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In the lung cancer classification (TNM), the involvement of thoracic lymph nodes is relevant from a diagnostic and prognostic point of view. Even if imaging modality could help in selecting patients who should undergo surgery, a systematic lymph node dissection during lung surgery is mandatory to identify the subgroup of patients who can benefit from an adjuvant treatment. Patients undergoing elective lobectomy/bilobectomy/segmentectomy) for non-small cell lung cancer and lymphadenectomy with lymph nodes station 10-11-12-13-14 sampling that meet the inclusion and exclusion criteria will be recorded in a multicenter prospective database. The overall incidence of N1 patients (subclassified in: Hilar Lymph nodes, Lobar Lymph nodes and Sublobar Lymph nodes) will be examined as well as the incidence of visceral pleural invasion. The aim of this multicenter prospective study is to evaluate the incidence of intrapulmonary lymph nodes metastases and the possible relation with visceral pleural invasion. Identifying patients with lymph node station 13 and 14 metastases and/or a link between visceral pleural invasion and presence of micro/macro metastases in intrapulmonary lymph nodes may have an impact on decision-making process. ClinicalTrials.gov ID: NCT05596578.

Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor and inhibitory regulator of T-cells. Here, we analyzed the prevalence of LAG3 rs870849 in B-cell lymphoma patients and the treatment outcomes according to the LAG3 genetic background and discovered that LAG3 germline variants may affect the risk of developing lymphoma and also affect the treatment outcome of DLBCL patients in the current CD19 CAR-T cell therapies. The LAG3 rs870849 was prevalent at high frequency in DLBCL patients. Significant differences in treatment outcomes to CAR-T cell therapy emerged in LAG3 I455hom versus I455Thet and T455hom carriers. The overall and complete response rates to CAR-T cell therapy were lower in the I455hom genetic subgroup with median PFS in the I455hom of 2 versus 20 months in the T455hom and I455Thet subgroups (p = 0.025). Median OS was 6 months in the LAG3 I455hom versus 41 months in the T455hom and I455Thet subgroups (p = 0.007). LAG3 rs870849 may affect treatment outcome in CAR-T cell therapy, with favorable outcomes in T455 carriers. Specific combinations of CTLA4 and LAG3 germline variants may cooperate to affect the response to CAR-T cell therapy.

Chronic liver diseases pose a serious public health issue. Identifying patients at risk for advanced liver fibrosis is crucial for early intervention. The Fibrosis-4 score (FIB-4), a simple non-invasive test, classifies patients into three risk groups for advanced fibrosis. This study aimed to estimate the prevalence of patients at risk for advanced hepatic fibrosis at a Swiss tertiary care hospital by calculating the FIB-4 score in routine blood analysis. A retrospective study was conducted using data from 36,360 patients who visited outpatient clinics at eight main clinics of the University Hospital Bern in Switzerland. The data collection period ran from January 1st to December 31st, 2022. Patients attending the hepatology outpatient clinic were excluded. We then calculated the overall and clinic-specific prevalence of patients falling into the high risk category for advanced fibrosis according to FIB-4. Among the 36,360 patients, 26,245 (72.2%) had a low risk of advanced fibrosis (FIB-4 <1.3), whereas 3913 (10.8%) and 2597 (7.1%) patients were flagged to have a high risk of advanced fibrosis (FIB-4 >2.67 and FIB-4 >3.25 respectively). Geriatrics and Cardiology had the highest proportions of patients at risk for advanced fibrosis over all clinics. This study demonstrates a high prevalence of high FIB-4 score in a Swiss tertiary care hospital. The implementation of the automatically generated FIB-4 score in daily practice, not only in primary care, but also within tertiary care hospitals, could be crucial for early identification of outpatients at high risk of advanced liver fibrosis requiring further hepatological investigations.

