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
Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6 . The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.
- MeSH
- Adult MeSH
- Epigenesis, Genetic MeSH
- Epigenomics MeSH
- Gene Fusion * MeSH
- Genetic Predisposition to Disease MeSH
- Genomics MeSH
- Immunohistochemistry MeSH
- Polymorphism, Single Nucleotide MeSH
- Juxtaglomerular Apparatus pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Methylation MeSH
- Biomarkers, Tumor * genetics MeSH
- Kidney Neoplasms * genetics pathology chemistry MeSH
- Whole Genome Sequencing MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
Crude oil contamination has been shown to impair reproduction in aquatic animals through carcinogenic and genotoxic properties. Here, we assessed the endocrine-disrupting function of crude oil on male reproductive system based on testicular histology, sex steroid hormones, and fertility endpoints in adult male goldfish (Carassius auratus), which were exposed to 0.02- to 2-mg/L crude oil for 21 days (Experiment #1) or to 5- to 250-mg/L crude oil for 9 days (Experiment #2). The crude oil contained 0.22-mg/L nickel (Ni), 1.10-mg/L vanadium (V), and 12.87-mg/L polycyclic aromatic hydrocarbons (PAHs). Twenty-four hours after adding crude oil, the sum of PAHs ranged from 0.30 to 2.28 μg/L in the aquaria containing 0.02- and 250-mg/L crude oil, respectively. Water analyses for heavy metals in Experiment #2 showed high concentrations (mg/L) of Ni (0.07-0-09) and V (0.10-0.21). For both experiments, exposure to crude oil did not impact gonadosomatic index; however, testes showed histopathological defects including hyperplasia or hypertrophy of Sertoli cells, depletion of the Leydig cells, necrosis of germ cells, and fibrosis of lobular wall. In Experiment #1, sperm production and motility, testosterone (T), and 17β-estradiol (E2) were not significantly different among treatments. In Experiment #2, the number of spermiating males decreased by ~50% following exposure to 250-mg/L crude oil. Sperm production, motility kinematics, T, and the T/E2 ratio significantly decreased in males exposed to ≥ 50-mg/L crude oil; however, E2 remained unchanged. Results show crude oil-induced imbalance of sex steroid hormones disrupts spermatogenesis resulting in diminished sperm production and motility.
- MeSH
- Water Pollutants, Chemical * toxicity MeSH
- Endocrine Disruptors * toxicity MeSH
- Goldfish * physiology MeSH
- Sperm Motility * drug effects MeSH
- Gonadal Steroid Hormones * metabolism blood MeSH
- Petroleum * toxicity MeSH
- Reproduction drug effects MeSH
- Spermatozoa * drug effects pathology MeSH
- Testis * drug effects pathology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
AIMS: Ossifying fibromyxoid tumour is a rare mesenchymal neoplasm predominantly affecting adults characterised by a multinodular growth pattern and the presence of a fibrous pseudocapsule with areas of ossification. Prompted by the recognition of a non-ossifying ossifying fibromyxoid tumour with lipomatous differentiation which caused diagnostic difficulty, we sought to further explore cases of ossifying fibromyxoid tumour with non-osseous heterologous elements. METHODS AND RESULTS: A search of our institutional and consultation archives revealed three additional cases that demonstrated lipomatous components and two cases with cartilaginous differentiation. RNA-sequencing revealed fusions involving PHF1 (n = 4) or EPC1 (n = 1) in all (five of five) cases tested, including EPC1::PHC1 and JAZF1::PHF1 fusions, which have not been reported before in ossifying fibromyxoid tumour. CONCLUSION: These six cases expand the histomorphological spectrum of ossifying fibromyxoid tumour, introducing lipomatous differentiation as a hitherto undocumented feature. Awareness of these rare variants will ensure appropriate diagnosis and clinical management.
