer patients, antibody response was lower in the hematological cohort (geometric mean titer (GMT) 17·61 IU/mL [95% CI 7·17-43·24]) and the chemotherapy cohort (GMT 234·05 IU/mL [95% 95%CI 122·10-448·66]) when compared to healthy individuals (n=40; GMT 1844·93 IU/mL [95% CI 1383·57-2460·14]), irrespective of timing of vaccination during chemotherapy cycles. Only 55% and 7% of patients receiving chemotherapy or rituximab could be categorized as high-responders at 28 days post-booster. During the study period, five subjects tested positive for SARS-CoV-2 infection, including three after full vaccination. Local and systemic AEs were mostly mild to moderate, with only 1-3% of patients experiencing severe AEs. Local, but not systemic, AEs occurred more frequently after booster than after priming dose. Interpretation: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections. Trial Registration: EudraCT number 2021-000300-38 Funding: The regulatory sponsor was the Antwerp University Hospital (EudraCT number 2021-000300-38). The trial was funded by the Belgian Government through Sciensano (COVID-19_SC004, COVID- 19_SC059, COVID-19_SC061). Declaration of Interest: MP declares to have an advisory role within Remedus, all other authors declare no competing interests. Ethical Approval: The study was approved by the local ethics committee and was executed in accordance with Good Clinical Practice and the Declaration of Helsinki (ICH GCP E6(R2)).

Purpose - The role of diet in bladder carcinogenesis has yet to be established. To date most studies have investigated dietary components individually, rather than as dietary patterns, which may provide stronger evidence for any influence of diet on bladder carcinogenesis. The Mediterranean diet has been associated with many health benefits, but few studies have investigated its association with bladder cancer risk. Methods - We investigated the potential association between the Mediterranean diet score (MDS) and risk of developing bladder cancer by pooling 13 prospective cohort studies included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study and applying a Cox regression analysis. Results - Dietary data from 646,222 study participants, including 3639 incident bladder cancer cases, were analysed. We observed an inverse association between Mediterranean diet and bladder cancer risk (HRhigh 0.85 [95% CI 0.77, 0.93]). When stratifying the results on non-muscle-invasive or muscle-invasive disease or sex the association remained similar and the HR estimate was consistently below 1.00 both for medium and high adherence to the Mediterranean diet. A consistent association was observed when disregarding fat or alcohol intake. Conclusion - We found evidence that adherence to the Mediterranean diet was associated with reduced risk of developing bladder cancer, suggesting a positive effect of the diet as a whole and not just one component.

Pancreatic cancer is one of the most lethal tumours, and it is the fourth cause of cancer death in Europe. Despite its important public health impact, no effective treatments exist, nor are there high-visibility research efforts to improve care. This alarming situation is emblematic of a larger group of cancer diseases, known as neglected cancers. To address the impact of these diseases, the European Commission-supported Innovative Partnership for Action Against Cancer launched a multi-stakeholder initiative to determine key steps that healthcare systems can rapidly implement to improve their response. A working group comprising 20 representatives from European medical societies, patient associations, cancer plan organisations and other relevant European healthcare stakeholders was organised. A consensus process based on the results of different studies, discussion of research outcomes, and development and endorsement of draft statements resulted in 22 consensus recommendations (the Bratislava Statement). The statement argues that substantial improvements can be achieved in patient outcomes by centralising pancreatic cancer care around state-of-the-art reference centres, staffed by expert multidisciplinary teams capable of providing high-quality care. This organisational model requires a specific care framework encompassing primary, palliative and survivorship care, and a policy environment prioritising the use of quality criteria and performance assessments as well as research investments dedicated to prevention, risk prediction, early detection and diagnosis. In order to address the challenges posed by neglected cancers in general and pancreatic cancer in particular, a specific control strategy tailored to this reality is required.

OBJECTIVE: The aim of this study is to look at the influence of metformin intake and duration, on urinary bladder cancer (UBC) risk, with sulfonylurea (SU) only users as control using a new-user design (inception cohort). METHODS: We conducted a retrospective cohort study using data from the UK Clinical Practice Research Datalink (CPRD) including all patients with at least one prescription of oral anti-diabetic drugs (ADD) and/or insulin. The risk of UBC in different groups of ADD users (metformin alone (1), metformin in combination (2) with other ADD medication (glinides, glitazones, DPP-4-inhibitors, SUs, insulin or more than one combination), all metformin users (1 + 2) was compared with SU only users using Cox proportional hazards models. The estimates were adjusted for age, gender, smoking status, BMI and diabetes duration. RESULTS: The inception cohort included 165,398 participants of which 132,960 metformin users and 32,438 SU only users. During a mean follow-up time of more than five years 693 patients developed UBC, 124 of the control group and 461 of the all metformin users. There was no association between metformin use and UBC risk (HR = 1.12 (95% CI 0.90-1.40)) compared to SU only users, even after adjustment for diabetes duration (HR = 1.13 (95% CI 0.90-1.40)). We found a pattern of decreasing risk of UBC with increasing duration of metformin intake, which was statistically not significant. CONCLUSION: Metformin has no influence on the risk of UBC compared to SU in type 2 diabetes patients using a new-user design. This article is protected by copyright. All rights reserved.