Background: Chimeric antigen receptor T-cell therapy (CAR T-cell therapy) is associated with potentially life-threatening toxicities, most commonly cytokine release syndrome (CRS) and immune-effector-cell-associated neurotoxicity syndrome (ICANS). These frequent adverse events are managed with the IL-6 receptor antagonist tocilizumab and/or corticosteroids. The prophylactic and early use of corticosteroids for CRS and ICANS have previously been reported, but eventual negative impacts on CAR T-cell efficacy are feared. Methods: Retrospective comparative analysis of two patient cohorts with hematological malignancies treated with CAR T-cell therapy: 43 patients received early administration of 10 mg dexamethasone preceding each dose of tocilizumab (“early corticosteroid/ tocilizumab”, EcsTcz cohort) vs. 40 patients who received tocilizumab alone (“tocilizumab alone”, Tcz cohort) for treatment of low-grade CRS. Results: Despite overall higher CRS incidence (91% vs. 70%; p = 0.0249), no high-grade CRS was observed (0% vs. 10%; p = 0.0497) among patients receiving early corticosteroids in combination with tocilizumab. In terms of neurotoxicity, no worsening regarding incidence of ICANS (30% vs. 33%; p = 0.8177) or high-grade ICANS (20% vs. 14%; p = 0.5624) was observed in the EcsTcz cohort. Moreover, overall response rates (80% vs. 77%; p = 0.7936), complete response rates (50% vs. 44%; p = 0.6628), progression-free survival (p = 0.6345) and overall survival (p = 0.1215) were comparable for both cohorts. Conclusions: Our study suggests that the early use of corticosteroids in combination with the standard tocilizumab schedule for low-grade CRS following CAR T-cell therapy may significantly reduce the risk of high-grade CRS without negative impact on neurotoxicity or treatment outcome.

Background: D-dimer determined in citrated plasma is a well-established and efficient biomarker, particularly for ruling out venous thromboembolism. In certain clinical settings, the availability of citrated plasma may pose challenges when not readily available. To address this issue, we investigated the feasibility of using ethylenediaminetetraacetic acid (EDTA) plasma as an alternative specimen for D-dimer measurement. Methods: Our study evaluated anonymized plasma samples (n = 99, for both citrate and EDTA) using the INNOVANCE® D-dimer assay, an automated particle-enhanced immunoassay, and the INNOVANCE® LOCI hs D-dimer assay, leveraging the luminescent oxygen channeling assay (LOCI) method. Results: The assays demonstrated a correlation of r ≥ 0.97 (95% CI 0.96 to 0.98) within citrated plasma and maintained a similar correlation r ≥ 0.96 (95% CI 0.94 to 0.97) between citrate and EDTA plasma upon correction for the dilution effect of the sodium citrate solution. Conclusions: These results indicate that the utilization of EDTA instead of citrate plasma is feasible and may provide similar diagnostic information. However, the observed variance could have an impact on clinical interpretation and risk assessment. Therefore, future studies are needed to confirm the results and, if necessary, determine cut-off values and clinical performance.

Aim of this study is to evaluate whether magnetic particle imaging (MPI) is capable of measuring velocities occurring in the coronary arteries and to compute coronary flow reserve (CFR) in a canonical phantom as a preliminary study. For basic velocity measurements, a circulation phantom was designed containing replaceable glass tubes with three varying inner diameters, matching coronary-vessel diameters. Standardised boluses of superparamagnetic-iron-oxide-nanoparticles were injected and visualised by MPI. Two image-based techniques were competitively applied to calibrate the respective glass tube and to compute the mean velocity: full-duration-at-half-maximum (FDHM) and tracer dilution (TD) method. For CFR-calculation, four necessary settings of the circulation model of a virtual vessel with an inner diameter of 4 mm were generated using differently sized glass tubes and a stenosis model. The respective velocities in stenotic glass tubes were computed without recalibration. On velocity level, comparison showed a good agreement (rFDHM = 0.869, rTD = 0.796) between techniques, preferably better for 4 mm and 6 mm inner diameter glass tubes. On CFR level MPI-derived CFR-prediction performed considerably inferior with a relative error of 20-44%. MPI has the ability to reliably measure coronary blood velocities at rest as well as under hyperaemia and therefore may be suitable for CFR calculation. Calibration-associated accuracy of CFR-measurements has to be improved substantially in further studies.