- MeSH
- Cell Differentiation MeSH
- Cartilage pathology MeSH
- Diagnosis, Differential MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Lipoma * pathology diagnosis genetics MeSH
- Soft Tissue Neoplasms * pathology diagnosis genetics MeSH
- Fibroma, Ossifying * pathology diagnosis genetics MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
OBJECTIVES: Despite increasing interest, prospective data on the use of degradable starch microsphere-transarterial chemoembolization (DSM-TACE) in the management of patients with unresectable HCC are still scarce. The objective of the HepaStar study was to collect prospective safety and effectiveness data in a prospective multicenter observational study. MATERIALS AND METHODS: Between January 2017 and December 2022, consecutive participants with unresectable or recurrent HCC treated with DSM-TACE as standard of care at 6 participating centers in Europe were enrolled. Tumor response was evaluated according to the mRECIST criteria. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were assessed by using Kaplan-Meier analysis and Common Terminology Criteria for Adverse Events, version 5. Liver function deterioration was assessed by monitoring changes in liver blood tests during the follow-up. RESULTS: Seventy-nine participants (median age, 69 years (IQR, 51-87 years); 67 men (85%)) were enrolled and treated. The median follow-up time was 18 months (IQR 9.5-38.0 months). The estimated median OS and PFS for the entire cohort was 32 months (CI, 95% 21-NaN) and 9 months (CI, 95% 7-NaN), respectively. Eleven (13.9%) participants experienced at least one grade 3 or 4 AE. The most frequent grade 3-4 AE was elevated bilirubin (2.2%, 5 of 79). Deterioration of bilirubin, AST, ALT, and albumin were observed in 24.1%, 23.7%, 19%, and 24% of participants, respectively. CONCLUSION: DSM-TACE achieves promising survival in patients with unresectable or recurrent HCC. This technique shows a favorable safety profile both in terms of treatment-related AEs and liver function deterioration. KEY POINTS: Question Although degradable starch microspheres transarterial chemoembolization is widely used in clinical practice across Europe, prospective data on its application in hepatocellular carcinoma patients remains limited. Findings Degradable starch microspheres transarterial chemoembolization results in promising survival rates, good tumor response rates, and low rates of treatment-related adverse events. Clinical relevance In patients with unresectable hepatocellular carcinoma, degradable starch microspheres transarterial chemoembolization represents a safe and effective alternative to more well-established chemoembolization techniques like conventional transarterial chemoembolization and drug-eluting beads transarterial chemoembolization.
- MeSH
- Chemoembolization, Therapeutic * methods MeSH
- Carcinoma, Hepatocellular * therapy mortality MeSH
- Middle Aged MeSH
- Humans MeSH
- Microspheres MeSH
- Liver Neoplasms * therapy mortality MeSH
- Prospective Studies MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Starch * administration & dosage MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
Clinical trials in oncology are important tools to identify and establish new effective drugs for cancer treatment. Since the development of the concept of precision oncology, a huge number of multi-centric biomarker-driven clinical trials have been performed and promoted by either academic institutions or pharmaceutical companies. In this scenario, the role of pathologists is essential in multiple aspects, with new challenges that should be addressed. In this position paper of the European Society of Pathology, the role of pathologists as contributors to the design of the clinical trial, as local collaborators, or as members of central review laboratories is discussed. Moreover, the paper emphasizes the important role of pathologists in guiding methods and criteria of tissue biomarker testing in the biomarker-driven clinical trials. The paper also addresses issues regarding quality control, training, and the possible role of digital pathology.