Urinary bladder cancer (UBC) ranks ninth in worldwide cancer incidence. The most common histological type in Western countries is transitional cell carcinoma (TCC), while in Africa, a substantial proportion of squamous cell carcinomas (SCC) are observed related to the prevalence of infection with Schistosoma haematobium (bilharziasis). UBC has the highest per-patient lifetime cost for cancer in terms of healthcare expenditure compared to all other types of cancer. It is more frequent in men than in women and age is now widely accepted as the greatest single risk factor for developing UBC. The median age at diagnosis is 70 years. Cigarette smoking and specific occupational exposures, such as carcinogenic dyes for painters, are the main known causes of UBC.

Background Many European citizens regularly consult homeopathic doctors. Especially for children there is very little data available about the reasons they visit a homeopathic doctor. What are the expectations of the parents consulting a Homeopath MD with their child, who are they and last but not least are they satisfied with their initiative? This study including 773 children from six European countries and Brazil is aimed to look at parent-proxy satisfaction with homeopathic treatment prescribed for their children by a homeopathic doctor after a follow-up of two months. The questionnaire was developed from the methodology used in a survey of adults published in 2002. Method An initial questionnaire included demographic information and questions for assessing health-related Quality of Life (QoL). A follow-up questionnaire collected data on changes in QoL. Results The demographic characteristics of respondents showed more male children (53.1%) but more female parent-proxies (93.4%). 73.7% of respondents had previously tried conventional treatments; 26.3% non-conventional approaches. Satisfaction with the medical homeopathic consultation was high. Reported differences between baseline and final QoL ondexes are positive for all four studied conditions. It range from 3.206 to 10.188. Considering 7% as a reference value for “minimal clinical difference”, this is reached for 2 on 4 conditions (8.473 and 10.188). Changes in complaint limitations visual scales are positive, even if uncertain for skin complaints and influenced parents satisfaction. Conclusions on clinical impact must be cautious. 4.2% of patients experienced side-effects which they attribute to homeopathic treatment. 10.1% of patients reported significant aggravation at the beginning of homeopathic treatment, 19% slight aggravation of symptoms. Conclusions The satisfaction of parents using a medical homeopathic approach for their children is linked to the perceived competence of the doctor homeopath, the perceived improvement of the main complaint limitations and the completeness of the received information.

Background Many patients throughout the world consult homeopathic medical doctors. Using a similar methodology as in a first survey published in 2002 a second survey was done including 919 adults receiving homeopathic treatment in six European countries and Brazil aimed to look at who are they, their reasons for consultations and expectations and satisfaction with homeopathy prescribed by a homeopathic doctor after a follow-up time of six months. Method An initial questionnaire included demographic information and questions for assessing health-related Quality of Life (QoL). A follow-up questionnaire collected data on changes in QoL. Results 77% patients had initially used conventional treatments and 23% other non-conventional treatments. Satisfaction of patients with the medical homeopathic consultation is high. The difference between the final QoL scores after six months and the baseline are positive. Reported differences between baseline and final index range from 3.87 to 10.41 depending on diagnosis. Taking 7% as a reference value for 'minimal clinically significant difference', this is reached for 3 of 8 conditions. Changes in complaint limitations visual scales are positive. Conclusions on clinical impact must be cautious. 6% of the patients experienced side-effects which they attributed to homeopathic treatment. 7.8% of the patients reported significant aggravation at the beginning of the homeopathic treatment and 26.2% slight aggravation of symptoms. Conclusions The satisfaction of patients using a medical homeopathic approach is linked to the perceived competence of the doctor homeopath, the perceived improvement of the main complaints limitations and the time dedicated to them by the doctor.

