Incidence, etiology, risk factors, and outcomes of pre-engraftment bloodstream infections after first and second allogeneic hematopoietic cell transplantation.

INTRODUCTION: With an increasing number of allogeneic hematopoietic cell transplantations (allo-HCT) bloodstream infections (BSI) are still among the most common and serious complications. This study aimed to analyze the incidence, etiology, risk factors, and outcomes of pre-engraftment BSI after the first and the second allo-HCT. MATERIALS AND METHODS: This is a retrospective study of 284 patients who underwent the first allo-HCT and 37 patients after the second allo-HCT at the National Research Center for Hematology in Moscow, Russia, from January 2018 till September 2021. RESULTS: Cumulative incidence of pre-engraftment BSI was 29.9% after the first allo-HCT and 35.1% after the second (p = .805). The median time to the first BSI was 9 days (range 0-61 days) after the first and 16 days (range 1-28 days) after the second allo-HCT (p = .014). A total of 113 pathogens were isolated during 94 BSI episodes after the first allo-HCT (gram-negative bacteria 52.2%; gram-positive bacteria 47.7%). Fourteen pathogens were isolated during 14 BSI episodes after the second allo-HCT (gram-negative bacteria 50.0%; gram-positive bacteria 50.0%). The only significant difference was found in the rate of carbapenem-resistant gram-negative bacteria, which was higher after the second allo-HCT compared to the first (57.1% vs. 13.6%; p = .048). Mismatched unrelated donor (hazards ratio [HR] 3.01; 95% confidence interval [CI]: 1.62-5.60; p < .0001) and haploidentical donor transplantations (HR 1.84; 95% CI: 1.02-3.33; p = .042) were the only independent risk factors associated with the higher risk of pre-engraftment BSI. Overall 30-day survival after all BSI episodes was 94.4%. Survival was lower after BSI during the second allo-HCT compared to the first (71.4% vs. 97.9%; p < .0001), particularly after BSI was caused by carbapenem-resistant gram-negative bacteria (25.0% vs. 100.0%; p = .0023). The non-relapse mortality rate at day +60 was 4.0%, and the risk was highly associated with primary graft failure (HR 9.62; 95% CI: 1.33-71.43), second allo-HCT (HR 6.80; 95% CI: 1.36-34.48), and pre-engraftment BSI caused by carbapenem-resistant gram-negative bacteria (HR 32.11; 95% CI: 4.91-210.15). CONCLUSIONS: Pre-engraftment BSI is still a common complication after allo-HCT, particularly after mismatched unrelated and haploidentical donor transplantations. BSI incidence was slightly higher after the second allo-HCT with a significantly higher rate of carbapenem-resistant BSI. Although pre-engraftment BSI would generally follow a benign clinical course, survival was dramatically lower during the second allo-HCT, especially after carbapenem-resistant BSI.

Health Policy for Prostate Cancer Early Detection in the European Union and the Impact of Opportunistic Screening: PRAISE-U Consortium.

With the new policy recommendation in 2022 to explore the possibilities of screening for prostate cancer by the European Commission, the landscape for prostate cancer early detection is evolving. In line with this recommendation, the PRAISE-U project aims to evaluate the early detection and diagnosis of prostate cancer through customised and risk-based screening programmes, with the goal to align protocols across European Union member states. This systematic review is part of the PRAISE-U project, with the goal to review the policy, medical guideline recommendations, and the current level of opportunistic screening presented in the scientific literature on prostate cancer early detection from 2016 to 2023 in European Union member states. An extensive literature search was performed on 1 June 2023 in a large number of databases, including Embase.com, Medline (Ovid), Web of Science Core Collection, Google Scholar, and Policy Commons. We identified 318 articles (qualitative, quantitative, and reviews), of which 41 were included in the full-text screening. Seventeen articles were ultimately identified as eligible for inclusion. The included articles revealed significant variations towards PSA-based early detection policies for prostate cancer in nine European countries. Despite official recommendations, opportunistic screening was prevalent across all nine countries regardless of recommendations for or against PSA-based early detection. This systematic review suggests that the current early detection policies are not fit for purpose. High levels of opportunistic screening and overdiagnosis persist, prompting policy recommendations for standardised guidelines, informed decision making, and increased awareness to improve efficiency and effectiveness in early detection.

Understanding the Barriers to Prostate Cancer Population-Based Early Detection Programs: The PRAISE-U BEST Survey.