- MeSH
- Clinical Trials as Topic * MeSH
- Pathology, Clinical standards methods MeSH
- Humans MeSH
- Biomarkers, Tumor * analysis MeSH
- Neoplasms * pathology drug therapy MeSH
- Pathologists * MeSH
- Societies, Medical MeSH
- Research Design standards MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Geographicals
- Europe MeSH
Global obesity rates have risen dramatically, now exceeding deaths from starvation. Metabolic and bariatric surgery (MBS), initially for severe obesity (BMI ≥35 kg/m2), is performed globally over 500 000 times annually, offering significant metabolic benefits beyond weight loss. However, varying eligibility criteria globally impact patient care and healthcare resources. Updated in 2022, ASMBS and IFSO guidelines aim to standardise MBS indications, reflecting current understanding and emphasising comprehensive preoperative assessments. Yet, clinical variability persists, necessitating consensus-based recommendations. This modified Delphi study engaged 45 global experts to establish consensus on perioperative management in MBS. Experts selected from bariatric societies possessed expertise in MBS and participated in a two-round Delphi protocol. Consensus was achieved on 90 of 169 statements (53.3%), encompassing multidisciplinary team composition, patient selection criteria, preoperative testing, and referral pathways. The agreement highlighted the critical role of comprehensive preoperative assessments and the integration of healthcare professionals in MBS. These findings offer essential insights to standardise perioperative practices and advocate for evidence-based guidelines in MBS globally. The study underscores the need for unified protocols to optimise outcomes and guide future research in MBS.
- MeSH
- Bariatric Surgery * standards methods MeSH
- Delphi Technique * MeSH
- Consensus * MeSH
- Humans MeSH
- Obesity, Morbid surgery MeSH
- Preoperative Care * standards methods MeSH
- Patient Selection MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.
- MeSH
- Azoxymethane toxicity MeSH
- Chronic Disease MeSH
- Indoles pharmacology therapeutic use MeSH
- Colitis drug therapy chemically induced metabolism pathology MeSH
- Colorectal Neoplasms * drug therapy metabolism pathology MeSH
- Disease Models, Animal * MeSH
- Molecular Mimicry MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Colitis-Associated Neoplasms pathology drug therapy metabolism MeSH
- Dextran Sulfate toxicity MeSH
- Inflammation drug therapy metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
AIM: This study aimed to identify sleep profiles in a representative sample of Slovak adolescents and investigate their associations with adiposity indicators and cardiorespiratory fitness. METHODS: Data from the 2022 Health Behaviour in School-aged Children (HBSC) study conducted in Slovakia were analysed. Survey questions on sleep duration and problems from the entire HBSC sample (n = 8906) were used to identify sleep profiles. Associations with adiposity indicators and cardiorespiratory fitness were investigated in a subsample of 924 adolescents (average age 13.3 ± 1.48; 56.2% boys) who completed the HBSC survey, bioimpedance analysis, and 20-metre shuttle run test. RESULTS: Three sleep profiles were identified-optimal sleepers, optimal sleepers with sporadic sleep problems and poor sleepers. Crude models showed that poor sleepers had significantly higher body fat percentage and fat mass index, along with lower cardiorespiratory fitness, compared to optimal sleepers. After adjustment, only the association between sleep profiles and cardiorespiratory fitness remained significant. CONCLUSION: The observed associations between sleep profiles and cardiorespiratory fitness may help better target future intervention resources towards adolescents with low cardiorespiratory fitness levels.
- MeSH
- Adiposity * MeSH
- Child MeSH
- Cardiorespiratory Fitness * physiology MeSH
- Humans MeSH
- Adolescent MeSH
- Cross-Sectional Studies MeSH
- Sleep * physiology MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Slovakia MeSH
BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved. METHODS: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria. RESULTS: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified. CONCLUSIONS: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).
- MeSH
- Progression-Free Survival MeSH
- Adult MeSH
- Smoldering Multiple Myeloma * diagnosis mortality therapy MeSH
- Injections, Subcutaneous MeSH
- Kaplan-Meier Estimate MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma * diagnosis epidemiology prevention & control MeSH
- Antibodies, Monoclonal * administration & dosage adverse effects MeSH
- Watchful Waiting * statistics & numerical data MeSH
- Disease Progression MeSH
- Antineoplastic Agents * administration & dosage adverse effects MeSH
- Aged, 80 and over MeSH
- Aged 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
- Comparative Study MeSH