Background In Belgium, bladder cancer (BC) is the fifth most common cancer in men. The per-patient lifetime cost is high. Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of BC. We therefore hypothesised that selenium may be suitable for chemoprevention of recurrence of BC. Method The Selenium and Bladder Cancer Trial (SELEBLAT) was an academic phase III placebo-controlled, double-blind, randomised clinical trial designed to determine the effect of selenium on recurrence of non-invasive urothelial carcinoma conducted in 14 Belgian hospitals. Patients were randomly assigned by a computer program to oral selenium yeast 200 μg once a day or placebo for three years, in addition to standard care. All study personnel and participants were blinded to treatment assignment for the duration of the study. All randomised patients were included in the intention to treat (ITT) and safety analyses. Per protocol analyses (PPAs) included all patients in the study three months after start date. Results Between September 18, 2009 and April 18, 2013, 151 and 141 patients were randomised in the selenium and placebo group. Patients were followed until December 31, 2015. The ITT analysis resulted in 43 (28%; 95% CI, 0.21–0.35) and 45 (32%; 95% CI, 0.24–0.40) recurrences in the selenium and placebo group. The hazard ratio (HR) was 0.85 (95% CI, 0.56–1.29; p = 0.44) while the HR for the PPA resulted in 42 and 39 (28%; 95% CI, 0.20–0.35) recurrences in the selenium and placebo group (HR = 0.96 [95% CI, 0.62–1.48]; p = 0.93). Conclusion Selenium supplementation does not lower the probability of recurrence in BC patients.

Published version. Source at http://dx.doi.org/10.1186/s13690-016-0140-1 Background: In 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7th most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage. Methods/design: The BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case–control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer. Discussion: The substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer.

Background: Nausea and vomiting in pregnancy (NVP) and hyperemesis gravidarum (HG) have a significant impact on quality of life. Medication to relieve symptoms of NVP and HG are available but pregnant women and their caregivers have been concerned about the teratogenic effect, side effects and poor efficacy. The aim of this review was to investigate if there is any clinical evidence for the efficacy of acustimulation in the treatment of NVP or HG. Methods: A systematic review of randomized controlled trials (RCTs), including both English and Chinese databases was conducted to assess the efficacy of various techniques of acustimulation for NVP and HG. The methodological quality of the studies was assessed using the Cochrane's risks of bias tool. Revised STRICTA (2010) criteria were used to appraise acustimulation procedures. Pooled relative risks (RRp) and standard mean deviations (SMD) with 95 % confidence intervals (CI) were calculated from the data provided by the investigators of the original trials. Results: Twenty-nine trials including 3519 patients met the inclusion criteria. Twenty trials could be included in statistical pooling. The overall effect of different acustimulation techniques shows a significant reduction for the combined outcome for NVP or HG in pregnancy as a dichotomous variable (RRp 1.73, 95 % CI 1.43 to 2.08). Studies with continuous outcome measures for nausea, vomiting and the combined outcome did not show any evidence for relieving symptoms of NVP and HG (SMD -0.12, 95 % CI -0.35 to 0.12). Conclusions: Although there is some evidence for an effect of acustimulation on nausea and vomiting or hyperemesis in pregnancy, results are not conclusive. Future clinical trials with a rigorous design and large sample sizes should be conducted to evaluate the efficacy and safety of these interventions for NVP and HG.

Homeopathy is controversial and hotly debated. The conclusions of systematic reviews of randomised controlled trials of homeopathy vary from 'comparable to conventional medicine' to 'no evidence of effects beyond placebo'. It is claimed that homeopathy conflicts with scientific laws and that homoeopaths reject the naturalistic outlook, but no evidence has been cited. We are homeopathic physicians and researchers who do not reject the scientific outlook; we believe that examination of the prior beliefs underlying this enduring stand-off can advance the debate. We show that interpretations of the same set of evidence--for homeopathy and for conventional medicine--can diverge. Prior disbelief in homeopathy is rooted in the perceived implausibility of any conceivable mechanism of action. Using the 'crossword analogy', we demonstrate that plausibility bias impedes assessment of the clinical evidence. Sweeping statements about the scientific impossibility of homeopathy are themselves unscientific: scientific statements must be precise and testable. There is growing evidence that homeopathic preparations can exert biological effects; due consideration of such research would reduce the influence of prior beliefs on the assessment of systematic review evidence.

Background: Quality of life (QoL) is an important outcome measure in the treatment of seasonal allergic rhinitis (SAR), a condition for which homeopathy is frequently used. Objective: The assessment of the effect of homeopathic medical prescriptions with the Rhino-conjunctivitis Quality of Life Questionnaire (RQLQ) in the treatment of SAR. Methods: A prospective, open, non-comparative study was conducted in Belgium. Patients aged between 14 and 68 years with SAR were treated by one of seven homeopathic physicians. Patients completed the RQLQ at baseline and again after three and four weeks of homeopathic treatment. Results: Seventy-four patients were screened, of whom 46 met the study eligibility criteria (average age 36 years, 70% female). The mean RQLQ score at baseline was 3.40 (±.98). After three and four weeks of homeopathic treatment it had fallen to 1.97 (±1.32) (P = 0.0001), and 1.6 (±1.28) (P = 0.0001), respectively. Conclusions: After homeopathic treatment, patients reported an alleviation of their symptoms of allergic rhinitis as reported in the RQLQ. A formal Randomized Clinical Trial (RCT) is indicated. Homeopathy (2009) 98, 11–16.