In 2022, the European Commission updated its recommendation on cancer screening, inviting the Member States (MSs) to explore the feasibility of stepwise implementation of population-based screening for prostate cancer (PCa). In line with this recommendation, the PRAISE-U (Prostate Cancer Awareness and Initiative for Screening in the European Union (EU)) project was initiated. As part of the PRAISE-U, we aim to understand the current practice towards early detection in the EU MSs, the barriers to implementing or planning population-based screening programmes, and potential solutions to overcome these barriers. METHODS: We adapted the Barriers to Effective Screening Tool (BEST) survey to the PCa context. However, it has not been validated in this context. We translated it into all spoken languages in the EU27 and disseminated it to different stakeholders across the EU using a snowballing approach. RESULTS: We received 410 responses from 55 countries, of which 301 (73%) were from the 27 EU MSs. The most represented stakeholder group was urologists (218 (54%)), followed by general practitioners (GPs) (83 (21%)), patient representatives (35 (9%)), policy stakeholders (27 (7%)), researchers (23 (6%)), oncologists, pathologists, radiologists, nurses, and others (16 (4%)) and one industry representative. Among all respondents, 286 (69%) reported the absence of a population-based screening programme, mainly attributed to resource limitations and a lack of political and medical society support. Out of these 286 respondents, 196 (69%) indicated that opportunistic screening is being applied in their country, and 199 (70%) expressed their support for population-based screening programmes (which was highest amongst patient representatives and urologists and lowest amongst GPs and policy stakeholders). The highest scored barriers were lack of political support, insufficient operational resources, and inadequate participation. Suggested solutions to overcome these included awareness campaigns, consensus meetings, political lobbying and European guidelines (to overcome political support barriers), compatible IT systems (to overcome operational barriers), and easy access (to overcome participation barriers). CONCLUSIONS: Participants have noted the presence of opportunistic screening, and particularly urologists and patient representatives expressed their support for the establishment of a population-based PCa screening programme. Nevertheless, successful implementation of population-based screening programmes is complex; it requires political and medical society support, operational resources and capacity, awareness campaigns, as well as the development of protocols, guidelines, and legal frameworks.

Systematic Review on the Cost Effectiveness of Prostate Cancer Screening in Europe.

BACKGROUND AND OBJECTIVE: In Europe, prostate cancer (PCa) is the most common cancer in men. Screening may therefore be crucial to lower health care costs, morbidity, and mortality. This systematic review aimed to provide a contemporary overview of the costs and benefits of PCa screening programmes. METHODS: A peer-reviewed literature search was conducted, using the PICO method. A detailed search strategy was developed in four databases based on the following key search terms: "PCa", "screening", and "cost effectiveness". Any type of economic evaluation was included. The search strategy was restricted to European countries, but no restrictions were set on the year of publication. KEY FINDINGS AND LIMITATIONS: A total of 7484 studies were identified initially. Of these, 19 studies described the cost effectiveness of PCa screening in Europe. Among the studies using an initially healthy study population, most focussed on risk- and/or age- and/or magnetic resonance imaging (MRI)-based screening in addition to prostate-specific antigen (PSA) testing and compared this with no screening. Incremental cost ratios (ICERs) varied from €5872 per quality-adjusted life year (QALY) to €372 948/QALY, with a median of €56 487/QALY. Risk-based screening followed by MRI testing seemed to be a more cost-effective strategy than no screening. CONCLUSIONS AND CLINICAL IMPLICATIONS: This systematic review indicates that screening programmes incorporating a risk-based approach and MRI have the potential to be cost effective. PATIENT SUMMARY: In this review, we looked at the cost effectiveness of prostate cancer screening in Europe. We found that a risk-based approach and incorporation of magnetic resonance imaging has the potential to be cost effective. However, there remains a knowledge gap regarding cost effectiveness of prostate cancer screening. Therefore, determinants of cost effectiveness require further investigation.

Prostate Cancer Early Detection in the European Union and UK.

BACKGROUND AND OBJECTIVE: While prostate cancer (PCa) incidence and mortality rates continue to rise, early detection of PCa remains highly controversial, and the research landscape is rapidly evolving. Existing systematic reviews (SRs) and meta-analyses (MAs) provide valuable insights, but often focus on single aspects of early detection, hindering a comprehensive understanding of the topic. We aim to fill this gap by providing a comprehensive SR of contemporary SRs covering different aspects of early detection of PCa in the European Union (EU) and the UK. METHODS: On June 1, 2023, we searched four databases (Medline ALL via Ovid, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) and Google Scholar. To avoid repetition of previous studies, only SRs (qualitative, quantitative, and/or MAs) were considered eligible. In the data, common themes were identified to present the evidence systematically. KEY FINDINGS AND LIMITATIONS: We identified 1358 citations, resulting in 26 SRs eligible for inclusion. Six themes were identified: (1) invitation: men at general risk should be invited at >50 yr of age, and testing should be discontinued at >70 yr or with <10 yr of life expectancy; (2) decision-making: most health authorities discourage population-based screening and instead recommend a shared decision-making (SDM) approach, but implementation of SDM in clinical practice varies widely; decision aids help men make more informed and value-consistent screening decisions and decrease men's intention to attempt screening, but these do not affect screening uptake; (3) acceptance: facilitators for men considering screening include social prompting by partners and clinician recommendations, while barriers include a lack of knowledge, low-risk perception, and masculinity attributes; (4) screening test and algorithm: prostate-specific antigen-based screening reduces PCa-specific mortality and metastatic disease in men aged 55-69 yr at randomisation if screened at least twice; (5) harms and benefits: these benefits come at the cost of unnecessary biopsies, overdiagnosis, and subsequent overtreatment; and (6) future of screening: risk-adapted screening including (prebiopsy) risk calculators, magnetic resonance imaging, and blood- and urine-based biomarkers could reduce these harms. To enable a comprehensive overview, we focused on SRs. These do not include the most recent prospective studies, which were therefore incorporated in the discussion. CONCLUSIONS AND CLINICAL IMPLICATIONS: By identifying consistent and conflicting evidence, this review highlights the evidence-based foundations that can be built upon, as well as areas requiring further research and improvement to reduce the burden of PCa in the EU and UK. PATIENT SUMMARY: This review of 26 reviews covers various aspects of prostate cancer screening such as invitation, decision-making, screening tests, harms, and benefits. This review provides insights into existing evidence, highlighting the areas of consensus and discrepancies, to guide future research and improve prostate cancer screening strategies in Europe.

