UNLABELLED: The aim of this study was to identify parameters influencing DNA extraction and PCR amplification efficiencies in an attempt to standardize Mucorales qPCR. The Fungal PCR Initiative Mucorales Laboratory Working Group distributed two panels of simulated samples to 26 laboratories: Panel A (six sera spiked with Mucorales DNA and one negative control serum) and Panel B (six Mucorales DNA extracts). Panel A underwent DNA extraction in each laboratory according to the local procedure and were sent to a central laboratory for testing using three different qPCR techniques: one in-house qPCR assay and two commercial assays (MucorGenius and Fungiplex). Panel B DNA extracts were PCR amplified in each laboratory using local procedures: nine in-house qPCR assays and two commercial kits (MucorGenius and MycoGENIE). All data were compiled and anonymously analyzed at the central laboratory. For Panel A, a total of six different automated platforms and five manual extraction methods were used. Positive rates were 64%, 70%, and 89%, for the MucorGenius, Fungiplex, and the in-house qPCR assay, respectively. Using a large volume of serum for DNA extraction provided the highest analytical sensitivity (82.5% for 1 mL compared with 62.7% for smaller volumes, P < 0.01). For Panel B, five in-house qPCR assays and two commercial kits had >78% positivity. Using larger PCR input volumes (≥7 μL) was associated with the highest sensitivity at 95.5% compared to 58.3% when lower input volumes were used (P < 0.01). Using larger sample volumes for nucleic acid extraction and DNA template volumes for PCR amplification significantly improves the performance of Mucorales qPCR when testing serum. IMPORTANCE: Mucormycosis is a life-threatening mold infection affecting immunosuppressed patients but also other patients with diabetes or trauma. Better survival is linked to shorter delays in diagnosis and treatment initiation. Detection of Mucorales-free DNA in serum or plasma using quantitative PCR allows a prompt diagnosis and earlier treatment. Several techniques and protocols of quantitative Mucorales PCR are used in Europe, and improving performance remains a common objective of laboratories participating in the fungal PCR Initiative Working Group. This study, which combined results from 26 laboratories in Europe, showed that the main parameters underpinning sensitivity are the preanalytical variables (volume of serum used for DNA extraction and DNA template volume), irrespective of the extraction platforms and qPCR assay/platform.
- MeSH
- Molecular Diagnostic Techniques standards methods MeSH
- DNA, Fungal * blood genetics MeSH
- Real-Time Polymerase Chain Reaction * standards methods MeSH
- Humans MeSH
- Mucorales * genetics isolation & purification MeSH
- Mucormycosis * diagnosis microbiology blood MeSH
- Sensitivity and Specificity * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Evaluation Study MeSH
Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.
- MeSH
- Quinolines * administration & dosage therapeutic use MeSH
- Adult MeSH
- Phenylurea Compounds * administration & dosage therapeutic use MeSH
- Antibodies, Monoclonal, Humanized * administration & dosage therapeutic use MeSH
- Carcinoma, Renal Cell * drug therapy pathology mortality secondary MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Kidney Neoplasms * drug therapy pathology mortality MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Sunitinib * administration & dosage therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype-phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (p < 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (p < 0.0001). Nine out of 33 patients died (p = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.
- MeSH
- Child MeSH
- Phenotype * MeSH
- Phosphotransferases (Phosphomutases) * genetics deficiency MeSH
- Genetic Association Studies MeSH
- Cardiomyopathies genetics MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Mutation MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Severity of Illness Index MeSH
- Congenital Disorders of Glycosylation * genetics MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Europe MeSH
CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.
- MeSH
- Chemotherapy, Adjuvant methods MeSH
- Immune Checkpoint Inhibitors * therapeutic use pharmacology MeSH
- Neoplasm Invasiveness MeSH
- Carcinoma, Transitional Cell drug therapy pathology MeSH
- Humans MeSH
- Urinary Bladder Neoplasms drug therapy pathology MeSH
- Network Meta-Analysis as Topic MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
BACKGROUND: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.