OBJECTIVE: The aim of this study is to look at the influence of metformin intake and duration, on urinary bladder cancer (UBC) risk, with sulfonylurea (SU) only users as control using a new-user design (inception cohort). METHODS: We conducted a retrospective cohort study using data from the UK Clinical Practice Research Datalink (CPRD) including all patients with at least one prescription of oral anti-diabetic drugs (ADD) and/or insulin. The risk of UBC in different groups of ADD users (metformin alone (1), metformin in combination (2) with other ADD medication (glinides, glitazones, DPP-4-inhibitors, SUs, insulin or more than one combination), all metformin users (1 + 2) was compared with SU only users using Cox proportional hazards models. The estimates were adjusted for age, gender, smoking status, BMI and diabetes duration. RESULTS: The inception cohort included 165,398 participants of which 132,960 metformin users and 32,438 SU only users. During a mean follow-up time of more than five years 693 patients developed UBC, 124 of the control group and 461 of the all metformin users. There was no association between metformin use and UBC risk (HR = 1.12 (95% CI 0.90-1.40)) compared to SU only users, even after adjustment for diabetes duration (HR = 1.13 (95% CI 0.90-1.40)). We found a pattern of decreasing risk of UBC with increasing duration of metformin intake, which was statistically not significant. CONCLUSION: Metformin has no influence on the risk of UBC compared to SU in type 2 diabetes patients using a new-user design. This article is protected by copyright. All rights reserved.

The aim of this study was to look at the influence of metformin intake and duration, on urinary bladder cancer (UBC) risk, with sulfonylurea (SU) only users as control using a new user design (inception cohort).We conducted a retrospective cohort study using data from the UK Clinical Practice Research Datalink (CPRD) including all patients with at least one prescription of oral anti-diabetic drugs (ADD) and/or insulin. The risk of UBC in different groups of ADD users (metformin alone (one), metformin in combination (two) with other ADD medication (glinides, glitazones, DPP-4-inhibitors, SUs, insulin or more than one combination), all metformin users (1 + 2) was compared with SU only users using Cox proportional hazards models. The estimates were adjusted for age, gender, smoking status, BMI and diabetes duration.The inception cohort included 165,398 participants of whom 132,960 were metformin users and 32,438 were SU only users. During a mean follow-up time of more than 5 years 693 patients developed UBC, 124 of the control group and 461 of the all metformin users. There was no association between metformin use and UBC risk (HR = 1.12, 95% CI 0.90, 1.40) compared with SU only users, even after adjustment for diabetes duration (HR = 1.13, 95% CI 0.90, 1.40). We found a pattern of decreasing risk of UBC with increasing duration of metformin intake, which was statistically not significant.Metformin has no influence on the risk of UBC compared with SU in type 2 diabetes patients using a new user design.

A meta-analysis of epidemiological studies reported no increased risk for cancer in users of thiazolidinediones; however, subanalyses showed a small 1.1- to 1.2-fold increased risk for bladder cancer with thiazolidinedione use. This analysis was probably distorted by “duplicate publication bias.”

Background In Belgium, bladder cancer is the fifth most common cancer in males (5.2%) and the sixth most frequent cause of death from cancer in males (3.8%). Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of bladder cancer. This suggests that selenium may also be suitable for chemoprevention of recurrence. Method The SELEBLAT study opened in September 2009 and is still recruiting all patients with non-invasive transitional cell carcinoma of the bladder on TURB operation in 15 Belgian hospitals. Recruitment progress can be monitored live at http://www.seleblat.org. Patients are randomly assigned to selenium yeast (200 μg/day) supplementation for 3 years or matching placebo, in addition to standard care. The objective is to determine the effect of selenium on the recurrence of bladder cancer. Randomization is stratified by treatment centre. A computerized algorithm randomly assigns the patients to a treatment arm. All study personnel and participants are blinded to treatment assignment for the duration of the study. Design The SELEnium and BLAdder cancer Trial (SELEBLAT) is a phase III randomized, placebo-controlled, academic, double-blind superior trial. Discussion This is the first report on a selenium randomized trial in bladder cancer patients. Trial registration ClinicalTrials.gov identifier: NCT00729287

Background In Belgium, bladder cancer is the fifth most common cancer in males (5.2%) and the sixth most frequent cause of death from cancer in males (3.8 %). The per-patient lifetime cost is the highest of all other types of cancer. Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of bladder cancer. We therefore hypothesized that selenium may also be suitable for chemoprevention of recurrence.