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

The prevalence of centenarians, people who lived 100 years and longer, is steadily growing in the last decades. This exceptional longevity is based on multifaceted processes influenced by a combination of intrinsic and extrinsic factors such as sex, (epi-)genetic factors, gut microbiota, cellular metabolism, exposure to oxidative stress, immune status, cardiovascular risk factors, environmental factors, and lifestyle behavior. Epidemiologically, the incidence rate of cardiovascular diseases is reduced in healthy centenarians along with late onset of age-related diseases compared with the general aged population. Understanding the mechanisms that affect vascular ageing in centenarians and the underlying factors could offer valuable insights for developing strategies to improve overall healthy life span in the elderly. This review discusses these key factors influencing vascular ageing and how their modulation could foster healthy longevity.

• MeSH
• Longevity * physiology   MeSH
• Cardiovascular Diseases physiopathology   epidemiology   MeSH
• Humans MeSH
• Oxidative Stress physiology   MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aging * physiology   MeSH
• Gastrointestinal Microbiome physiology   MeSH
• Healthy Aging physiology   MeSH
• Life Style MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

OBJECTIVE: We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes. METHODS: We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors. RESULTS: All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings. SIGNIFICANCE: This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.

• MeSH
• Child MeSH
• Electroencephalography * methods   MeSH
• Epilepsy MeSH
• Focal Cortical Dysplasia MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Malformations of Cortical Development, Group I * surgery   complications   diagnostic imaging   MeSH
• Malformations of Cortical Development surgery   complications   diagnostic imaging   MeSH
• Adolescent MeSH
• Positron-Emission Tomography MeSH
• Child, Preschool MeSH
• Drug Resistant Epilepsy * surgery   diagnostic imaging   physiopathology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND AND OBJECTIVE: Bladder cancer (BCa) imposes a substantial economic burden on health care systems and patients. Understanding these financial implications is crucial for effective resource allocation and optimization of treatment cost effectiveness. Here, we aim to systematically review and analyze the financial burden of BCa from the health care and patient perspectives. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review was conducted, searching PubMed/Medline, Embase, and public sources for studies evaluating the financial impact of BCa, encompassing costs, cost effectiveness, and financial toxicity (FT). KEY FINDINGS AND LIMITATIONS: Non-muscle-invasive BCa (NMIBC) incurs significant costs for surveillance and treatment, with costs exceeding $200 000 after 5 yr for high-risk NMIBC patients progressing after bacillus Calmette-Guerin (BCG) treatment (including inpatient, outpatient, and physician service expenses). Muscle-invasive BCa generates substantial costs from radical cystectomy (RC) and neoadjuvant chemotherapy, averaging $30 000-40 000 from surgical costs of RC, with additional expenses in case of complications. Trimodal therapy has higher costs (1-yr management cost >$200 000) than RC because of higher outpatient, radiology, and medication costs. Metastatic BCa incurs the highest financial burden, with systemic therapy costs ranging from $40 000 to over $100 000 per five-cycle course, increasing further with combination therapies (ie, enfortumab vedotin and pembrolizumab), treatment-related toxicity, and supportive care. FT is particularly prevalent among younger, less educated, and minority populations. CONCLUSIONS AND CLINICAL IMPLICATIONS: BCa treatment, particularly in advanced stages, imposes a substantial economic burden. Innovations in care, while improving oncologic outcomes, necessitate detailed cost-effectiveness assessments. Addressing these economic challenges is essential for optimizing BCa management, targeting patients at a higher risk of FT, and improving patient quality of life.

• MeSH
• Cost-Benefit Analysis MeSH
• Cystectomy economics   adverse effects   MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Urinary Bladder Neoplasms * economics   therapy   pathology   MeSH
• Health Care Costs * MeSH
• Cost of Illness * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Systematic Review MeSH

The treatment of relapsed/refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed as salvage therapy. Reduced intensity conditioning protocols have been developed with the aim of reducing the leukemia burden without increasing their toxicity. We compared the reduced intensity conditioning FM140 (fludarabine, 150 mg/m2; melphalan 140 mg/m2) with FBM110 (fludarabine 150 mg/m2; BCNU, also known as carmustine, 300-400 mg/m2; and melphalan 110 mg/m2). From the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party registry, we identified 293 adult patients (FM140, n = 118 and FBM110, n = 175) with AML with relapsed/refractory disease prior to allo-HCT. There were some differences such as age (FM140 = 59.5 years vs. FBM110 = 65.1 years, p < 0.001) and graft-versus-host disease (GvHD) prophylaxis based on in vivo T-cell depletion (TCD, FM140 = 39% vs. FBM110 = 75%, p < 0.001). No differences were observed between FM140- and FBM110-treated patients regarding overall survival (OS) (2-year OS: 39.3% vs. 45.7%, p = 0.58), progression-free survival (PFS) (2-year PFS: 36.1% vs. 37.3%, p = 0.69), non-relapse mortality (NRM) (2-year NRM: 15.3% vs. 25.7%, p = 0.10) and relapse incidence (RI) (2-year RI: 48.6% vs. 37.0%, p = 0.7). In conclusion, despite differences in age and GvHD prophylaxis, AML patients with active disease undergoing allo-HCT after FBM110 conditioning showed similar outcomes compared to FM140.