- MeSH
- Adenocarcinoma * pathology drug therapy therapy MeSH
- Chemotherapy, Adjuvant methods MeSH
- Adult MeSH
- Gastrectomy MeSH
- Esophagogastric Junction * pathology MeSH
- Immunotherapy methods MeSH
- Ipilimumab administration & dosage therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local * pathology prevention & control drug therapy epidemiology MeSH
- Esophageal Neoplasms * pathology drug therapy therapy MeSH
- Stomach Neoplasms * pathology drug therapy therapy surgery MeSH
- Neoadjuvant Therapy * methods adverse effects MeSH
- Nivolumab administration & dosage therapeutic use MeSH
- Disease-Free Survival MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Autologous hematopoietic cell transplants (auto-HCTs) remain the standard of care for transplant-eligible MM patients. The general practice has been to undergo upfront apheresis following induction to collect sufficient number of CD34+ cells to facilitate two auto-HCTs. However, 5-30% of MM patients do not initially mobilise a sufficient number of hematopoietic stem cells and are classified as poor mobilizers (PM). We compared the baseline characteristics and outcomes of 61 PMs and 816 non-PM patients who underwent a second auto-HCT and who were enrolled in the non-interventional CALM study (NCT01362972). Only patients who collected CD34+ prior to auto-HCT1 were included. Auto-HCT2 comprised both tandem and salvage transplants. PMs were re-mobilized with plerixafor (n = 24, 39.3%) or non-plerixafor-based regimens (n = 37, 60.7%). There were no significant differences in engraftment, progression-free survival (PFS) or overall survival (OS) after the second auto-HCT between PM and non-PM patients. There was a trend to shorter PFS in PM patients undergoing salvage auto-HCT (median 9.6 vs. 12.9 months; p = 0.08) but no significant difference in OS. The median OS was 41.1 months for PM and 41.2 months for non-PM patients (p = 0.86). These data suggest that salvage mobilization is effective and does not affect overall outcomes after a second auto-HCT.
- MeSH
- Transplantation, Autologous * methods MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma * therapy mortality MeSH
- Hematopoietic Stem Cell Mobilization * methods MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Hematopoietic Stem Cell Transplantation * methods MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
INTRODUCTION: Current trends in the addiction field reflect a significant emphasis on the workforce development and education. There are already some data about university-based addiction studies programs, but not much from Australasia. METHODS: The aim is to provide an overview and describe the academic programs for addiction professionals in Australia and Aotearoa NZ. The research was conducted in 2017 and updated in 2023. Firstly, university websites were searched using pre-defined keywords, followed by a content analysis of the identified programs. The data were analysed and interpreted by using descriptive statistics. RESULTS: We found 21 universities in Australia (13) and Aotearoa NZ (8) where 46 single programs are provided. There are three bachelor programs, nine masters, and the majority of degrees include (post)graduate certificates and diplomas. No doctorate programs are identified. The taught courses provide comprehensive coverage of the addiction field topics. Twelve programs state clearly that there is clinical practice/internship included. Application to most programs requires completion of a relevant degree and in some cases possible clinical experience. DISCUSSION AND CONCLUSIONS: In comparison to educational options in other regions, we observe a trend towards preparing university graduates for the workforce, thereby expanding the range of programs at lower levels. Most programs possibly represent clinically oriented education primarily specialising in addictions, and graduate programs in addictions for professionals with other disciplinary bases. Great emphasis is given to the quality standards of education, and also to relationship between education and labour market. Findings help opening opportunities to collaborate globally.
- MeSH
- Humans MeSH
- Behavior, Addictive epidemiology MeSH
- Substance-Related Disorders * epidemiology MeSH
- Universities MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Geographicals
- Australia MeSH
- New Zealand MeSH
OBJECTIVES: This study aims to explore the lasting effects of stress experienced by pregnant women during World War II (WWII) on body and head measurements of their adult daughters. METHODS: The research sample consists of 336 female university students born in Poland between 1925 and 1951. The data include body measurements and socioeconomic information (parental occupation and number of siblings) acquired from questionnaires collected between the 1950s and 1970s. Student's t-test, Mann-Whitney test and Analysis of Variance were used to analyze differences in body measurements between groups of women born before and during the war, as well as the possible influences of socioeconomic variables. RESULTS: The mean measurements of body height, symphysion height, and waist circumference were lower in women conceived and born during the war compared to those born in the pre-war period. In contrast, the mean measurements of biacromial (shoulder) width, trunk length, and three head dimensions were higher in women conceived and born during the war. Additionally, the number of siblings appeared to be a significant factor that may have influenced the body measurements of women in both groups. For instance, a higher number of living siblings, particularly sisters, was associated with reduced body dimensions, such as body height and waist circumference, while a greater number of deceased siblings was linked to an increase in certain body dimensions. CONCLUSION: The results suggest that war-related prenatal conditions may have influenced the postnatal growth and development of women conceived and born during the war. Notably, the direction of these changes varied, which indicates that the growth response to the war-related conditions was a complex adaptation, reflecting both positive and negative changes in different body parts, rather than a uniform pattern of growth suppression.