Navigating through the Controversies and Emerging Paradigms in Early Detection of Prostate Cancer: Bridging the Gap from Classic RCTs to Modern Population-Based Pilot Programs.

Over the last three decades, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening have steered the conversation around the early detection of prostate cancer. These two randomized trials assessed the effect of screening on prostate cancer disease-specific mortality. Elevated PSA levels were followed by a systematic sextant prostate biopsy. Standard repeat testing intervals were applied. After controversies from 2009 to 2016 due to contradicting results of the two trials, the results aligned in 2016 and showed that early PSA detection reduces prostate cancer-specific mortality. However, overdiagnosis rates of up to 50% were reported, and this sparked an intense debate on harms and benefits for almost 20 years. The balance between harms and benefits is highly debated and has initiated further research to investigate new ways of early detection. In the meantime, the knowledge and tools for the diagnostic algorithm improved. This is a continuously ongoing effort which focuses on individual risk-based screening algorithms that preserve the benefits of the purely PSA-based screening algorithms, while reducing the side effects. An important push towards investigating new techniques for early detection came from the European Commission on the 20th of September 2022. The European Commission published its updated recommendation to investigate prostate, lung, and gastric cancer early detection programs. This opened a new window of opportunity to move away from the trial setting to population-based early detection settings. With this review, we aim to review 30 years of historical evidence of prostate cancer screening, which led to the initiation of the 'The Prostate Cancer Awareness and Initiative for Screening in the European Union' (PRAISE-U) project, which aims to encourage the early detection and diagnosis of PCa through customized and risk-based screening programs.

Bowel wall thickness is a strong predictor of steroid-refractory acute graft-versus-host disease with gut involvement after allo-HSCT.

OBJECTIVE: Acute graft-versus-host-disease (aGVHD) develops in 10-80% of allo-HSCT patients. More than half of all aGVHD cases are refractory to first-line therapy with steroids. We hypothesized that bowel wall thickness at the time of aGVHD diagnosis could be an early sign of steroid-refractory aGVHD with gut involvement. METHOD: Our prospective study included 85 patients with hematological malignancies who had undergone allo-HSCT. We used an inexpensive, widespread and simple method of transabdominal ultrasonography to examine bowel wall thickness in patients suspected to have gut aGVHD. RESULTS: Descending colon wall thickness was significantly greater in patients with gut aGVHD later found to be steroid-refractory than in patients with steroid-sensitive gut aGVHD, with AUC-0.73 (95% CI 0.58-0.87, p = 0.013). We showed that bowel wall thickness could predict the steroid-refractoriness of aGVHD. CONCLUSION: Transabdominal ultrasonography could be used as a marker of steroid-refractory aGVHD with gut involvement after allo-HSCT.

Level of Granzyme B-positive T-regulatory cells is a strong predictor biomarker of acute Graft-versus-host disease after day +30 after allo-HSCT.

Acute Graft-versus-host-disease (aGVHD), the major complication and one of the main causes of poor outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays there are no widely accepted cell, plasma or another biomarker that can be used for aGVHD prediction. We hypothesized that a level of Granzyme B-positive T regulatory (GZMB-positive Treg) cells on day+30 after allo-HSCT could be the measure of immune response suppression and could predict aGVHD development after day +30. We applied a widespread and easy-to-perform method of multicolor flow cytometry to measure level of GZMB-positive Treg cells. Levels of GZMB-positive Tregs on day +30 after allo-HSCT were significantly higher in those patients who never developed aGVHD in comparison with the other group of patient with aGVHD after day +30 (p=0.0229). We conclude that the level of GZMB-positive Treg cells is a strong predictor of acute Graft-versus-host disease after day +30 after allo-HSCT.