• MeSH
• Leukemia, Myeloid, Acute * therapy   mortality   MeSH
• Adult MeSH
• Transplantation, Homologous methods   MeSH
• Carmustine therapeutic use   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melphalan * therapeutic use   administration & dosage   MeSH
• Transplantation Conditioning methods   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Recurrence MeSH
• Registries * MeSH
• Aged MeSH
• Hematopoietic Stem Cell Transplantation * methods   MeSH
• Vidarabine * analogs & derivatives   therapeutic use   administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH

AIMS: Liver cytochromes (CYPs) play an important role in drug metabolism but display a large interindividual variability resulting both from genetic and environmental factors. Most drug dose adjustment guidelines are based on genetics performed in healthy volunteers. However, hospitalized patients are not only more likely to be the target of new prescriptions and drug treatment modifications than healthy volunteers, but will also be more subject to polypharmacy, drug-drug interactions, or to suffer from disease or inflammation affecting CYP activities. METHODS: We compared predicted phenotype based on genetic data and measured phenotype using the Geneva cocktail to determine the extent of drug metabolizing enzyme variability in a large population of hospitalized patients (>500) and healthy young volunteers (>300). We aimed to assess the correlation between predicted and measured phenotype in the two populations. RESULTS: We found that, even in cases where the genetically predicted metabolizer group correlates well with measured CYP activity at group level, this prediction lacks accuracy for the determination of individual metabolizer capacities. Drugs can have a profound impact on CYP activity, but even after combining genetic and drug treatment information, the activity of a significant proportion of extreme metabolizers could not be explained. CONCLUSIONS: Our results support the use of measured metabolic ratios in addition to genotyping for accurate determination of individual metabolic capacities to guide personalized drug prescription.

• MeSH
• Adult MeSH
• Phenotype MeSH
• Genotype MeSH
• Hospitalization MeSH
• Pharmaceutical Preparations metabolism   MeSH
• Drug Interactions MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Aged MeSH
• Cytochrome P-450 Enzyme System * genetics   metabolism   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

• MeSH
• Deoxycytidine analogs & derivatives   administration & dosage   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Doxorubicin analogs & derivatives   administration & dosage   MeSH
• Phthalazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Gemcitabine MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * drug therapy   MeSH
• Ovarian Neoplasms * drug therapy   genetics   mortality   pathology   MeSH
• Paclitaxel administration & dosage   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * therapeutic use   adverse effects   MeSH
• Piperazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Polyethylene Glycols administration & dosage   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged MeSH
• Topotecan administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

Papillary thyroid carcinoma (PTC) represents ~80% of all thyroid cancers, most frequently presenting in women in the third and fourth decade of life. The first clinical manifestation of PTC commonly includes a palpable mass in the thyroid area or cervical lymphadenopathy in cases of metastatic disease. Hematogenous distant metastases are a sign of an advanced stage of the tumour. The present study reported an extremely rare occurrence of solitary metastasis of a PTC in the left breast of a 63-year-old male patient, mimicking primary male breast cancer (MBC). The presence of a male breast lesion that did not follow the typical imaging criteria for MBC aroused suspicion of a different primary origin. The combination of imaging methods, laboratory findings and fine-needle aspiration techniques enabling cytological and histopathological examination, with the use of a wide panel of immunohistochemical markers, is crucial to establishing a definitive and correct diagnosis.

• Publication type
• Journal Article MeSH
• Case Reports MeSH

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

• MeSH
• Bendamustine Hydrochloride * administration & dosage   therapeutic use   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   mortality   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Piperidines therapeutic use   administration & dosage   adverse effects   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Pyrazoles * therapeutic use   administration & dosage   adverse effects   MeSH
• Pyrimidines * therapeutic use   administration & dosage   adverse effects   MeSH
• Rituximab * administration & dosage   therapeutic use   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