- MeSH
- World War II * MeSH
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Stress, Psychological MeSH
- Socioeconomic Factors MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Poland MeSH
OBJECTIVES: The development of External Quality Assessment Schemes (EQAS) for clinical flow cytometry (FCM) is challenging in the context of rare (immunological) diseases. Here, we introduce a novel EQAS monitoring the primary immunodeficiency Orientation Tube (PIDOT), developed by EuroFlow, in both a 'wet' and 'dry' format. This EQAS provides feedback on the quality of individual laboratories (i.e., accuracy, reproducibility and result interpretation), while eliminating the need for sample distribution. METHODS: In the wet format, marker staining intensities (MedFIs) within landmark cell populations in PIDOT analysis performed on locally collected healthy control (HC) samples, were compared to EQAS targets. In the dry format, participants analyzed centrally distributed PIDOT flow cytometry data (n=10). RESULTS: We report the results of six EQAS rounds across 20 laboratories in 11 countries. The wet format (212 HC samples) demonstrated consistent technical performance among laboratories (median %rCV on MedFIs=34.5 %; average failure rate 17.3 %) and showed improvement upon repeated participation. The dry format demonstrated effective proficiency of participants in cell count enumeration (range %rCVs 3.1-7.1 % for the major lymphoid subsets), and in identifying lymphoid abnormalities (79.3 % alignment with reference). CONCLUSIONS: The PIDOT-EQAS allows laboratories, adhering to the standardized EuroFlow approach, to monitor interlaboratory variations without the need for sample distribution, and provides them educational support to recognize rare clinically relevant immunophenotypic patterns of primary immunodeficiencies (PID). This EQAS contributes to quality improvement of PID diagnostics and can serve as an example for future flow cytometry EQAS in the context of rare diseases.
BACKGROUND AND OBJECTIVE: Biparametric magnetic resonance imaging (bpMRI), excluding dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), is a potential replacement for multiparametric MRI (mpMRI) in diagnosing clinically significant prostate cancer (csPCa). An extensive international multireader multicase observer study was conducted to assess the noninferiority of bpMRI to mpMRI in csPCa diagnosis. METHODS: An observer study was conducted with 400 mpMRI examinations from four European centers, excluding examinations with prior prostate treatment or csPCa (Gleason grade [GG] ≥2) findings. Readers assessed bpMRI and mpMRI sequentially, assigning lesion-specific Prostate Imaging Reporting and Data System (PI-RADS) scores (3-5) and a patient-level suspicion score (0-100). The noninferiority of patient-level bpMRI versus mpMRI csPCa diagnosis was evaluated using the area under the receiver operating curve (AUROC) alongside the sensitivity and specificity at PI-RADS ≥3 with a 5% margin. The secondary outcomes included insignificant prostate cancer (GG1) diagnosis, diagnostic evaluations at alternative risk thresholds, decision curve analyses (DCAs), and subgroup analyses considering reader expertise. Histopathology and ≥3 yr of follow-up were used for the reference standard. KEY FINDINGS AND LIMITATIONS: Sixty-two readers (45 centers and 20 countries) participated. The prevalence of csPCa was 33% (133/400); bpMRI and mpMRI showed similar AUROC values of 0.853 (95% confidence interval [CI], 0.819-0.887) and 0.859 (95% CI, 0.826-0.893), respectively, with a noninferior difference of -0.6% (95% CI, -1.2% to 0.1%, p < 0.001). At PI-RADS ≥3, bpMRI and mpMRI had sensitivities of 88.6% (95% CI, 84.8-92.3%) and 89.4% (95% CI, 85.8-93.1%), respectively, with a noninferior difference of -0.9% (95% CI, -1.7% to 0.0%, p < 0.001), and specificities of 58.6% (95% CI, 52.3-63.1%) and 57.7% (95% CI, 52.3-63.1%), respectively, with a noninferior difference of 0.9% (95% CI, 0.0-1.8%, p < 0.001). At alternative risk thresholds, mpMRI increased sensitivity at the expense of reduced specificity. DCA demonstrated the highest net benefit for an mpMRI pathway in cancer-averse scenarios, whereas a bpMRI pathway showed greater benefit for biopsy-averse scenarios. A subgroup analysis indicated limited additional benefit of DCE MRI for nonexperts. Limitations included that biopsies were conducted based on mpMRI imaging, and reading was performed in a sequential order. CONCLUSIONS AND CLINICAL IMPLICATIONS: It has been found that bpMRI is noninferior to mpMRI in csPCa diagnosis at AUROC, along with the sensitivity and specificity at PI-RADS ≥3, showing its value in individuals without prior csPCa findings and prostate treatment. Additional randomized prospective studies are required to investigate the generalizability of outcomes.
- MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Multiparametric Magnetic Resonance Imaging * MeSH
- Prostatic Neoplasms * diagnostic imaging pathology MeSH
- Observer Variation MeSH
- Aged MeSH
- Neoplasm Grading MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Comparative Study MeSH
- Geographicals
- Europe MeSH