Background: Currently, assessing the diagnostic performance of new laboratory tests assumes a perfect reference standard, which is rarely the case. Wrong classifications of the true disease status will inevitably lead to biased estimates of sensitivity and specificity. Objectives: Using Bayesian’ latent class models (BLCMs), an approach that does not assume a perfect reference standard, we re-analyzed data of a large prospective observational study assessing the diagnostic accuracy of an antigen test for the diagnosis of SARS-CoV-2 infection in clinical practice. Methods: A cohort of consecutive patients presenting to a COVID-19 testing facility affiliated with a Swiss University Hospital were recruited (n = 1465). Two real-time PCR tests were conducted in parallel with the Roche/SD Biosensor rapid antigen test on nasopharyngeal swabs. A two-test (PCR and antigen test), three-population BLCM was fitted to the frequencies of paired test results. Results: Based on the BLCM, the sensitivities of the RT-PCR and the Roche/SD Biosensor rapid antigen test were 98.5% [95% CRI 94.8;100] and 82.7% [95% CRI 66.8;100]. The specificities were 97.7% [96.1;99.7] and 99.9% [95% CRI 99.6;100]. Conclusions: Applying the BLCM, the diagnostic accuracy of RT-PCR was high but not perfect. In contrast to previous results, the sensitivity of the antigen test was higher. Our results suggest that BLCMs are valuable tools for investigating the diagnostic performance of laboratory tests in the absence of perfect reference standard.

Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63–84% and complete response observed in 43–54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months (p = 0.06), overall survival was 37 vs. 8 months (p = 0.11), complete response rates were 51% vs. 30% (p = 0.05), and refractory disease rates were 14% vs. 32% (p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome.

(1) Background: The combination of venetoclax and hypomethylating agents (HMAs) is a standard first-line regimen for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Since venetoclax-HMAs are usually administered until progression and delayed hematologic recovery is one of the limiting toxicities, cyclic administration including 7–14-day breaks is recommended. However, whether longer venetoclax schedules lead to higher response rates and how venetoclax pharmacokinetics correlate with toxicity and efficacy remains unclarified. In this single-center retrospective study, we analyzed how venetoclax plasma levels and treatment duration impact hematologic toxicity and treatment responses. (2) Methods: We analyzed the safety and efficacy of venetoclax-HMA combination regimens in a cohort of AML patients unfit for intensive chemotherapy treated at our institution between June 2020 and September 2023. The primary endpoint was the correlation between venetoclax plasma levels or administration schedule with hematologic recovery after the first cycle. Secondary endpoints included the following clinical outcomes: correlation with complete response (CR) status, progression-free survival, and overall survival. (3) Results: Within our cohort of 75 AML patients, we found no correlation between venetoclax plasma peak and trough levels, or venetoclax treatment duration (≤ or >14 days), and hematologic toxicity. Patients receiving shorter venetoclax schedules (≤14 days) had similar CR rates compared to patients treated with longer schedules. (4) Conclusions: Our results suggest that shorter (≤14 days) venetoclax schedules may have no negative impact on tumor responses in AML patients receiving venetoclax and HMA combinations. However, prospective validation studies would be required to confirm these findings.

Introduction: The growing body of evidence around sexual and gender dimorphism in medicine, particularly in oncology, has highlighted differences in treatment response, outcomes, and side effects between males and females. Differences in drug metabolism, distribution, and elimination, influenced by factors like body composition and enzyme expression, contribute to these variations. Methods: We retrospectively analyzed data of 112 multiple myeloma (MM) patients treated with first-line high-dose chemotherapy (HDCT) with treosulfan and melphalan (TreoMel) followed by autologous stem cell transplantation (ASCT) at a single academic center between January 2020 and August 2022. We assessed response rate, progression-free survival (PFS), overall survival (OS), and toxicities in relation to gender and treosulfan exposure. Results: Our analysis revealed significant gender-specific differences in treosulfan exposure. Females had higher peak levels (343.8 vs. 309.0 mg/L, p = 0.0011) and area under the curve (AUC) (869.9 vs. 830.5 mg*h/L, p = 0.0427) compared to males. Higher treosulfan exposure was associated with increased mortality in females but not in males. Females with treosulfan AUC > 900 mg*h/L had significantly shorter overall survival, while PFS was unaffected by treosulfan exposure. Conclusion: Our study demonstrates that female patients undergoing TreoMel HDCT have higher treosulfan exposure than males and that females with higher levels are at increased risk for toxicity and adverse outcomes. These data suggest that higher treosulfan doses do not confer a benefit in terms of better outcomes for females. Therefore, exploring lower treosulfan doses for female MM patients undergoing TreoMel HDCT may be warranted to mitigate toxicity and improve outcomes.